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Goyal S, Tibrewal S, Ratna R, Vanita V. Genetic and environmental factors contributing to anophthalmia and microphthalmia: Current understanding and future directions. World J Clin Pediatr 2025; 14:101982. [DOI: 10.5409/wjcp.v14.i2.101982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 02/19/2025] [Accepted: 02/25/2025] [Indexed: 03/18/2025] Open
Abstract
Anophthalmia is defined as a complete absence of one eye or both the eyes, while microphthalmia represents the presence of a small eye within the orbit. The estimated birth prevalence for anophthalmia is approximately 3 per 100000 live births, and for microphthalmia, it is around 14 per 100000 live births. However, combined evidence suggests that the prevalence of these malformations could be as high as 30 per 100000 individuals. Microphthalmia is reported to occur in 3.2% to 11.2% of blind children. Anophthalmia and microphthalmia (A/M) are part of a phenotypic spectrum alongside ocular coloboma, hypothesized to share a common genetic basis. Both A/M can occur in isolation or as part of a syndrome. Their complex etiology involves chromosomal aberrations, monogenic inheritance pattern, and the contribution of environmental factors such as gestational-acquired infections, maternal vitamin A deficiency (VAD), exposure to X-rays, solvent misuse, and thalidomide exposure. A/M exhibit significant clinical and genetic heterogeneity with over 90 genes identified so far. Familial cases of A/M have a complex genetic basis, including all Mendelian modes of inheritance, i.e., autosomal dominant, recessive, and X-linked. Most cases arise sporadically due to de novo mutations. Examining gene expression during eye development and the effects of various environmental variables will help us better understand the phenotypic heterogeneity found in A/M, leading to more effective diagnosis and management strategies. The present review focuses on key genetic factors, developmental abnormalities, and environmental modifiers linked with A/M. It also emphasizes at potential research areas including multiomic methods and disease modeling with induced pluripotent stem cell technologies, which aim to create innovative treatment options.
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Affiliation(s)
- Shiwali Goyal
- Department of Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, MD 20852, United States
| | - Shailja Tibrewal
- Department of Pediatric Ophthalmology, Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Ria Ratna
- Department of Ocular Genetics (Center for Unknown and Rare Eye Diseases), Dr. Shroff’s Charity Eye Hospital, New Delhi 110002, Delhi, India
| | - Vanita Vanita
- Department of Human Genetics, Guru Nanak Dev University, Amritsar 143005, Punjab, India
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Noero J, Weber M, Chassaing N, Gaston V, Plaisancié J, Chesneau B. Genetic screening of the RNA-binding protein RBM24 and its binding sites in the SOX2 3' untranslated region in a cohort of 50 patients with micro-anophthalmia. Ophthalmic Genet 2025; 46:256-260. [PMID: 39957481 DOI: 10.1080/13816810.2025.2467334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 01/27/2025] [Accepted: 02/10/2025] [Indexed: 02/18/2025]
Abstract
Microphthalmia and anophthalmia (M/A) are rare congenital eye anomalies with a birth prevalence of up to 1 in 10,000 births. The etiology of M/A can involve environmental and/or genetic factors, with a genetic origin identified in approximately 50% of cases through analysis of key genes. The transcription factor SOX2 is the most commonly implicated gene, accounting for around 15% of M/A cases. Recent studies have shown that the RNA-binding protein Rbm24 post-transcriptionally regulates Sox2 expression in mice and zebrafish, with Rbm24 null models exhibiting eye phenotypes in both species. Rbm24 can bind to Sox2 mRNA via three AU-Rich elements (AREs) located in its 3' untranslated region (UTR). In this study, we aimed to determine whether pathogenic variants within RBM24 or the SOX2 3'UTR AREs were present in a cohort of 50 individuals with M/A with no identified genetic cause for their condition. Despite the ocular defects observed in animal models, we did not detect any variant of interest in these candidate regions in our cohort. Although we cannot exclude the involvement of pathogenic variations in RBM24 or the SOX2 3'UTR AREs in ocular developmental defects, our study shows that they are unlikely to represent a frequent cause of M/A.
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Affiliation(s)
- Julien Noero
- Laboratoire de Référence (LBMR) des anomalies malformatives de l'œil, Institut Fédératif de Biologie (IFB), CHU de Toulouse, Toulouse, France
- CNRS UMR5077, Centre de Biologie Intégrative, Université Toulouse III, Toulouse, France
| | - Mathys Weber
- Laboratoire de Référence (LBMR) des anomalies malformatives de l'œil, Institut Fédératif de Biologie (IFB), CHU de Toulouse, Toulouse, France
| | - Nicolas Chassaing
- Laboratoire de Référence (LBMR) des anomalies malformatives de l'œil, Institut Fédératif de Biologie (IFB), CHU de Toulouse, Toulouse, France
- Centre de Référence des Affections Rares en Génétique Ophtalmologique, CARGO, CHU de Toulouse, Toulouse, France
| | - Véronique Gaston
- Laboratoire de Référence (LBMR) des anomalies malformatives de l'œil, Institut Fédératif de Biologie (IFB), CHU de Toulouse, Toulouse, France
| | - Julie Plaisancié
- Laboratoire de Référence (LBMR) des anomalies malformatives de l'œil, Institut Fédératif de Biologie (IFB), CHU de Toulouse, Toulouse, France
- CNRS UMR5077, Centre de Biologie Intégrative, Université Toulouse III, Toulouse, France
- Centre de Référence des Affections Rares en Génétique Ophtalmologique, CARGO, CHU de Toulouse, Toulouse, France
| | - Bertrand Chesneau
- Laboratoire de Référence (LBMR) des anomalies malformatives de l'œil, Institut Fédératif de Biologie (IFB), CHU de Toulouse, Toulouse, France
- CNRS UMR5077, Centre de Biologie Intégrative, Université Toulouse III, Toulouse, France
- Centre de Référence des Affections Rares en Génétique Ophtalmologique, CARGO, CHU de Toulouse, Toulouse, France
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Brinkmeier ML, Cheung LYM, O'Connell SP, Gutierrez DK, Rhoads EC, Camper SA, Davis SW. Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation. Hum Mol Genet 2025; 34:870-881. [PMID: 40044116 PMCID: PMC12056309 DOI: 10.1093/hmg/ddaf032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 02/23/2025] [Indexed: 03/12/2025] Open
Abstract
Nucleoredoxin (Nxn) encodes a multi-functional enzyme with oxidoreductase activity that regulates many different signaling pathways and cellular processes in a redox-dependent manner. Rare NXN mutations are reported in individuals with recessive Robinow syndrome, which involves mesomelic skeletal dysplasia, short stature, craniofacial dysmorphisms, and incompletely penetrant heart and palate defects. Here we report that Nxn is expressed in the ventral diencephalon and developing pituitary gland, and that Nxn deficient mice have pituitary dysmorphology and craniofacial abnormalities that include defects in the skull base and cleft palate. Nxn mutant mice exhibit reduced WNT signaling and reduced differentiation of pituitary stem cells into hormone-producing cells. These results suggest patients with Robinow syndrome could benefit from evaluation by endocrinologists for pituitary structural imaging and hormone insufficiency.
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Affiliation(s)
- Michelle L Brinkmeier
- Department of Human Genetics, 5805 Medical Science II, 1241 Catherine St, University of Michigan, Ann Arbor, MI 48109-5618, United States
| | - Leonard Y M Cheung
- Department of Human Genetics, 5805 Medical Science II, 1241 Catherine St, University of Michigan, Ann Arbor, MI 48109-5618, United States
| | - Sean P O'Connell
- Department of Biological Sciences, 715 Sumter St, CLS room 401, University of South Carolina, Columbia, SC 29208, United States
| | - Diana K Gutierrez
- Department of Biological Sciences, 715 Sumter St, CLS room 401, University of South Carolina, Columbia, SC 29208, United States
| | - Eve C Rhoads
- Department of Human Genetics, 5805 Medical Science II, 1241 Catherine St, University of Michigan, Ann Arbor, MI 48109-5618, United States
| | - Sally A Camper
- Department of Human Genetics, 5805 Medical Science II, 1241 Catherine St, University of Michigan, Ann Arbor, MI 48109-5618, United States
| | - Shannon W Davis
- Department of Biological Sciences, 715 Sumter St, CLS room 401, University of South Carolina, Columbia, SC 29208, United States
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Brinkmeier ML, Cheung LYM, O’Connell SP, Gutierrez DK, Rhoads EC, Camper SA, Davis SW. Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.30.635771. [PMID: 39975280 PMCID: PMC11838423 DOI: 10.1101/2025.01.30.635771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Nucleoredoxin (Nxn) encodes a multi-functional enzyme with oxidoreductase activity that regulates many different signaling pathways and cellular processes in a redox-dependent manner. Rare NXN mutations are reported in individuals with recessive Robinow syndrome, which involves mesomelic skeletal dysplasia, short stature, craniofacial dysmorphisms, and incompletely penetrant heart and palate defects. Here we report that Nxn is expressed in the ventral diencephalon and developing pituitary gland, and that Nxn deficient mice have pituitary dysmorphology and craniofacial abnormalities that include defects in the skull base and cleft palate. Nxn mutant mice exhibit reduced WNT signaling and reduced differentiation of pituitary stem cells into hormone-producing cells. These results suggest patients with Robinow syndrome could benefit from evaluation by endocrinologists for pituitary structural imaging and hormone insufficiency.
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Affiliation(s)
| | - Leonard Y. M. Cheung
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109-5618, USA
- Current address: Department of Physiology and Biophysics, Renaissance School of Medicine, State University of New York, Stonybrook, NY 11794, USA
| | - Sean P. O’Connell
- Department of Biological Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Diana K. Gutierrez
- Department of Biological Sciences, University of South Carolina, Columbia, SC, 29208, USA
| | - Eve C. Rhoads
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109-5618, USA
| | - Sally A. Camper
- Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109-5618, USA
| | - Shannon W. Davis
- Department of Biological Sciences, University of South Carolina, Columbia, SC, 29208, USA
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Bahya AM, Abid MF, Aljohani KA, Porntaveetus T. Polymorphisms in SOX2/ FGFR1 are associated with skeletal class III maxillary and mandibular dimensions: A preliminary study. J Taibah Univ Med Sci 2025; 20:112-119. [PMID: 40092567 PMCID: PMC11906286 DOI: 10.1016/j.jtumed.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 11/28/2024] [Accepted: 01/25/2025] [Indexed: 03/19/2025] Open
Abstract
Objectives The aim of the present study was to assess the association between class III malocclusion and genetic polymorphisms in two genes: SOX2 (rs4434184) and FGFR1 (rs881301). Methods A total of 60 patients, 30 with skeletal class I and 30 with skeletal class III malocclusion, were included in this study. Salivary DNA samples were collected and analyzed with Sanger sequencing. Digital tracing was performed on lateral cephalometric radiographs loaded into AutoCAD software (Version 2017) to assess the anteroposterior and vertical relationships of the maxillary and mandibular arches. Genotype distribution was compared between groups with the chi-square test to assess Hardy-Weinberg equilibrium. Multiple logistic regression analysis was conducted. Results The SOX2 rs4434184 polymorphism was associated with longer mandibular length. In contrast, shorter maxillary length, longer mandibular length, and hypodivergent face were correlated with the rs881301 polymorphism in FGFR1. New polymorphisms, including FGFR1 rs881300, rs881299, and rs7829058, have been identified in association with various phenotypes. Notably, rs881300 and rs7829058 displayed a substantial association with skeletal class III, whereas rs881299 revealed a significant association with a hypodivergent face and longer mandibular anteroposterior length. Conclusions A potential association was observed between class III skeletal malocclusion-related traits and polymorphisms of SOX2 (rs4434184) and FGFR1 (rs881301, rs881300, rs881299, and rs7829058). This finding holds promise for enhancing skeletal prediction and informing orthodontic treatment planning.
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Affiliation(s)
- Aqeel M. Bahya
- Orthodontic Department, College of Dentistry/ University of Babylon, Babylon, Iraq
| | - Mushriq F. Abid
- Orthodontic Department, College of Dentistry/ University of Baghdad, Baghdad, Iraq
| | - Khalid A. Aljohani
- Department of Oral Diagnostic Sciences, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Thantrira Porntaveetus
- Center of Excellence in Genomics and Precision Dentistry, Department of Physiology, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
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Sokolowski DJ, Hou H, Yuki KE, Roy A, Chan C, Choi W, Faykoo-Martinez M, Hudson M, Corre C, Uusküla-Reimand L, Goldenberg A, Palmert MR, Wilson MD. Age, sex, and cell type-resolved hypothalamic gene expression across the pubertal transition in mice. Biol Sex Differ 2024; 15:83. [PMID: 39449090 PMCID: PMC11515584 DOI: 10.1186/s13293-024-00661-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 10/07/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND The hypothalamus plays a central role in regulating puberty. However, our knowledge of the postnatal gene regulatory networks that control the pubertal transition in males and females is incomplete. Here, we investigate the age-, sex- and cell-type-specific gene regulation in the hypothalamus across the pubertal transition. METHODS We used RNA-seq to profile hypothalamic gene expression in male and female mice at five time points spanning the onset of puberty (postnatal days (PD) 12, 22, 27, 32, and 37). By combining this data with hypothalamic single nuclei RNA-seq data from pre- and postpubertal mice, we assigned gene expression changes to their most likely cell types of origin. In our colony, pubertal onset occurs earlier in male mice, allowing us to focus on genes whose expression is dynamic across ages and offset between sexes, and to explore the bases of sex effects. RESULTS Our age-by-sex pattern of expression enriched for biological pathways involved hormone production, neuronal activation, and glial maturation. Additionally, we inferred a robust expansion of oligodendrocytes precursor cells into mature oligodendrocytes spanning the prepubertal (PD12) to peri-pubertal (PD27) timepoints. Using spatial transcriptomic data from postpubertal mice, we observed the lateral hypothalamic area and zona incerta were the most oligodendrocyte-rich regions and that these cells expressed genes known to be involved in pubertal regulation. CONCLUSION Together, by incorporating multiple biological timepoints and using sex as a variable, we identified gene and cell-type changes that may participate in orchestrating the pubertal transition and provided a resource for future studies of postnatal hypothalamic gene regulation.
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Affiliation(s)
- Dustin J Sokolowski
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Huayun Hou
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
| | - Kyoko E Yuki
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
| | - Anna Roy
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
| | - Cadia Chan
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
- Donnelly Centre for Cellular & Biomolecular Research, Toronto, ON, Canada
| | - Wendy Choi
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON, Canada
| | - Mariela Faykoo-Martinez
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada
| | - Matt Hudson
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Christina Corre
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
| | | | - Anna Goldenberg
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Department of Computer Science, University of Toronto, Toronto, ON, Canada
- Vector Institute, Toronto, ON, Canada
- CIFAR, Toronto, ON, Canada
| | - Mark R Palmert
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada
- Division of Endocrinology, The Hospital for Sick Children, Toronto, ON, Canada
- Departments of Pediatrics and Physiology, University of Toronto, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Michael D Wilson
- Genetics and Genome Biology, SickKids Research Institute, Toronto, ON, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
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Kamimura M, Shima H, Suzuki E, Sogi C, Fujiwara I, Adachi M, Haruna H, Takubo N, Fukami M, Kikuchi A, Kanno J. CHARGE syndrome in a child with a CHD7 variant and a novel pathogenic SOX2 variant: A case report. Clin Pediatr Endocrinol 2024; 33:214-218. [PMID: 39359670 PMCID: PMC11442703 DOI: 10.1297/cpe.2024-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 06/04/2024] [Indexed: 10/04/2024] Open
Abstract
CHARGE syndrome is a clinically heterogeneous condition that typically presents with a loss-of-function mutation in CHD7. SOX2 anophthalmia syndrome is a rare condition associated with hypogonadism and hearing loss. Herein, we describe the case of a Japanese boy presenting with a micropenis, bilateral cryptorchidism, cupped ear, right facial nerve palsy, and bilateral hearing loss, clinically meeting the diagnostic criteria for CHARGE syndrome, but with optic nerve hypoplasia, which is atypical for the syndrome. Therefore, a genetic analysis (next-generation sequencing) was performed. In addition to the missense variant p.[Arg1940Cys] in CHD7, a novel nonsense variant, p. [Tyr110*] in SOX2 was identified. Although most features, including genital abnormalities and hearing loss, were clinically compatible with CHARGE syndrome caused by a CHD7 variant, optic nerve hypoplasia may have been caused by a pathogenic SOX2 variant. Prior research has shown that SOX2 is related to the development of male genitalia and the inner ear. Therefore, the genital abnormalities and hearing loss in this patient may be attributed to both the CHD7 and SOX2 variants. Furthermore, the interactions between SOX2 and CHD7 may have affected symptoms independently or reciprocally.
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Affiliation(s)
- Miki Kamimura
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
- Department of Pediatrics, National Hospital Organization Sendai Medical Center, Sendai, Japan
| | - Hirohito Shima
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
- Department of Molecular Endocrinology, National Center for Child Health and Development, Tokyo, Japan
| | - Erina Suzuki
- Department of Molecular Endocrinology, National Center for Child Health and Development, Tokyo, Japan
| | - Chisumi Sogi
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
- Department of Pediatrics, JCHO Sendai Hospital, Sendai, Japan
| | - Ikuma Fujiwara
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
- Department of Pediatrics, Sendai City Hospital, Sendai, Japan
| | - Mika Adachi
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Hospital, Sendai, Japan
| | - Hidenori Haruna
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Noriyuki Takubo
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Maki Fukami
- Department of Molecular Endocrinology, National Center for Child Health and Development, Tokyo, Japan
| | - Atsuo Kikuchi
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
| | - Junko Kanno
- Department of Pediatrics, Tohoku University Hospital, Sendai, Japan
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Benítez-Burraco A, Uriagereka J, Nataf S. The genomic landscape of mammal domestication might be orchestrated by selected transcription factors regulating brain and craniofacial development. Dev Genes Evol 2023; 233:123-135. [PMID: 37552321 PMCID: PMC10746608 DOI: 10.1007/s00427-023-00709-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 07/27/2023] [Indexed: 08/09/2023]
Abstract
Domestication transforms once wild animals into tamed animals that can be then exploited by humans. The process entails modifications in the body, cognition, and behavior that are essentially driven by differences in gene expression patterns. Although genetic and epigenetic mechanisms were shown to underlie such differences, less is known about the role exerted by trans-regulatory molecules, notably transcription factors (TFs) in domestication. In this paper, we conducted extensive in silico analyses aimed to clarify the TF landscape of mammal domestication. We first searched the literature, so as to establish a large list of genes selected with domestication in mammals. From this list, we selected genes experimentally demonstrated to exhibit TF functions. We also considered TFs displaying a statistically significant number of targets among the entire list of (domestication) selected genes. This workflow allowed us to identify 5 candidate TFs (SOX2, KLF4, MITF, NR3C1, NR3C2) that were further assessed in terms of biochemical and functional properties. We found that such TFs-of-interest related to mammal domestication are all significantly involved in the development of the brain and the craniofacial region, as well as the immune response and lipid metabolism. A ranking strategy, essentially based on a survey of protein-protein interactions datasets, allowed us to identify SOX2 as the main candidate TF involved in domestication-associated evolutionary changes. These findings should help to clarify the molecular mechanics of domestication and are of interest for future studies aimed to understand the behavioral and cognitive changes associated to domestication.
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Affiliation(s)
- Antonio Benítez-Burraco
- Department of Spanish, Linguistics, and Theory of Literature (Linguistics), Faculty of Philology, University of Seville, Seville, Spain.
- Área de Lingüística General, Departamento de Lengua Española, Lingüística y Teoría de la Literatura, Facultad de Filología, Universidad de Sevilla, C/ Palos de la Frontera s/n., 41007-, Sevilla, España.
| | - Juan Uriagereka
- Department of Linguistics and School of Languages, Literatures & Cultures, University of Maryland, College Park, MD, USA
| | - Serge Nataf
- Stem-cell and Brain Research Institute, 18 avenue de Doyen Lépine, F-69500, Bron, France
- University of Lyon 1, 43 Bd du 11 Novembre 1918, F-69100, Villeurbanne, France
- Bank of Tissues and Cells, Hospices Civils de Lyon, Hôpital Edouard Herriot, Place d'Arsonval, F-69003, Lyon, France
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Okoye O, Capasso J, Kopinsky SM, Amlie-Wolf L, Levin AV, Schneider A. SOX2 pathogenic variants with normal eyes: Expanding the phenotypic spectrum. Am J Med Genet A 2023; 191:2198-2203. [PMID: 37163579 DOI: 10.1002/ajmg.a.63239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/19/2023] [Accepted: 04/26/2023] [Indexed: 05/12/2023]
Abstract
SOX2 pathogenic variants, though rare, constitute the most commonly known genetic cause of clinical anophthalmia and microphthalmia. However, patients without major ocular malformation, but with multi-system developmental disorders, have been reported, suggesting that the range of clinical phenotypes is broader than previously appreciated. We detail two patients with bilateral structurally normal eyes along with 11 other previously published patients. Our findings suggest that there is no obvious phenotypic or genotypic pattern that may help set apart patients with normal eyes. Our patients provide further evidence for broadening the phenotypic spectrum of SOX2 mutations and re-appraising the designation of SOX2 disorder as an anophthalmia/microphthalmia syndrome. We emphasize the importance of considering SOX2 pathogenic variants in the differential diagnoses of individuals with normal eyes, who may have varying combinations of features such as developmental delay, urogenital abnormalities, gastro-intestinal anomalies, pituitary dysfunction, midline structural anomalies, and complex movement disorders, seizures or other neurological issues.
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Affiliation(s)
- Onochie Okoye
- Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, University of Rochester, New York, New York, USA
- Department of Ophthalmology, University of Nigeria Teaching Hospital, Enugu, Nigeria
| | - Jenina Capasso
- Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, University of Rochester, New York, New York, USA
- Pediatric Genetics, Golisano Children's Hospital, University of Rochester, Rochester, New York, USA
| | | | | | - Alex V Levin
- Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, University of Rochester, New York, New York, USA
- Pediatric Genetics, Golisano Children's Hospital, University of Rochester, Rochester, New York, USA
| | - Adele Schneider
- Department of Pediatrics, Wills Eye Hospital, Philadelphia, Pennsylvania, USA
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10
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Kantaputra PN, Tripuwabhrut K, Anthonappa RP, Chintakanon K, Ngamphiw C, Adisornkanj P, Porntrakulseree N, Olsen B, Intachai W, Hennekam RC, Vieira AR, Tongsima S. Heterozygous Variants in FREM2 Are Associated with Mesiodens, Supernumerary Teeth, Oral Exostoses, and Odontomas. Diagnostics (Basel) 2023; 13:diagnostics13071214. [PMID: 37046432 PMCID: PMC10093539 DOI: 10.3390/diagnostics13071214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/10/2023] [Accepted: 03/16/2023] [Indexed: 04/14/2023] Open
Abstract
BACKGROUND Supernumerary teeth refer to extra teeth that exceed the usual number of dentitions. A mesiodens is a particular form of supernumerary tooth, which is located in the premaxilla region. The objective of the study was to investigate the genetic etiology of extra tooth phenotypes, including mesiodens and isolated supernumerary teeth. METHODS Oral and radiographic examinations and whole-exome sequencing were performed on every patient in our cohort of 122 patients, including 27 patients with isolated supernumerary teeth and 94 patients with mesiodens. A patient who had multiple supernumerary teeth also had odontomas. RESULTS We identified a novel (c.8498A>G; p.Asn2833Ser) and six recurrent (c.1603C>T; p.Arg535Cys, c.5852G>A; p.Arg1951His, c.6949A>T; p.Thr2317Ser; c.1549G>A; p.Val517Met, c.1921A>G; p.Thr641Ala, and c.850G>C; p.Val284Leu) heterozygous missense variants in FREM2 in eight patients with extra tooth phenotypes. CONCLUSIONS Biallelic variants in FREM2 are implicated in autosomal recessive Fraser syndrome with or without dental anomalies. Here, we report for the first time that heterozygous carriers of FREM2 variants have phenotypes including oral exostoses, mesiodens, and isolated supernumerary teeth.
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Affiliation(s)
- Piranit Nik Kantaputra
- Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Kanich Tripuwabhrut
- Division of Orthodontics, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Robert P Anthonappa
- Department of Pediatric Dentistry, University of Western Australia Dental School, Nedlands, WA 6009, Australia
| | - Kanoknart Chintakanon
- Division of Orthodontics, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Chumpol Ngamphiw
- National Biobank of Thailand, National Science and Technology Development Agency, Khlong Luang 12120, Thailand
| | - Ploy Adisornkanj
- Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- Division of Pediatric Dentistry, Department of Orthodontics and Pediatric Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
- Dental Department, Sawang Daen Din Crown Prince Hospital, Sakon Nakhon 47110, Thailand
| | | | - Bjorn Olsen
- Department of Developmental Biology, Harvard School of Dental Medicine, Harvard University, Boston, MA 02115, USA
| | - Worrachet Intachai
- Center of Excellence in Medical Genetics Research, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Raoul C Hennekam
- Department of Pediatrics, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands
| | - Alexandre R Vieira
- Department of Oral and Craniofacial Sciences, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
| | - Sissades Tongsima
- National Biobank of Thailand, National Science and Technology Development Agency, Khlong Luang 12120, Thailand
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11
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Xu Y, Li L, Shan J, Du L, Jin X, Zhou P. Extreme myopia is more susceptible to SOX2 gene than high myopia. Exp Eye Res 2023; 230:109435. [PMID: 36921835 DOI: 10.1016/j.exer.2023.109435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/10/2023] [Accepted: 03/06/2023] [Indexed: 03/16/2023]
Abstract
PURPOSE To explore the association between two single-nucleotide polymorphisms (SNPs) in the SOX2 gene and high and extreme myopia in the Han Chinese population. MATERIALS AND METHODS A genetic association study using a case-control method was performed with 139 high myopia, 318 extreme myopia, and 918 healthy participants from the Chinese Han population. Two SNPs (rs4459940 and rs4575941) near SOX2 gene were selected for genotyping. We compared the allelic frequencies and haplotypes of the SNPs to assess their association with high and extreme myopia. This study was adjusted for sex and age of participants in the groups. RESULT The mean ages of the extreme myopia and control subjects were 47.44 ± 15.59 and 44.15 ± 14.08 years, respectively. The rs4575941 SNP of the SOX2 gene and the GG and AG genotypes showed no significant association with the risk of high myopia as opposed to the AA genotype (GG, OR = 0.94, 95% CI = 0.55-1.60, P = 0.820, Pc = NS; AG, OR = 0.91, 95% CI = 0.54-1.52, P = 0.708, Pc = NS). However, the frequency of the risk G allele of rs4575941 was significantly higher in the extreme myopia group than in the control group (OR = 1.31, 95% CI = 1.08-1.59; P = 0.007; Pc = 0.014). Furthermore, there were significant differences in the GG genotype frequency between the extreme myopia and control groups (OR = 1.77, 95% CI = 1.45-2.74, P = 0.009, Pc = 0.036). The A-G haplotype frequency was higher in the extreme group (OR = 1.27, 95% CI = 1.05-1.55, P = 0.014), while there were no significant differences found in high myopia group (OR = 1.18, 95% CI = 0.77-1.31, P = 0.979). CONCLUSION The SOX2 rs4575941 polymorphism, in Chinese Han population, contributes to the susceptibility of extreme myopia. SOX2 may thus be implicated in extreme myopia rather than in high myopia.
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Affiliation(s)
- Youmei Xu
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, PR China
| | - Lin Li
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Jiankang Shan
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China; The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, PR China
| | - Liping Du
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Xuemin Jin
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
| | - Pengyi Zhou
- Department of Ophthalmology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China.
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12
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Cassin J, Stamou MI, Keefe KW, Sung KE, Bojo CC, Tonsfeldt KJ, Rojas RA, Ferreira Lopes V, Plummer L, Salnikov KB, Keefe DL, Ozata M, Genel M, Georgopoulos NA, Hall JE, Crowley WF, Seminara SB, Mellon PL, Balasubramanian R. Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms. JCI Insight 2023; 8:e164324. [PMID: 36602867 PMCID: PMC9977424 DOI: 10.1172/jci.insight.164324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Pathogenic SRY-box transcription factor 2 (SOX2) variants typically cause severe ocular defects within a SOX2 disorder spectrum that includes hypogonadotropic hypogonadism. We examined exome-sequencing data from a large, well-phenotyped cohort of patients with idiopathic hypogonadotropic hypogonadism (IHH) for pathogenic SOX2 variants to investigate the underlying pathogenic SOX2 spectrum and its associated phenotypes. We identified 8 IHH individuals harboring heterozygous pathogenic SOX2 variants with variable ocular phenotypes. These variant proteins were tested in vitro to determine whether a causal relationship between IHH and SOX2 exists. We found that Sox2 was highly expressed in the hypothalamus of adult mice and colocalized with kisspeptin 1 (KISS1) expression in the anteroventral periventricular nucleus of adult female mice. In vitro, shRNA suppression of mouse SOX2 protein in Kiss-expressing cell lines increased the levels of human kisspeptin luciferase (hKiss-luc) transcription, while SOX2 overexpression repressed hKiss-luc transcription. Further, 4 of the identified SOX2 variants prevented this SOX2-mediated repression of hKiss-luc. Together, these data suggest that pathogenic SOX2 variants contribute to both anosmic and normosmic forms of IHH, attesting to hypothalamic defects in the SOX2 disorder spectrum. Our study describes potentially novel mechanisms contributing to SOX2-related disease and highlights the necessity of SOX2 screening in IHH genetic evaluation irrespective of associated ocular defects.
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Affiliation(s)
- Jessica Cassin
- Department of Obstetrics, Gynecology, and Reproductive Sciences; Center for Reproductive Science and Medicine; and
- Center for Circadian Biology, University of California, San Diego, La Jolla, California, USA
| | - Maria I. Stamou
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Kimberly W. Keefe
- Center for Infertility and Reproductive Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Kaitlin E. Sung
- Department of Obstetrics, Gynecology, and Reproductive Sciences; Center for Reproductive Science and Medicine; and
| | - Celine C. Bojo
- Department of Obstetrics, Gynecology, and Reproductive Sciences; Center for Reproductive Science and Medicine; and
| | - Karen J. Tonsfeldt
- Department of Obstetrics, Gynecology, and Reproductive Sciences; Center for Reproductive Science and Medicine; and
- Center for Circadian Biology, University of California, San Diego, La Jolla, California, USA
| | - Rebecca A. Rojas
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Vanessa Ferreira Lopes
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lacey Plummer
- Center for Infertility and Reproductive Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | - Kathryn B. Salnikov
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David L. Keefe
- Center for Infertility and Reproductive Surgery, Brigham and Women’s Hospital, Boston, Massachusetts, USA
| | | | - Myron Genel
- Section of Pediatric Endocrinology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Neoklis A. Georgopoulos
- Division of Endocrinology, Department of Medicine, University of Patras Medical School, Patras, Greece
| | - Janet E. Hall
- National Institute of Environmental Health Sciences, Durham, North Carolina, USA
| | - William F. Crowley
- Endocrine Unit, Department of Medicine, and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Stephanie B. Seminara
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Pamela L. Mellon
- Department of Obstetrics, Gynecology, and Reproductive Sciences; Center for Reproductive Science and Medicine; and
- Center for Circadian Biology, University of California, San Diego, La Jolla, California, USA
| | - Ravikumar Balasubramanian
- Massachusetts General Hospital Harvard Center for Reproductive Medicine and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
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13
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Gasco V, Matarazzo P, De Sanctis L, Ghigo E. Growth hormone deficiency in a case of septo-optic-dysplasia due to SOX2 mutation: should we re-test patients during the transition period? BMJ Case Rep 2022; 15:e251897. [PMID: 36581364 PMCID: PMC9806035 DOI: 10.1136/bcr-2022-251897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/19/2022] [Indexed: 12/30/2022] Open
Abstract
Gene mutations encoding transcription factors, including SOX2, have been associated with growth hormone deficiency (GHD) and abnormal pituitary development. Guidelines on GHD management in the transition period state that patients with genetic-based childhood-onset GHD can skip retesting due to a high likelihood of permanent GHD. We describe a case of septo-optic-dysplasia due to SOX2 mutation characterised by childhood-onset GHD, which showed a normal somatotropic function at the transition period. This case raises the opportunity to retest for GHD during the transition period, even in patients with a known genetic cause, in order to avoid inappropriate GH treatment.
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Affiliation(s)
- Valentina Gasco
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, Turin, Piedmont, Italy
| | - Patrizia Matarazzo
- Department of Public Health and Pediatrics, University of Turin, Turin, Piedmont, Italy
| | - Luisa De Sanctis
- Department of Public Health and Pediatrics, University of Turin, Turin, Piedmont, Italy
| | - Ezio Ghigo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medical Science, University of Turin, Turin, Piedmont, Italy
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14
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Al-Jawahiri R, Foroutan A, Kerkhof J, McConkey H, Levy M, Haghshenas S, Rooney K, Turner J, Shears D, Holder M, Lefroy H, Castle B, Reis LM, Semina EV, Lachlan K, Chandler K, Wright T, Clayton-Smith J, Hug FP, Pitteloud N, Bartoloni L, Hoffjan S, Park SM, Thankamony A, Lees M, Wakeling E, Naik S, Hanker B, Girisha KM, Agolini E, Giuseppe Z, Alban Z, Tessarech M, Keren B, Afenjar A, Zweier C, Reis A, Smol T, Tsurusaki Y, Nobuhiko O, Sekiguchi F, Tsuchida N, Matsumoto N, Kou I, Yonezawa Y, Ikegawa S, Callewaert B, Freeth M, Kleinendorst L, Donaldson A, Alders M, De Paepe A, Sadikovic B, McNeill A. SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile. Genet Med 2022; 24:1261-1273. [PMID: 35341651 PMCID: PMC9245088 DOI: 10.1016/j.gim.2022.02.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/28/2022] Open
Abstract
PURPOSE This study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants. METHODS Individuals with protein altering variants in SOX11 were identified through exome and genome sequencing and international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation was assessed using Infinium MethylationEPIC array. The expression pattern of SOX11 in developing human brain was defined using RNAscope. RESULTS We reported 38 new patients with SOX11 variants. Idiopathic hypogonadotropic hypogonadism was confirmed as a feature of SOX11 syndrome. A distinctive pattern of blood DNA methylation was identified in SOX11 syndrome, separating SOX11 syndrome from other BAFopathies. CONCLUSION SOX11 syndrome is a distinct clinical entity with characteristic clinical features and episignature differentiating it from BAFopathies.
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Affiliation(s)
- Reem Al-Jawahiri
- Department of Psychology, The University of Sheffield, Sheffield, United Kingdom
| | - Aidin Foroutan
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada
| | - Jennifer Kerkhof
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada
| | - Haley McConkey
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada
| | - Michael Levy
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada
| | - Sadegheh Haghshenas
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada
| | - Kathleen Rooney
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada; The Archie and Irene Verspeeten Clinical Genome Centre, London Health Sciences Foundation, London Health Sciences Centre, London, Ontario, Canada
| | - Jasmin Turner
- Biosciences Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Debbie Shears
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Muriel Holder
- Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Henrietta Lefroy
- Peninsula Clinical Genetics Service, RD&E Heavitree Hospital, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
| | - Bruce Castle
- Peninsula Clinical Genetics Service, RD&E Heavitree Hospital, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
| | - Linda M Reis
- Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI
| | - Elena V Semina
- Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI
| | - Katherine Lachlan
- Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Kate Chandler
- Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Thomas Wright
- Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Jill Clayton-Smith
- Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Franziska Phan Hug
- Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Nelly Pitteloud
- Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Lucia Bartoloni
- Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Sabine Hoffjan
- Ruhr-Universitat Bochum, Abteilung für Humangenetik, Bochum, Germany
| | - Soo-Mi Park
- Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Ajay Thankamony
- Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Melissa Lees
- Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Emma Wakeling
- Clinical Genetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Swati Naik
- West Midlands Regional Clinical Genetics Centre and Department of Clinical Genetics, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, United Kingdom
| | - Britta Hanker
- Ambulanzzentrum UKSH, Institut für Humangenetik, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
| | - Katta M Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Emanuele Agolini
- Medical Genetics Laboratory, Bambino Gesu Children's Hospital, Rome, Italy
| | - Zampino Giuseppe
- Paediatric Department, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | | | | | - Boris Keren
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Alexandra Afenjar
- Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christiane Zweier
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andre Reis
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Thomas Smol
- EA7364 RADEME, Institute of Medical Genetics, Lille University Hospital, Lille University, Lille, France
| | - Yoshinori Tsurusaki
- Faculty of Nutritional Science, Sagami Women's University, Sagamihara, Japan
| | - Okamoto Nobuhiko
- Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Futoshi Sekiguchi
- Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Naomi Tsuchida
- Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Ikuyo Kou
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
| | - Yoshiro Yonezawa
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; Department of Orthopedic Surgery, Keio University School of Medicine, Keio University, Tokyo, Japan
| | - Shiro Ikegawa
- Laboratory for Bone and Joint Diseases, Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan
| | - Bert Callewaert
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Megan Freeth
- Department of Psychology, The University of Sheffield, Sheffield, United Kingdom
| | - Lotte Kleinendorst
- Centrum voor Medische Genetica - UZ Gent, Ghent University Hospital, Gent, Belgium
| | - Alan Donaldson
- Department of Clinical Genetics Service, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom
| | - Marielle Alders
- Department of Human Genetics, Amsterdam Reproduction & Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Anne De Paepe
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium
| | - Bekim Sadikovic
- Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada.
| | - Alisdair McNeill
- Department of Neuroscience, The Medical School, The University of Sheffield, Sheffield, United Kingdom; Department of Clinical Genetics, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, United Kingdom.
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15
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Mercurio S, Serra L, Pagin M, Nicolis SK. Deconstructing Sox2 Function in Brain Development and Disease. Cells 2022; 11:cells11101604. [PMID: 35626641 PMCID: PMC9139651 DOI: 10.3390/cells11101604] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/28/2022] [Accepted: 05/04/2022] [Indexed: 02/04/2023] Open
Abstract
SOX2 is a transcription factor conserved throughout vertebrate evolution, whose expression marks the central nervous system from the earliest developmental stages. In humans, SOX2 mutation leads to a spectrum of CNS defects, including vision and hippocampus impairments, intellectual disability, and motor control problems. Here, we review how conditional Sox2 knockout (cKO) in mouse with different Cre recombinases leads to very diverse phenotypes in different regions of the developing and postnatal brain. Surprisingly, despite the widespread expression of Sox2 in neural stem/progenitor cells of the developing neural tube, some regions (hippocampus, ventral forebrain) appear much more vulnerable than others to Sox2 deletion. Furthermore, the stage of Sox2 deletion is also a critical determinant of the resulting defects, pointing to a stage-specificity of SOX2 function. Finally, cKOs illuminate the importance of SOX2 function in different cell types according to the different affected brain regions (neural precursors, GABAergic interneurons, glutamatergic projection neurons, Bergmann glia). We also review human genetics data regarding the brain defects identified in patients carrying mutations within human SOX2 and examine the parallels with mouse mutants. Functional genomics approaches have started to identify SOX2 molecular targets, and their relevance for SOX2 function in brain development and disease will be discussed.
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16
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Müller HL, Tauber M, Lawson EA, Özyurt J, Bison B, Martinez-Barbera JP, Puget S, Merchant TE, van Santen HM. Hypothalamic syndrome. Nat Rev Dis Primers 2022; 8:24. [PMID: 35449162 DOI: 10.1038/s41572-022-00351-z] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/08/2022] [Indexed: 12/11/2022]
Abstract
Hypothalamic syndrome (HS) is a rare disorder caused by disease-related and/or treatment-related injury to the hypothalamus, most commonly associated with rare, non-cancerous parasellar masses, such as craniopharyngiomas, germ cell tumours, gliomas, cysts of Rathke's pouch and Langerhans cell histiocytosis, as well as with genetic neurodevelopmental syndromes, such as Prader-Willi syndrome and septo-optic dysplasia. HS is characterized by intractable weight gain associated with severe morbid obesity, multiple endocrine abnormalities and memory impairment, attention deficit and reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition but treatments for general obesity are often used in patients with HS, including surgery, medication and counselling. However, these are mostly ineffective and no medications that are specifically approved for the treatment of HS are available. Specific challenges in HS are because the syndrome represents an adverse effect of different diseases, and that diagnostic criteria, aetiology, pathogenesis and management of HS are not completely defined.
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Affiliation(s)
- Hermann L Müller
- Department of Paediatrics and Paediatric Hematology/Oncology, University Children's Hospital, Klinikum Oldenburg AöR, Carl von Ossietzky University, Oldenburg, Germany.
| | - Maithé Tauber
- Centre de Référence du Syndrome de Prader-Willi et autres syndromes avec troubles du comportement alimentaire, Hôpital des Enfants, CHU-Toulouse, Toulouse, France
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity) INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France
| | - Elizabeth A Lawson
- Neuroendocrine Unit, Massachusetts General Hospital, and Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jale Özyurt
- Biological Psychology Laboratory, Department of Psychology, School of Medicine and Health Sciences, Carl von Ossietzky University, Oldenburg, Germany
- Research Center Neurosensory Science, Carl von Ossietzky University, Oldenburg, Germany
| | - Brigitte Bison
- Department of Neuroradiology, University Hospital Augsburg, Augsburg, Germany
| | - Juan-Pedro Martinez-Barbera
- Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Stephanie Puget
- Service de Neurochirurgie, Hôpital Necker-Enfants Malades, Sorbonne Paris Cité, Paris, France
- Service de Neurochirurgie, Hopital Pierre Zobda Quitman, Martinique, France
| | - Thomas E Merchant
- Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hanneke M van Santen
- Department of Paediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center, Utrecht, Netherlands
- Princess Máxima Center for Paediatric Oncology, Utrecht, Netherlands
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17
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Sather ΙΙΙ R, Thompson D, Ihinger J, Montezuma SR. Septo-optic dysplasia presenting with nystagmus, pseudo-disc edema, and fovea hypoplasia. Ophthalmic Genet 2022; 43:522-529. [DOI: 10.1080/13816810.2022.2039720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Richard Sather ΙΙΙ
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA
| | - Dorothy Thompson
- Tony Kriss Visual Electrophysiology Unit, Great Ormond Hospital for Children, London, UK
| | - Jacqueline Ihinger
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sandra R. Montezuma
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, USA
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18
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Chesneau B, Aubert-Mucca M, Fremont F, Pechmeja J, Soler V, Isidor B, Nizon M, Dollfus H, Kaplan J, Fares-Taie L, Rozet JM, Busa T, Lacombe D, Naudion S, Amiel J, Rio M, Attie-Bitach T, Lesage C, Thouvenin D, Odent S, Morel G, Vincent-Delorme C, Boute O, Vanlerberghe C, Dieux A, Boussion S, Faivre L, Pinson L, Laffargue F, Le Guyader G, Le Meur G, Prieur F, Lambert V, Laudier B, Cottereau E, Ayuso C, Corton-Pérez M, Bouneau L, Le Caignec C, Gaston V, Jeanton-Scaramouche C, Dupin-Deguine D, Calvas P, Chassaing N, Plaisancié J. First evidence of SOX2 mutations in Peters' anomaly: lessons from molecular screening of 95 patients. Clin Genet 2022; 101:494-506. [PMID: 35170016 DOI: 10.1111/cge.14123] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 11/30/2022]
Abstract
Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some Copy Number Variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of Comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Bertrand Chesneau
- Génétique Médicale, Hôpital Purpan, CHU, Toulouse, France.,Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France
| | | | - Félix Fremont
- Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France.,Service d'ophtalmologie, Hôpital Purpan, CHU Toulouse, France
| | - Jacmine Pechmeja
- Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France.,Service d'ophtalmologie, Hôpital Purpan, CHU Toulouse, France
| | - Vincent Soler
- Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France.,Service d'ophtalmologie, Hôpital Purpan, CHU Toulouse, France
| | - Bertrand Isidor
- Génétique Médicale, Institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - Mathilde Nizon
- Génétique Médicale, Institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
| | - Hélène Dollfus
- Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpitaux Universitaires, Strasbourg, France
| | - Josseline Kaplan
- Laboratoire de Génétique Ophtalmologique, INSERM U1163, Institut Imagine, Paris, France
| | - Lucas Fares-Taie
- Laboratoire de Génétique Ophtalmologique, INSERM U1163, Institut Imagine, Paris, France
| | - Jean-Michel Rozet
- Laboratoire de Génétique Ophtalmologique, INSERM U1163, Institut Imagine, Paris, France
| | - Tiffany Busa
- Génétique Clinique, AP- HM CHU Timone Enfants, Marseille, France
| | - Didier Lacombe
- Département de Génétique Médicale, CHU Bordeaux, Bordeaux, France
| | - Sophie Naudion
- Département de Génétique Médicale, CHU Bordeaux, Bordeaux, France
| | - Jeanne Amiel
- Service de Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Marlène Rio
- Service de Génétique Médicale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
| | - Tania Attie-Bitach
- Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, AP-, HP, Paris, France
| | | | | | - Sylvie Odent
- Service de Génétique Clinique, Centre Labellisé pour les Anomalies du Développement Ouest, CHU Rennes; Institut de Génétique et Développement de Rennes, CNRS, UMR 6290, Université de Rennes, ERN ITHACA, France
| | - Godelieve Morel
- Service de Génétique Clinique, Centre Labellisé pour les Anomalies du Développement Ouest, CHU Rennes; Institut de Génétique et Développement de Rennes, CNRS, UMR 6290, Université de Rennes, ERN ITHACA, France
| | | | | | | | | | | | - Laurence Faivre
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU, Dijon, France
| | - Lucile Pinson
- Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, France
| | | | | | | | | | - Victor Lambert
- Service d'ophtalmologie, Hôpital Nord, Saint-Etienne, France
| | | | | | - Carmen Ayuso
- Genetics & Genomics Department, Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD-UAM). Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
| | - Marta Corton-Pérez
- Genetics & Genomics Department, Jiménez Díaz University Hospital-Universidad Autónoma de Madrid (IIS-FJD-UAM). Centre for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
| | | | | | | | | | | | - Patrick Calvas
- Génétique Médicale, Hôpital Purpan, CHU, Toulouse, France.,Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France
| | - Nicolas Chassaing
- Génétique Médicale, Hôpital Purpan, CHU, Toulouse, France.,Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France
| | - Julie Plaisancié
- Génétique Médicale, Hôpital Purpan, CHU, Toulouse, France.,Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), CHU, Toulouse, France.,INSERM U1214, ToNIC, Université Toulouse III, France
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19
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Amlie-Wolf L, Bardakjian T, Kopinsky SM, Reis LM, Semina EV, Schneider A. Review of 37 patients with SOX2 pathogenic variants collected by the Anophthalmia/Microphthalmia Clinical Registry and DNA research study. Am J Med Genet A 2022; 188:187-198. [PMID: 34562068 PMCID: PMC9169870 DOI: 10.1002/ajmg.a.62518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/30/2021] [Accepted: 09/05/2021] [Indexed: 01/03/2023]
Abstract
SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients with SOX2 variants, some of whom have been followed for 20+ years. Medical records from patients enrolled in the A/M Research Registry and carrying SOX2 variants were reviewed. Thirty-seven patients were identified, ranging in age from infant to 30 years old. Eye anomalies were bilateral in 30 patients (81.1%), unilateral in 5 (13.5%), and absent in 2 (5.4%). Intellectual disability was present in all with data available and ranged from mild to profound. Seizures were noted in 18 of 27 (66.6%) patients, usually with abnormal brain MRIs (10/15, 66.7%). Growth issues were reported in 14 of 21 patients (66.7%) and 14 of 19 (73.7%) had gonadotropin deficiency. Genitourinary anomalies were seen in 15 of 19 (78.9%) male patients and 5 of 15 (33.3%) female patients. Patients with SOX2 nucleotide variants, whole gene deletions or translocations are typically affected with bilateral or unilateral microphthalmia and anophthalmia. Other associated features include intellectual disability, seizures, brain anomalies, growth hormone deficiency, gonadotropin deficiency, and genitourinary anomalies. Recommendations for newly diagnosed patients with SOX2 variants include eye exams, MRI of the brain and orbits, endocrine and neurology examinations. Since the clinical spectrum associated with SOX2 alleles has expanded beyond the originally reported phenotypes, we propose a broader term, SOX2-associated disorder, for this condition.
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Affiliation(s)
- Louise Amlie-Wolf
- Einstein Medical Center Philadelphia, West Philadelphia, Pennsylvania, USA
- Nemours Children’s Hospital Delaware, Wilmington, DE, USA
| | - Tanya Bardakjian
- Einstein Medical Center Philadelphia, West Philadelphia, Pennsylvania, USA
- Department of Pediatrics and Children’s Research Institute, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, Wisconsin, USA
| | - Sarina M. Kopinsky
- Einstein Medical Center Philadelphia, West Philadelphia, Pennsylvania, USA
| | - Linda M. Reis
- Department of Pediatrics and Children’s Research Institute, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, Wisconsin, USA
| | - Elena V. Semina
- Einstein Medical Center Philadelphia, West Philadelphia, Pennsylvania, USA
- Department of Ophthalmology and Visual Sciences, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Adele Schneider
- Department of Neurology, Hospital of University of Pennsylvania, 330 South Ninth Street, Philadelphia, PA, USA
- Department of Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA, USA
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20
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Yamada H, Okanishi T, Okazaki T, Oguri M, Fukuda H, Uchiyama Y, Mizuguchi T, Matsumoto N, Maegaki Y. Gait disturbance in a patient with de novo 1.0-kb SOX2 microdeletion. Brain Dev 2022; 44:68-72. [PMID: 34332824 DOI: 10.1016/j.braindev.2021.07.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 07/07/2021] [Accepted: 07/15/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Sex-determining region Y-box 2 (SOX2) plays an important role in the early embryogenesis of the eye, forebrain, and hypothalamic-pituitary axis. Anophthalmia, microphthalmia, and hormonal abnormalities are commonly observed in patients with SOX2-related disorders. Although gait disturbance, particularly ataxic gait, has recently been observed in several cases, detailed data regarding the clinical course of gait disturbance in SOX2-related disorders are limited. CASE REPORT A 9-year-old Japanese boy presented with focal dyskinesia only during walking and running after he started walking at the age of 3 years. He also exhibited intellectual disability and mild dysmorphic features, including microcephaly, micropenis, and short stature associated with hormonal abnormalities. Gait disturbance with involuntary extremity movements only during walking and running was indicative of choreoathetosis and dystonia. Genetic analysis detected a de novo heterozygous 1.0-kb deletion including SOX2 at 3q26.32, as described in a previous technical paper. CONCLUSIONS SOX2-related disorders should be considered in patients with some anomalies having a differential diagnosis of dyskinesia. Focal dyskinesia only during walking and running may be a characteristic feature of SOX2-related disorders.
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Affiliation(s)
- Hiroyuki Yamada
- Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
| | - Tohru Okanishi
- Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
| | - Tetsuya Okazaki
- Division of Clinical Genetics, Tottori University Hospital, Yonago, Japan
| | - Masayoshi Oguri
- Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan; Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Japan
| | - Hiromi Fukuda
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yuri Uchiyama
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan
| | - Takeshi Mizuguchi
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yoshihiro Maegaki
- Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan
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21
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Mastromauro C, Chiarelli F. Novel Insights Into the Genetic Causes of Short Stature in Children. Endocrinology 2022; 18:49-57. [PMID: 35949366 PMCID: PMC9354945 DOI: 10.17925/ee.2022.18.1.49] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 04/19/2022] [Indexed: 11/24/2022]
Abstract
Short stature is a common reason for consulting a growth specialist during childhood. Normal height is a polygenic trait involving a complex interaction between hormonal, nutritional and psychosocial components. Genetic factors are becoming very important in the understanding of short stature. After exclusion of the most frequent causes of growth failure, clinicians need to evaluate whether a genetic cause might be taken into consideration. In fact, genetic causes of short stature are probably misdiagnosed during clinical practice and the underlying cause of short stature frequently remains unknown, thus classifying children as having idiopathic short stature (ISS). However, over the past decade, novel genetic techniques have led to the discovery of novel genes associated with linear growth and thus to the ability to define new possible aetiologies of short stature. In fact, thanks to the newer genetic advances, it is possible to properly re-classify about 25–40% of children previously diagnosed with ISS. The purpose of this article is to describe the main monogenic causes of short stature, which, thanks to advances in molecular genetics, are assuming an increasingly important role in the clinical approach to short children.
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22
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Hermans F, Hemeryck L, Lambrichts I, Bronckaers A, Vankelecom H. Intertwined Signaling Pathways Governing Tooth Development: A Give-and-Take Between Canonical Wnt and Shh. Front Cell Dev Biol 2021; 9:758203. [PMID: 34778267 PMCID: PMC8586510 DOI: 10.3389/fcell.2021.758203] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 10/11/2021] [Indexed: 11/13/2022] Open
Abstract
Teeth play essential roles in life. Their development relies on reciprocal interactions between the ectoderm-derived dental epithelium and the underlying neural crest-originated mesenchyme. This odontogenic process serves as a prototype model for the development of ectodermal appendages. In the mouse, developing teeth go through distinct morphological phases that are tightly controlled by epithelial signaling centers. Crucial molecular regulators of odontogenesis include the evolutionarily conserved Wnt, BMP, FGF and sonic hedgehog (Shh) pathways. These signaling modules do not act on their own, but are closely intertwined during tooth development, thereby outlining the path to be taken by specific cell populations including the resident dental stem cells. Recently, pivotal Wnt-Shh interaction and feedback loops have been uncovered during odontogenesis, showing conservation in other developing ectodermal appendages. This review provides an integrated overview of the interplay between canonical Wnt and Shh throughout mouse tooth formation stages, extending from the initiation of dental placode to the fully formed adult tooth.
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Affiliation(s)
- Florian Hermans
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, KU Leuven (University of Leuven), Leuven, Belgium.,Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Diepenbeek, Belgium
| | - Lara Hemeryck
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, KU Leuven (University of Leuven), Leuven, Belgium
| | - Ivo Lambrichts
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Diepenbeek, Belgium
| | - Annelies Bronckaers
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Diepenbeek, Belgium
| | - Hugo Vankelecom
- Laboratory of Tissue Plasticity in Health and Disease, Cluster of Stem Cell and Developmental Biology, Department of Development and Regeneration, Leuven Stem Cell Institute, KU Leuven (University of Leuven), Leuven, Belgium
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23
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SOX2 heterozygous mutations cause multiple extraocular phenotypes in boys. Chin Med J (Engl) 2021; 135:477-479. [PMID: 34759222 PMCID: PMC8869626 DOI: 10.1097/cm9.0000000000001805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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24
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Keçeli M. Imaging Findings of Septooptic Dysplasia and Joubert's Syndrome in A Patient with Mixed Gonadal Dysgenesis: A New Coexistence? JOURNAL OF PEDIATRIC NEUROLOGY 2021. [DOI: 10.1055/s-0040-1715858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
AbstractAmbiguous genitalia is a common feature in most disorders of sexual development. These disorders can be evaluated within three groups: sex chromosome disorders, 46,XY disorders, and 46,XX disorders. Except for Turner's syndrome, these anomalies are not related to neurological developmental anomalies. A 6-month-old patient presenting with ambiguous genitalia had developmental and motor retardation with nystagmus. In karyotype analysis, 45,X/46,XY sequences were found, compatible with mixed gonadal dysgenesis (GD). Laboratory findings were normal except for low serum total testosterone level. The uterus and left adnexal structures were seen in imaging. There were no gonads in the labial/scrotal regions. Septooptic dysplasia (SOD) and Joubert's syndrome (JS) were detected in cranial magnetic resonance imaging. This presentation reports rare association of SOD and JS in a child with mixed GD.
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Affiliation(s)
- Merter Keçeli
- Department of Pediatric Radiology, University of Health Sciences Turkey, Konya Education and Research Hospital, Konya, Turkey
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25
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Zhang T, Liu T, Mora N, Guegan J, Bertrand M, Contreras X, Hansen AH, Streicher C, Anderle M, Danda N, Tiberi L, Hippenmeyer S, Hassan BA. Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum. Cell Rep 2021; 35:109208. [PMID: 34107249 DOI: 10.1016/j.celrep.2021.109208] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 03/29/2021] [Accepted: 05/11/2021] [Indexed: 12/17/2022] Open
Abstract
Brain neurons arise from relatively few progenitors generating an enormous diversity of neuronal types. Nonetheless, a cardinal feature of mammalian brain neurogenesis is thought to be that excitatory and inhibitory neurons derive from separate, spatially segregated progenitors. Whether bi-potential progenitors with an intrinsic capacity to generate both lineages exist and how such a fate decision may be regulated are unknown. Using cerebellar development as a model, we discover that individual progenitors can give rise to both inhibitory and excitatory lineages. Gradations of Notch activity determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate, while intermediate levels of Notch activity generate inhibitory neurons, and daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch-mediated binary cell fate choice is a mechanism for regulating the ratio of excitatory to inhibitory neurons from common progenitors.
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Affiliation(s)
- Tingting Zhang
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France; Doctoral School of Biomedical Sciences, KU Leuven, 3000 Leuven, Belgium
| | - Tengyuan Liu
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France; Doctoral School of Biomedical Sciences, KU Leuven, 3000 Leuven, Belgium
| | - Natalia Mora
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Justine Guegan
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Mathilde Bertrand
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Ximena Contreras
- Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
| | - Andi H Hansen
- Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
| | - Carmen Streicher
- Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
| | - Marica Anderle
- Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Natasha Danda
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France
| | - Luca Tiberi
- Armenise-Harvard Laboratory of Brain Disorders and Cancer, CIBIO, University of Trento, Via Sommarive 9, 38123 Trento, Italy
| | - Simon Hippenmeyer
- Institute of Science and Technology Austria, Am Campus 1, 3400 Klosterneuburg, Austria
| | - Bassem A Hassan
- Institut du Cerveau (ICM), Sorbonne Université, INSERM, CNRS, Hôpital Pitié-Salpêtrière, Paris, France.
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26
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Bosch i Ara L, Katugampola H, Dattani MT. Congenital Hypopituitarism During the Neonatal Period: Epidemiology, Pathogenesis, Therapeutic Options, and Outcome. Front Pediatr 2021; 8:600962. [PMID: 33634051 PMCID: PMC7902025 DOI: 10.3389/fped.2020.600962] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 12/31/2020] [Indexed: 12/13/2022] Open
Abstract
Introduction: Congenital hypopituitarism (CH) is characterized by a deficiency of one or more pituitary hormones. The pituitary gland is a central regulator of growth, metabolism, and reproduction. The anterior pituitary produces and secretes growth hormone (GH), adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and prolactin. The posterior pituitary hormone secretes antidiuretic hormone and oxytocin. Epidemiology: The incidence is 1 in 4,000-1 in 10,000. The majority of CH cases are sporadic; however, a small number of familial cases have been identified. In the latter, a molecular basis has frequently been identified. Between 80-90% of CH cases remain unsolved in terms of molecular genetics. Pathogenesis: Several transcription factors and signaling molecules are involved in the development of the pituitary gland. Mutations in any of these genes may result in CH including HESX1, PROP1, POU1F1, LHX3, LHX4, SOX2, SOX3, OTX2, PAX6, FGFR1, GLI2, and FGF8. Over the last 5 years, several novel genes have been identified in association with CH, but it is likely that many genes remain to be identified, as the majority of patients with CH do not have an identified mutation. Clinical manifestations: Genotype-phenotype correlations are difficult to establish. There is a high phenotypic variability associated with different genetic mutations. The clinical spectrum includes severe midline developmental disorders, hypopituitarism (in isolation or combined with other congenital abnormalities), and isolated hormone deficiencies. Diagnosis and treatment: Key investigations include MRI and baseline and dynamic pituitary function tests. However, dynamic tests of GH secretion cannot be performed in the neonatal period, and a diagnosis of GH deficiency may be based on auxology, MRI findings, and low growth factor concentrations. Once a hormone deficit is confirmed, hormone replacement should be started. If onset is acute with hypoglycaemia, cortisol deficiency should be excluded, and if identified this should be rapidly treated, as should TSH deficiency. This review aims to give an overview of CH including management of this complex condition.
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Affiliation(s)
- Laura Bosch i Ara
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Harshini Katugampola
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom
| | - Mehul T. Dattani
- Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
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27
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Russell JP, Lim X, Santambrogio A, Yianni V, Kemkem Y, Wang B, Fish M, Haston S, Grabek A, Hallang S, Lodge EJ, Patist AL, Schedl A, Mollard P, Nusse R, Andoniadou CL. Pituitary stem cells produce paracrine WNT signals to control the expansion of their descendant progenitor cells. eLife 2021; 10:59142. [PMID: 33399538 PMCID: PMC7803373 DOI: 10.7554/elife.59142] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 01/04/2021] [Indexed: 12/16/2022] Open
Abstract
In response to physiological demand, the pituitary gland generates new hormone-secreting cells from committed progenitor cells throughout life. It remains unclear to what extent pituitary stem cells (PSCs), which uniquely express SOX2, contribute to pituitary growth and renewal. Moreover, neither the signals that drive proliferation nor their sources have been elucidated. We have used genetic approaches in the mouse, showing that the WNT pathway is essential for proliferation of all lineages in the gland. We reveal that SOX2+ stem cells are a key source of WNT ligands. By blocking secretion of WNTs from SOX2+ PSCs in vivo, we demonstrate that proliferation of neighbouring committed progenitor cells declines, demonstrating that progenitor multiplication depends on the paracrine WNT secretion from SOX2+ PSCs. Our results indicate that stem cells can hold additional roles in tissue expansion and homeostasis, acting as paracrine signalling centres to coordinate the proliferation of neighbouring cells.
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Affiliation(s)
- John P Russell
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
| | - Xinhong Lim
- Skin Research Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Alice Santambrogio
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom.,Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Val Yianni
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
| | - Yasmine Kemkem
- Institute of Functional Genomics (IGF), University of Montpellier, CNRS, Montpellier, France
| | - Bruce Wang
- Howard Hughes Medical Institute, Stanford University School of Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States.,Department of Medicine and Liver Center, University of California San Francisco, San Francisco, United States
| | - Matthew Fish
- Howard Hughes Medical Institute, Stanford University School of Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States
| | - Scott Haston
- Developmental Biology and Cancer, Birth Defects Research Centre, UCL GOS Institute of Child Health, London, United Kingdom
| | | | - Shirleen Hallang
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
| | - Emily J Lodge
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
| | - Amanda L Patist
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom
| | | | - Patrice Mollard
- Institute of Functional Genomics (IGF), University of Montpellier, CNRS, Montpellier, France
| | - Roel Nusse
- Howard Hughes Medical Institute, Stanford University School of Medicine, Department of Developmental Biology, Stanford University School of Medicine, Stanford, United States
| | - Cynthia L Andoniadou
- Centre for Craniofacial and Regenerative Biology, King's College London, London, United Kingdom.,Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Eintracht J, Toms M, Moosajee M. The Use of Induced Pluripotent Stem Cells as a Model for Developmental Eye Disorders. Front Cell Neurosci 2020; 14:265. [PMID: 32973457 PMCID: PMC7468397 DOI: 10.3389/fncel.2020.00265] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 07/28/2020] [Indexed: 12/15/2022] Open
Abstract
Approximately one-third of childhood blindness is attributed to developmental eye disorders, of which 80% have a genetic cause. Eye morphogenesis is tightly regulated by a highly conserved network of transcription factors when disrupted by genetic mutations can result in severe ocular malformation. Human-induced pluripotent stem cells (hiPSCs) are an attractive tool to study early eye development as they are more physiologically relevant than animal models, can be patient-specific and their use does not elicit the ethical concerns associated with human embryonic stem cells. The generation of self-organizing hiPSC-derived optic cups is a major advancement to understanding mechanisms of ocular development and disease. Their development in vitro has been found to mirror that of the human eye and these early organoids have been used to effectively model microphthalmia caused by a VSX2 variant. hiPSC-derived optic cups, retina, and cornea organoids are powerful tools for future modeling of disease phenotypes and will enable a greater understanding of the pathophysiology of many other developmental eye disorders. These models will also provide an effective platform for identifying molecular therapeutic targets and for future clinical applications.
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Affiliation(s)
| | - Maria Toms
- UCL Institute of Ophthalmology, London, United Kingdom.,The Francis Crick Institute, London, United Kingdom
| | - Mariya Moosajee
- UCL Institute of Ophthalmology, London, United Kingdom.,The Francis Crick Institute, London, United Kingdom.,Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom.,Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
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Abstract
The development of the anterior pituitary gland occurs in distinct sequential developmental steps, leading to the formation of a complex organ containing five different cell types secreting six different hormones. During this process, the temporal and spatial expression of a cascade of signaling molecules and transcription factors plays a crucial role in organ commitment, cell proliferation, patterning, and terminal differentiation. The morphogenesis of the gland and the emergence of distinct cell types from a common primordium are governed by complex regulatory networks involving transcription factors and signaling molecules that may be either intrinsic to the developing pituitary or extrinsic, originating from the ventral diencephalon, the oral ectoderm, and the surrounding mesenchyme. Endocrine cells of the pituitary gland are organized into structural and functional networks that contribute to the coordinated response of endocrine cells to stimuli; these cellular networks are formed during embryonic development and are maintained or may be modified in adulthood, contributing to the plasticity of the gland. Abnormalities in any of the steps of pituitary development may lead to congenital hypopituitarism that includes a spectrum of disorders from isolated to combined hormone deficiencies including syndromic disorders such as septo-optic dysplasia. Over the past decade, the acceleration of next-generation sequencing has allowed for rapid analysis of the patient genome to identify novel mutations and novel candidate genes associated with hypothalmo-pituitary development. Subsequent functional analysis using patient fibroblast cells, and the generation of stem cells derived from patient cells, is fast replacing the need for animal models while providing a more physiologically relevant characterization of novel mutations. Furthermore, CRISPR-Cas9 as the method for gene editing is replacing previous laborious and time-consuming gene editing methods that were commonly used, thus yielding knockout cell lines in a fraction of the time. © 2020 American Physiological Society. Compr Physiol 10:389-413, 2020.
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Affiliation(s)
- Kyriaki S Alatzoglou
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK
| | - Louise C Gregory
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK
| | - Mehul T Dattani
- Genetics and Genomic Medicine Programme, UCL Great Ormond Street Institute of Child Health, University College London (UCL), London, UK
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30
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Li L, Cui YJ, Zou Y, Yang L, Yin X, Li B, Yan L. Genetic association study of SOX2 gene polymorphisms with high myopia in a Chinese population. Eur J Ophthalmol 2020; 31:734-739. [PMID: 32037877 DOI: 10.1177/1120672120904666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE The aim of this study is to investigate whether SOX2 gene variants were associated with high myopia in a Chinese population. METHODS This study is conducted using case-control association analysis. This study recruited 83 healthy controls (with binocular spherical equivalent between -0.50 and +0.50 D) and 117 high myopia cases (spherical equivalent > -6.00 D in both eyes). Three single-nucleotide polymorphisms were selected from HapMap database for genotyping by direct sequencing. Statistical software (SPSS 22.0) was used for statistical analysis. The chi-square test was used to examine the difference in the frequency between cases and controls. RESULTS Genotype distributions in the three single-nucleotide polymorphisms were all in accordance with the Hardy-Weinberg equilibrium. The differences of rs4575941 locus genotype frequency and allele frequency between the case group and the control group were statistically significant (p = .043 and p = .029, respectively). The rs4575941 allele G frequency in the high myopia group was significantly higher than that in the control group with an odds ratio value of 1.579. However, the value of a chi-square test for the trend was 0.029, and after Bonferroni test, the p value was .087. CONCLUSION In Chinese population, rs4575941 in SOX2 gene was likely to play some roles in the genetic susceptibility to high myopia; the rs4575941 allele G might be a risk gene for high myopia.
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Affiliation(s)
- Lan Li
- Department of Ophthalmology, Langzhong People's Hospital, Langzhong, China
| | - Ying Juan Cui
- Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
| | - Yunchun Zou
- Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Department of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, China
| | - Liyuan Yang
- Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Department of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, China
| | - Ximin Yin
- Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Department of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, China
| | - Bo Li
- Department of Ophthalmology, Affiliated Hospital of North Sichuan Medical College, Nanchong, China.,Department of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, China
| | - Liying Yan
- Department of Ophthalmology and Optometry, North Sichuan Medical College, Nanchong, China.,Department of Ophthalmology, Suining Central Hospital, Suining, China
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31
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Rahhal MN, Kassem LS. AN UNEXPECTED COMBINATION OF PROLACTINOMA AND SEPTO-OPTIC DYSPLASIA. AACE Clin Case Rep 2020; 5:e282-e286. [PMID: 31967053 DOI: 10.4158/accr-2019-0127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 05/14/2019] [Indexed: 11/15/2022] Open
Abstract
Objective To describe the unusual finding of pituitary adenoma in a patient with septo-optic dysplasia (SOD). Methods We describe the clinical presentation, biochemical and radiological evaluation, treatment, and outcomes of a patient with macroprolactinoma and previously undiagnosed SOD. Results A 41-year-old woman with optic nerve hypoplasia and growth hormone deficiency presented with new-onset galactorrhea, polyuria, and polydipsia. Physical exam was notable for bilateral galactorrhea. Laboratory workup showed a prolactin level of 176 μg/L (reference range is 6 to 20 μg/L), serum cortisol of 7.7 μg/dL (reference range is 5.0 to 20.0 μg/dL), and adrenocorticotropic hormone of 54 pg/mL (reference range is 0 to 46 pg/mL). Thyroid function and pituitary-gonadal axis testing were normal. Low-dose cosyntropin test showed a borderline cortisol response and persistently low adrenal androgens, suggestive of partial secondary adrenal insufficiency. A water deprivation test showed evidence of diabetes insipidus (DI). Magnetic resonance imaging of the sella showed a 1.0 × 1.0 × 1.5-cm mass compatible with pituitary adenoma, absence of septum pellucidum, and atrophy of the optic nerves.The patient was diagnosed with SOD with partial hypopituitarism and a concomitant macroprolactinoma of more recent onset resulting in DI. The patient was treated with cabergoline with good clinical and biochemical response including resolution of DI symptoms. Subsequent magnetic resonance imaging of the sella showed near resolution of the prolactinoma. Conclusion We conclude that a diagnosis of SOD should not exclude the possibility of a pituitary adenoma in the appropriate clinical context, and that the pattern of hormonal deficits in such a combination may be uncharacteristic of the deficits expected with pituitary adenoma alone.
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Basaran R, Gundogan D, Senol M, Bozdogan C, Gezen F, Sav A. THE EXPRESSION OF STEM CELL MARKERS (CD133, NESTIN, OCT4, SOX2) IN INVASIVE PITUITARY ADENOMAS. ACTA ENDOCRINOLOGICA-BUCHAREST 2020; 16:303-310. [PMID: 33363651 DOI: 10.4183/aeb.2020.303] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction The pituitary gland serves as the center of the endocrine system. Stem cells are typically found in a specialized microenvironment of the tissue, called the niche, which regulates their maintenance, self-renewal, fate determination, and reaction to external influences. The aim of this study is to elucidate the role of stem cells in the initiation, invasion, and progression of pituitary adenomas. Materials and methods All specimens were collected between January 2007 and April 2015. Radiological classification (invasiveness) for all cases was performed according to the Wilson-Hardy classification system. Immunohistochemical staining was performed to all specimens for CD133, Oct4, Sox2 and nestin. Results The study included 48 patients. Of 48 patients, 17 (35.4%) were male and 31 (64.6%) were female. Mean age is 47.10±14.14 (17-86 yrs.). According to the Wilson-Hardy classification system, 27 (56.3%) were non-invasive adenomas. There was no statistical significance between the expression of pituitary stem cell markers (CD133, OCT4, SOX2, nestin) and invasiveness. Conclusion All stem cell markers are stained extensively in pituitary adenomas, except for SOX2 which was stained weakly. However, there is no effect of stem cells on invasiveness of pituitary adenomas because we cannot find a difference of the staining level between invasive and non-invasive adenomas. Nestin was stained extensively in functional adenomas, especially for GH, PRL, and gonadotropin secreting adenomas. SOX2 was stained extensively for ACTH-secreting adenomas.
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Affiliation(s)
- R Basaran
- University of Medical Sciences, Sancaktepe Education and Research Hospital - Dept. of Neurosurgery, Istanbul, Turkey
| | - D Gundogan
- Istanbul Surgery Hospital - Dept. of Neurosurgery, Istanbul, Turkey
| | - M Senol
- Erzurum Bolge Education and Research Hospital - Dept. of Neurosurgery, Istanbul, Turkey
| | - C Bozdogan
- Aydin State Hospital - Neurosurgery, Aydin, Turkey
| | - F Gezen
- Medeniyet University Faculty of Medicine - Dept. of Neurosurgery, Istanbul, Turkey
| | - A Sav
- Yeditepe University - Pathology, Istanbul, Turkey
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Li X, Zhou W, Li X, Gao M, Ji S, Tian W, Ji G, Du J, Hao A. SOX19b regulates the premature neuronal differentiation of neural stem cells through EZH2-mediated histone methylation in neural tube development of zebrafish. Stem Cell Res Ther 2019; 10:389. [PMID: 31842983 PMCID: PMC6915949 DOI: 10.1186/s13287-019-1495-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 10/29/2019] [Accepted: 11/14/2019] [Indexed: 12/15/2022] Open
Abstract
Objective Neural tube defects (NTDs) are the most serious and common birth defects in the clinic. The SRY-related HMG box B1 (SoxB1) gene family has been implicated in different processes of early embryogenesis. Sox19b is a maternally expressed gene in the SoxB1 family that is found in the region of the presumptive central nervous system (CNS), but its role and mechanism in embryonic neural stem cells (NSCs) during neural tube development have not yet been explored. Considering that Sox19b is specific to bony fish, we intended to investigate the role and mechanism of Sox19b in neural tube development in zebrafish embryos. Material and methods Morpholino (MO) antisense oligonucleotides were used to construct a Sox19b loss-of-function zebrafish model. The phenotype and the expression of related genes were analysed by in situ hybridization and immunolabelling. Epigenetic modifications were detected by western blot and chromatin immunoprecipitation. Results In this study, we found that zebrafish embryos exhibited a reduced or even deleted forebrain phenotype after the expression of the Sox19b gene was inhibited. Moreover, we found for the first time that knockdown of Sox19b reduced the proliferation of NSCs; increased the transcription levels of Ngn1, Ascl1, HuC, Islet1, and cyclin-dependent kinase (CDK) inhibitors; and led to premature differentiation of NSCs. Finally, we found that knockdown of Sox19b decreased the levels of EZH2/H3K27me3 and decreased the level of H3K27me3 at the promoters of Ngn1 and ascl1a. Conclusion Together, our data demonstrate that Sox19b plays an essential role in early NSC proliferation and differentiation through EZH2-mediated histone methylation in neural tube development. This study established the role of transcription factor Sox19b and epigenetic factor EZH2 regulatory network on NSC development, which provides new clues and theoretical guidance for the clinical treatment of neural tube defects.
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Affiliation(s)
- Xian Li
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China.,Foot and Ankle Surgery Center of Shandong University and Department of Hand and Foot Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China
| | - Wenjuan Zhou
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Xinyue Li
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Ming Gao
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China.,National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Center for Reproductive Medicine, Shandong University, Jinan, China
| | - Shufang Ji
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Wenyu Tian
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Guangyu Ji
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Jingyi Du
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China
| | - Aijun Hao
- Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong Provincial Key Laboratory of Mental Disorders, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, China.
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Zhang DL, Blair MP, Zeid JL, Basith SST, Shapiro MJ. FEVR phenotype associated with septo-optic dysplasia. Ophthalmic Genet 2019; 40:449-452. [PMID: 31755341 DOI: 10.1080/13816810.2019.1660380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/19/2019] [Accepted: 08/11/2019] [Indexed: 10/25/2022]
Abstract
Background: Septo-optic dysplasia, also known as de Morsier syndrome, is a disorder of brain development characterized by optic nerve hypoplasia, hypopituitarism, and midline brain defects.Materials and Methods: Single retrospective case report.Results: An infant born at 38 5/7 weeks gestation age weighing 3125 g developed respiratory distress shortly after birth. Systemic findings included myocardial dysfunction, hypopituitarism, feeding intolerance, microphallus, and dysmorphic features. Eye examination revealed tractional retinal detachments and optic nerve hypoplasia. In addition, peripheral non-perfusion and peripheral neovascularization were consistent with Familial Exudative Vitreoretinopathy (FEVR) phenotype. MRI showed hypoplastic optic nerves, ectopic posterior pituitary with hypoplastic pituitary infundibulum, and slightly thin corpus callosum, diagnostic of septo-optic dysplasia. Genetic testing revealed no pathogenic variants and two variants of uncertain significance.Conclusion: FEVR findings can be associated with septo-optic dysplasia and may point to an etiologic connection between neural development and subsequent vascular development.
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Affiliation(s)
| | - Michael P Blair
- Retina Consultants Ltd., Des Plaines, Illinois, USA
- Department of Ophthalmology and Visual Science, University of Chicago, Chicago, Illinois, USA
| | - Janice L Zeid
- Department of Pediatric Ophthalmology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Syeda S T Basith
- Department of Pediatric Ophthalmology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
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35
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Fletcher PA, Smiljanic K, Maso Prévide R, Iben JR, Li T, Rokic MB, Sherman A, Coon SL, Stojilkovic SS. Cell Type- and Sex-Dependent Transcriptome Profiles of Rat Anterior Pituitary Cells. Front Endocrinol (Lausanne) 2019; 10:623. [PMID: 31620083 PMCID: PMC6760010 DOI: 10.3389/fendo.2019.00623] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 08/28/2019] [Indexed: 01/14/2023] Open
Abstract
Understanding the physiology and pathology of an organ composed of a variety of cell populations depends critically on genome-wide information on each cell type. Here, we report single-cell transcriptome profiling of over 6,800 freshly dispersed anterior pituitary cells from postpubertal male and female rats. Six pituitary-specific cell types were identified based on known marker genes and characterized: folliculostellate cells and hormone-producing corticotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. Also identified were endothelial and blood cells from the pituitary capillary network. The expression of numerous developmental and neuroendocrine marker genes in both folliculostellate and hormone-producing cells supports that they have a common origin. For several genes, the validity of transcriptome analysis was confirmed by qRT-PCR and single cell immunocytochemistry. Folliculostellate cells exhibit impressive transcriptome diversity, indicating their major roles in production of endogenous ligands and detoxification enzymes, and organization of extracellular matrix. Transcriptome profiles of hormone-producing cells also indicate contributions toward those functions, while also clearly demonstrating their endocrine function. This survey highlights many novel genetic markers contributing to pituitary cell type identity, sexual dimorphism, and function, and points to relationships between hormone-producing and folliculostellate cells.
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Affiliation(s)
- Patrick A. Fletcher
- Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Kosara Smiljanic
- Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Rafael Maso Prévide
- Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
| | - James R. Iben
- Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Tianwei Li
- Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Milos B. Rokic
- Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Arthur Sherman
- Laboratory of Biological Modeling, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Steven L. Coon
- Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Stanko S. Stojilkovic
- Section on Cellular Signaling, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD, United States
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36
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Valensi M, Goldman G, Marchant D, Van Den Berghe L, Jonet L, Daruich A, Robert MP, Krejci E, Klein C, Mascarelli F, Versaux-Botteri C, Moulin A, Putterman M, Guimiot F, Molina T, Terris B, Brémond-Gignac D, Behar-Cohen F, Abitbol MM. Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes. Graefes Arch Clin Exp Ophthalmol 2019; 257:2401-2427. [PMID: 31529323 DOI: 10.1007/s00417-019-04462-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/20/2019] [Accepted: 09/04/2019] [Indexed: 01/16/2023] Open
Abstract
PURPOSE This study was conducted in order to study Sostdc1 expression in rat and human developing and adult eyes. METHODS Using the yeast signal sequence trap screening method, we identified the Sostdc1 cDNA encoding a protein secreted by the adult rat retinal pigment epithelium. We determined by in situ hybridization, RT-PCR, immunohistochemistry, and western blot analysis Sostdc1 gene and protein expression in developing and postnatal rat ocular tissue sections. We also investigated Sostdc1 immunohistolocalization in developing and adult human ocular tissues. RESULTS We demonstrated a prominent Sostdc1 gene expression in the developing rat central nervous system (CNS) and eyes at early developmental stages from E10.5 days postconception (dpc) to E13 dpc. Specific Sostdc1 immunostaining was also detected in most adult cells of rat ocular tissue sections. We also identified the rat ocular embryonic compartments characterized by a specific Sostdc1 immunohistostaining and specific Pax6, Sox2, Otx2, and Vsx2 immunohistostaining from embryonic stages E10.5 to E13 dpc. Furthermore, we determined the localization of SOSTDC1 immunoreactivity in ocular tissue sections of developing and adult human eyes. Indeed, we detected SOSTDC1 immunostaining in developing and adult human retinal pigment epithelium (RPE) and neural retina (NR) as well as in several developing and adult human ocular compartments, including the walls of choroidal and scleral vessels. Of utmost importance, we observed a strong SOSTDC1 expression in a pathological ocular specimen of type 2 Peters' anomaly complicated by retinal neovascularization as well in the walls ofother pathological extra-ocular vessels. CONCLUSION: As rat Sostdc1 and human SOSTDC1 are dual antagonists of the Wnt/β-catenin and BMP signaling pathways, these results underscore the potential crucial roles of these pathways and their antagonists, such as Sostdc1 and SOSTDC1, in developing and adult mammalian normal eyes as well as in syndromic and nonsyndromic congenital eye diseases.
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Affiliation(s)
- Maud Valensi
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
| | - Gabrielle Goldman
- APHP, Service de Pathologie de L'Hôpital Cochin-Hôtel-Dieu, Université Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Dominique Marchant
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
- Sorbonne Paris Cité, UFR SMBH, Laboratoire Hypoxie et poumons, Université Paris 13, EA 2363, 93017, Bobigny, France
| | - Loïc Van Den Berghe
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
- Inserm UMR 1037, CRCT (Cancer Research Center of Toulouse), 31037, Toulouse, France
| | - Laurent Jonet
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
| | - Alejandra Daruich
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
- AP-HP, Hôpital Universitaire Necker-Enfants-Malades, Service d'Ophtalmologie, 149 rue de Sèvres, 75015, Paris, France
| | - Matthieu P Robert
- AP-HP, Hôpital Universitaire Necker-Enfants-Malades, Service d'Ophtalmologie, 149 rue de Sèvres, 75015, Paris, France
- COGnition and Action Group, UMR 8257, CNRS, Université Paris Descartes, Paris, France
| | - Eric Krejci
- COGnition and Action Group, UMR 8257, CNRS, Université Paris Descartes, Paris, France
| | - Christophe Klein
- Centre d'Imagerie Cellulaire et de Cytométrie (CICC), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6, Université Paris Descartes - Paris 5, UMR_S 1138, 75006, Paris, France
| | - Frédéric Mascarelli
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
| | - Claudine Versaux-Botteri
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
| | - Alexandre Moulin
- Département de Pathologie, Hôpital Ophtalmique Jules-Gonin , 15, avenue de France, 1004, Lausanne, Switzerland
| | - Marc Putterman
- APHP, Service de Pathologie de l'Hôpital Universitaire Necker-Enfants-Malades, Université Paris Descartes, 149 rue de Sèvres, 75015, Paris, France
| | - Fabien Guimiot
- Unité Fonctionnelle de Foeto-Pathologie, Hôpital Universitaire Robert Debré, 48 Boulevard Serrurier, 75019, Paris, France
| | - Thierry Molina
- APHP, Service de Pathologie de l'Hôpital Universitaire Necker-Enfants-Malades, Université Paris Descartes, 149 rue de Sèvres, 75015, Paris, France
| | - Benoît Terris
- APHP, Service de Pathologie de L'Hôpital Cochin-Hôtel-Dieu, Université Paris Descartes, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Dominique Brémond-Gignac
- AP-HP, Hôpital Universitaire Necker-Enfants-Malades, Service d'Ophtalmologie, 149 rue de Sèvres, 75015, Paris, France
| | - Francine Behar-Cohen
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France
- AP-HP, Service d'Ophtalmologie, Hôpital Universitaire Cochin-Hôtel-Dieu, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Marc M Abitbol
- Centre de Recherches des Cordeliers, UMR_S INSERM 1138, Equipe 17, Université Paris Descartes, 15 rue de l'école de médecine, 75006, Paris, France.
- AP-HP, Hôpital Universitaire Necker-Enfants-Malades, Service d'Ophtalmologie, 149 rue de Sèvres, 75015, Paris, France.
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Fernández-Marmiesse A, Pérez-Poyato MS, Fontalba A, Marco de Lucas E, Martínez MT, Cabero Pérez MJ, Couce ML. Septo-optic dysplasia caused by a novel FLNA splice site mutation: a case report. BMC MEDICAL GENETICS 2019; 20:112. [PMID: 31234783 PMCID: PMC6591933 DOI: 10.1186/s12881-019-0844-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Accepted: 06/05/2019] [Indexed: 12/22/2022]
Abstract
Background Septo-optic dysplasia (SOD), also known as de-Morsier syndrome, is a rare disorder characterized by any combination of optic nerve hypoplasia, pituitary gland hypoplasia, and midline abnormalities of the brain including absence of the septum pellucidum and corpus callosum dysgenesis. The variable presentation of SOD includes visual, neurologic, and/or hypothalamic-pituitary endocrine defects. The unclear aetiology of a large proportion of SOD cases underscores the importance of identifying novel SOD-associated genes. Case presentation To identify the disease-causing gene in a male infant with neonatal hypoglycaemia, dysmorphic features, and hypoplasia of the optic nerve and corpus callosum, we designed a targeted next-generation sequencing panel for brain morphogenesis defects. We identified a novel hemizygous deletion, c.6355 + 4_6355 + 5delAG, in intron 38 of the FLNA gene that the patient had inherited from his mother. cDNA studies showed that this variant results in the production of 3 aberrant FLNA transcripts, the most abundant of which results in retention of intron 38 of FLNA. Conclusions We report for the first time a case of early-onset SOD associated with a mutation in the FLNA gene. This finding broadens the spectrum of genetic causes of this rare disorder and expands the phenotypic spectrum of the FLNA gene.
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Affiliation(s)
- A Fernández-Marmiesse
- Unit for the Diagnosis and Treatment of Congenital Metabolic Diseases, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Galicia, Spain.
| | - M S Pérez-Poyato
- Pediatric Neurology Unit, Department of Pediatrics, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
| | - A Fontalba
- Department of Genetics, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
| | - E Marco de Lucas
- Department of Radiology, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
| | - M T Martínez
- Department of Genetics, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
| | - M J Cabero Pérez
- Pediatric Neurology Unit, Department of Pediatrics, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
| | - M L Couce
- Unit for the Diagnosis and Treatment of Congenital Metabolic Diseases, Clinical University Hospital of Santiago de Compostela, Health Research Institute of Santiago de Compostela, Santiago de Compostela, Galicia, Spain
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38
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Doan RN, Shin T, Walsh CA. Evolutionary Changes in Transcriptional Regulation: Insights into Human Behavior and Neurological Conditions. Annu Rev Neurosci 2019; 41:185-206. [PMID: 29986162 DOI: 10.1146/annurev-neuro-080317-062104] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Understanding the biological basis for human-specific cognitive traits presents both immense challenges and unique opportunities. Although the question of what makes us human has been investigated with several different methods, the rise of comparative genomics, epigenomics, and medical genetics has provided tools to help narrow down and functionally assess the regions of the genome that seem evolutionarily relevant along the human lineage. In this review, we focus on how medical genetic cases have provided compelling functional evidence for genes and loci that appear to have interesting evolutionary signatures in humans. Furthermore, we examine a special class of noncoding regions, human accelerated regions (HARs), that have been suggested to show human-lineage-specific divergence, and how the use of clinical and population data has started to provide functional information to examine these regions. Finally, we outline methods that provide new insights into functional noncoding sequences in evolution.
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Affiliation(s)
- Ryan N Doan
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Boston, Massachusetts 02115, USA.,Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA
| | - Taehwan Shin
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Boston, Massachusetts 02115, USA
| | - Christopher A Walsh
- Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts 02115, USA; .,Allen Discovery Center for Human Brain Evolution, Boston Children's Hospital, Boston, Massachusetts 02115, USA.,Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA.,Departments of Pediatrics and Neurology, Harvard Medical School, Boston, Massachusetts 02138, USA
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39
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Capatina C, Cimpean AM, Raica M, Coculescu M, Poiana C. SOX 2 Expression in Human Pituitary Adenomas-Correlations With Pituitary Function. In Vivo 2019; 33:79-83. [PMID: 30587606 PMCID: PMC6364058 DOI: 10.21873/invivo.11442] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 10/06/2018] [Accepted: 10/08/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND/AIM The aim of this study was to evaluate SOX2 expression in pituitary adenomas and its correlation to their secretory state and clinicopathological parameters. PATIENTS AND METHODS Thirty-four patients were clinically evaluated and surgery was recommended for tumor removal. Histopathological diagnosis by hematoxylin eosin staining was followed by immunohistochemistry for pituitary hormones and SOX2 co-expression. RESULTS Fourteen of the 34 cases were GH-secreting adenomas, 10 were prolactinomas and 10 non-functioning pituitary adenomas. SOX2-positive expression was detected in 47.05% of total cases: 8 GH-secreting adenomas (57.14%), 6 prolactinomas (60%) and 2 non-functioning adenomas (20%). SOX2 positivity was significantly higher amongst secreting adenomas (p=0.041). SOX2-negative tumors were significantly associated with corticotrophin deficiency (p=0.047) and gonadotrophin deficiency (p=0.041). No correlation with tumor size or extrasellar extension was detected. CONCLUSION SOX2 is differentially expressed in pituitary adenomas and influences the secretory state or clinical behavior of pituitary adenomas.
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Affiliation(s)
- Cristina Capatina
- Endocrinology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- CI Parhon National Institute of Endocrinology, Bucharest, Romania
| | - Anca Maria Cimpean
- Department of Microscopic Morphology/Histology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Marius Raica
- Department of Microscopic Morphology/Histology, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania
| | - Mihail Coculescu
- Endocrinology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- CI Parhon National Institute of Endocrinology, Bucharest, Romania
| | - Catalina Poiana
- Endocrinology Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
- CI Parhon National Institute of Endocrinology, Bucharest, Romania
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40
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Blackburn PR, Chacon-Camacho OF, Ortiz-González XR, Reyes M, Lopez-Uriarte GA, Zarei S, Bhoj EJ, Perez-Solorzano S, Vaubel RA, Murphree MI, Nava J, Cortes-Gonzalez V, Parisi JE, Villanueva-Mendoza C, Tirado-Torres IG, Li D, Klee EW, Pichurin PN, Zenteno JC. Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma. Am J Med Genet A 2018; 176:2710-2719. [PMID: 30450772 DOI: 10.1002/ajmg.a.40644] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/26/2018] [Accepted: 09/04/2018] [Indexed: 01/05/2023]
Abstract
SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.
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Affiliation(s)
- Patrick R Blackburn
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Health Sciences Research, Rochester, Minnesota
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Oscar F Chacon-Camacho
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Xilma R Ortiz-González
- Department of Pediatrics, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
- Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mariana Reyes
- Department of Genetics, Hospital "Dr. Luis Sánchez Bulnes", Asociación para Evitar la Ceguera en México, Mexico City, Mexico
| | - Graciela A Lopez-Uriarte
- Genetics Department, University Hospital "Dr. José Eleuterio González" and Medical School, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Shabnam Zarei
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | - Elizabeth J Bhoj
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Sofia Perez-Solorzano
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Rachael A Vaubel
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Jessica Nava
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | - Vianney Cortes-Gonzalez
- Department of Genetics, Hospital "Dr. Luis Sánchez Bulnes", Asociación para Evitar la Ceguera en México, Mexico City, Mexico
| | - Joseph E Parisi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Cristina Villanueva-Mendoza
- Department of Genetics, Hospital "Dr. Luis Sánchez Bulnes", Asociación para Evitar la Ceguera en México, Mexico City, Mexico
| | - Iris G Tirado-Torres
- Genetics Department, University Hospital "Dr. José Eleuterio González" and Medical School, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Dong Li
- Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Eric W Klee
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
- Department of Health Sciences Research, Rochester, Minnesota
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
| | - Pavel N Pichurin
- Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota
| | - Juan C Zenteno
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
- Department of Biochemistry, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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41
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Wollenzien H, Voigt E, Kareta MS. Somatic Pluripotent Genes in Tissue Repair, Developmental Disease, and Cancer. SPG BIOMED 2018; 1. [PMID: 31172135 DOI: 10.32392/biomed.18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Embryonic stem cells possess the ability to differentiate into all cell types of the body. This pliable developmental state is achieved by the function of a series of pluripotency factors, classically identified as OCT4, SOX2, and NANOG. These pluripotency factors are responsible for activating the larger pluripotency networks and the self-renewal programs which give ES cells their unique characteristics. However, during differentiation pluripotency networks become downregulated as cells achieve greater lineage specification and exit the cell cycle. Typically the repression of pluripotency is viewed as a positive factor to ensure the fidelity of cellular identity by restricting cellular pliancy. Consistent with this view, the expression of pluripotency factors is greatly restricted in somatic cells. However, there are examples whereby cells either maintain or reactivate pluripotency factors to preserve the increased potential for the healing of wounds or tissue homeostasis. Additionally there are many examples where these pluripotency factors become reactivated in a variety of human pathologies, particularly cancer. In this review, we will summarize the somatic repression of pluripotency factors, their role in tissue homeostasis and wound repair, and the human diseases that are associated with pluripotency factor misregulation with an emphasis on their role in the etiology of multiple cancers.
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Affiliation(s)
- Hannah Wollenzien
- Genetics and Genomics Group, Cellular Therapies and Stem Cell Biology Group, and the Cancer Biology and Immunotherapies Group, Sanford Research, 2301 East 60th Street North, Sioux Falls, SD 57104, USA.,Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St. Vermillion, SD 57069, USA
| | - Ellen Voigt
- Genetics and Genomics Group, Cellular Therapies and Stem Cell Biology Group, and the Cancer Biology and Immunotherapies Group, Sanford Research, 2301 East 60th Street North, Sioux Falls, SD 57104, USA
| | - Michael S Kareta
- Genetics and Genomics Group, Cellular Therapies and Stem Cell Biology Group, and the Cancer Biology and Immunotherapies Group, Sanford Research, 2301 East 60th Street North, Sioux Falls, SD 57104, USA.,Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, 414 E. Clark St. Vermillion, SD 57069, USA.,Department of Pediatrics, Sanford School of Medicine, 1400 W. 22nd St., Sioux Falls, SD 57105, USA.,Department of Chemistry and Biochemistry, South Dakota State University, 1175 Medary Ave, Brookings, SD 57006, USA
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Murray PG, Stevens A, De Leonibus C, Koledova E, Chatelain P, Clayton PE. Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency. JCI Insight 2018; 3:93247. [PMID: 29618660 DOI: 10.1172/jci.insight.93247] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 02/28/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis. METHODS Prepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets. Whole blood gene expression was correlated with peak growth hormone (GH) using rank regression and a random forest algorithm tested for prediction of the presence of GHD and in classification of GHD as severe (peak GH <4 μg/l) and nonsevere (peak ≥4 μg/l). Performance was assessed using area under the receiver operating characteristic curve (AUC-ROC). RESULTS Rank regression identified 347 probe sets in which gene expression correlated with peak GH concentrations (r = ± 0.28, P < 0.01). These 347 probe sets yielded an AUC-ROC of 0.95 for prediction of GHD status versus controls and an AUC-ROC of 0.93 for prediction of GHD severity. CONCLUSION This study demonstrates highly accurate diagnosis and disease classification for GHD using a combination of transcriptomics and random forest analysis. TRIAL REGISTRATION NCT00256126 and NCT00699855. FUNDING Merck and the National Institute for Health Research (CL-2012-06-005).
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Affiliation(s)
- Philip G Murray
- Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom.,Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Adam Stevens
- Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Chiara De Leonibus
- Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Ekaterina Koledova
- Global Medical Affairs Endocrinology, Global Medical, Safety & CMO Office, Merck KGaA, Darmstadt, Germany
| | - Pierre Chatelain
- Department Pediatrie, Hôpital Mère-Enfant - Université Claude Bernard, Lyon, France
| | - Peter E Clayton
- Division of Developmental Biology and Medicine, Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom.,Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
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Vidya NG, Rajkumar S, Vasavada AR. Genetic investigation of ocular developmental genes in 52 patients with anophthalmia/microphthalmia. Ophthalmic Genet 2018; 39:344-352. [DOI: 10.1080/13816810.2018.1436184] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Nair Gopinathan Vidya
- Department of Molecular Genetics & Biochemistry, Iladevi Cataract & IOL Research Centre, Ahmedabad, India
- Research scholar, Manipal University, Karnataka
| | - Sankaranarayanan Rajkumar
- Department of Molecular Genetics & Biochemistry, Iladevi Cataract & IOL Research Centre, Ahmedabad, India
| | - Abhay R. Vasavada
- Department of Cataract and Refractive Surgery, Raghudeep Eye Hospital, Ahmedabad, India
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44
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Errichiello E, Gorgone C, Giuliano L, Iadarola B, Cosentino E, Rossato M, Kurtas NE, Delledonne M, Mattina T, Zuffardi O. SOX2: Not always eye malformations. Severe genital but no major ocular anomalies in a female patient with the recurrent c.70del20 variant. Eur J Med Genet 2018; 61:335-340. [PMID: 29371155 DOI: 10.1016/j.ejmg.2018.01.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 11/29/2017] [Accepted: 01/19/2018] [Indexed: 10/18/2022]
Abstract
SOX2 variants have been identified in multiple patients with severe ocular anomalies and pituitary dysfunction, in addition to various systemic features. We investigated a 26-year-old female patient suffering from spastic paraparesis, hypoplasia of corpus callosum, hypogonadotropic hypogonadism (HH) and intellectual disability, who was monitored for over 20 years, allowing a detailed genotype-phenotype correlation along time. Whole exome sequencing on the patient and her relatives identified a de novo SOX2 c.70del20 variant, which has been frequently reported in individuals with SOX2-related anophthalmia. Importantly, our patient lacked major ocular phenotype but showed vaginal agenesis, a feature never reported before. Although the involvement of male urogenital tract (cryptorchidism, hypospadias, small penis), is a well known consequence of SOX2 variants, their effect on the female genitalia has never been properly addressed, even considering the paradoxical female excess of SOX2 cases in the literature. Our findings emphasize the importance of testing for SOX2 variants in individuals with HH and genital anomalies even though anophthalmia or microphthalmia are not observed. Moreover, our case strengthens the role of SOX2 as a master regulator of female gonadal differentiation, as widely demonstrated for other SOX genes related to 46, XX sex reversal, such as SOX3 and SOX9.
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Affiliation(s)
| | - Cristina Gorgone
- Speciality School of Medical Genetics, University of Catania, Catania, Italy
| | - Loretta Giuliano
- Department of Medical and Surgical Sciences and Advanced Technologies "G.F. Ingrassia", University of Catania, Catania, Italy
| | - Barbara Iadarola
- Department of Biotechnologies, University of Verona, Verona, Italy
| | | | - Marzia Rossato
- Department of Biotechnologies, University of Verona, Verona, Italy
| | | | | | - Teresa Mattina
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Orsetta Zuffardi
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
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Levchenko A, Kanapin A, Samsonova A, Gainetdinov RR. Human Accelerated Regions and Other Human-Specific Sequence Variations in the Context of Evolution and Their Relevance for Brain Development. Genome Biol Evol 2018; 10:166-188. [PMID: 29149249 PMCID: PMC5767953 DOI: 10.1093/gbe/evx240] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2017] [Indexed: 12/24/2022] Open
Abstract
The review discusses, in a format of a timeline, the studies of different types of genetic variants, present in Homo sapiens, but absent in all other primate, mammalian, or vertebrate species, tested so far. The main characteristic of these variants is that they are found in regions of high evolutionary conservation. These sequence variations include single nucleotide substitutions (called human accelerated regions), deletions, and segmental duplications. The rationale for finding such variations in the human genome is that they could be responsible for traits, specific to our species, of which the human brain is the most remarkable. As became obvious, the vast majority of human-specific single nucleotide substitutions are found in noncoding, likely regulatory regions. A number of genes, associated with these human-specific alleles, often through novel enhancer activity, were in fact shown to be implicated in human-specific development of certain brain areas, including the prefrontal cortex. Human-specific deletions may remove regulatory sequences, such as enhancers. Segmental duplications, because of their large size, create new coding sequences, like new functional paralogs. Further functional study of these variants will shed light on evolution of our species, as well as on the etiology of neurodevelopmental disorders.
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Affiliation(s)
- Anastasia Levchenko
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
| | - Alexander Kanapin
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
- Department of Oncology, University of Oxford, United Kingdom
| | - Anastasia Samsonova
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
- Department of Oncology, University of Oxford, United Kingdom
| | - Raul R Gainetdinov
- Institute of Translational Biomedicine, Saint Petersburg State University, Russia
- Skolkovo Institute of Science and Technology, Skolkovo, Moscow, Russia
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46
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Taboada X, Viñas A, Adrio F. Comparative expression patterns ofSox2andSox19genes in the forebrain of developing and adult turbot (Scophthalmus maximus). J Comp Neurol 2017; 526:899-919. [DOI: 10.1002/cne.24374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 12/04/2017] [Accepted: 12/04/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Xoana Taboada
- Department of Zoology; Genetics and Physical Anthropology, CIBUS, Faculty of Biology, Universidade de Santiago de Compostela; Santiago de Compostela Spain
| | - Ana Viñas
- Department of Zoology; Genetics and Physical Anthropology, CIBUS, Faculty of Biology, Universidade de Santiago de Compostela; Santiago de Compostela Spain
| | - Fátima Adrio
- Department of Functional Biology, CIBUS, Faculty of Biology; Universidade de Santiago de Compostela; Santiago de Compostela Spain
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47
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Cox B, Roose H, Vennekens A, Vankelecom H. Pituitary stem cell regulation: who is pulling the strings? J Endocrinol 2017; 234:R135-R158. [PMID: 28615294 DOI: 10.1530/joe-17-0083] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 06/14/2017] [Indexed: 12/28/2022]
Abstract
The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.
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Affiliation(s)
- Benoit Cox
- Department of Development and RegenerationCluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven, Belgium
| | - Heleen Roose
- Department of Development and RegenerationCluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven, Belgium
| | - Annelies Vennekens
- Department of Development and RegenerationCluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven, Belgium
| | - Hugo Vankelecom
- Department of Development and RegenerationCluster of Stem Cell and Developmental Biology, Unit of Stem Cell Research, University of Leuven (KU Leuven), Leuven, Belgium
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Fang Q, George AS, Brinkmeier ML, Mortensen AH, Gergics P, Cheung LYM, Daly AZ, Ajmal A, Pérez Millán MI, Ozel AB, Kitzman JO, Mills RE, Li JZ, Camper SA. Genetics of Combined Pituitary Hormone Deficiency: Roadmap into the Genome Era. Endocr Rev 2016; 37:636-675. [PMID: 27828722 PMCID: PMC5155665 DOI: 10.1210/er.2016-1101] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 10/31/2016] [Indexed: 02/08/2023]
Abstract
The genetic basis for combined pituitary hormone deficiency (CPHD) is complex, involving 30 genes in a variety of syndromic and nonsyndromic presentations. Molecular diagnosis of this disorder is valuable for predicting disease progression, avoiding unnecessary surgery, and family planning. We expect that the application of high throughput sequencing will uncover additional contributing genes and eventually become a valuable tool for molecular diagnosis. For example, in the last 3 years, six new genes have been implicated in CPHD using whole-exome sequencing. In this review, we present a historical perspective on gene discovery for CPHD and predict approaches that may facilitate future gene identification projects conducted by clinicians and basic scientists. Guidelines for systematic reporting of genetic variants and assigning causality are emerging. We apply these guidelines retrospectively to reports of the genetic basis of CPHD and summarize modes of inheritance and penetrance for each of the known genes. In recent years, there have been great improvements in databases of genetic information for diverse populations. Some issues remain that make molecular diagnosis challenging in some cases. These include the inherent genetic complexity of this disorder, technical challenges like uneven coverage, differing results from variant calling and interpretation pipelines, the number of tolerated genetic alterations, and imperfect methods for predicting pathogenicity. We discuss approaches for future research in the genetics of CPHD.
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Affiliation(s)
- Qing Fang
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Akima S George
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Michelle L Brinkmeier
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Amanda H Mortensen
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Peter Gergics
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Leonard Y M Cheung
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Alexandre Z Daly
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Adnan Ajmal
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - María Ines Pérez Millán
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - A Bilge Ozel
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Jacob O Kitzman
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Ryan E Mills
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Jun Z Li
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
| | - Sally A Camper
- Department of Human Genetics (Q.F., A.S.G., M.L.B., A.H.M., P.G., L.Y.M.C., A.Z.D., M.I.P.M., A.B.O., J.O.K., R.E.M., J.Z.L., S.A.C.), Graduate Program in Bioinformatics (A.S.G.), Endocrine Division, Department of Internal Medicine (A.A.), and Department of Computational Medicine and Bioinformatics (J.O.K., R.E.M., J.Z.L.), University of Michigan, Ann Arbor, Michigan 48109
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Dennert N, Engels H, Cremer K, Becker J, Wohlleber E, Albrecht B, Ehret JK, Lüdecke HJ, Suri M, Carignani G, Renieri A, Kukuk GM, Wieland T, Andrieux J, Strom TM, Wieczorek D, Dieux-Coëslier A, Zink AM. De novo microdeletions and point mutations affecting SOX2 in three individuals with intellectual disability but without major eye malformations. Am J Med Genet A 2016; 173:435-443. [PMID: 27862890 DOI: 10.1002/ajmg.a.38034] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Accepted: 10/10/2016] [Indexed: 01/04/2023]
Abstract
Loss-of-function mutations and deletions of the SOX2 gene are known to cause uni- and bilateral anophthalmia and microphthalmia as well as related disorders such as anophthalmia-esophageal-genital syndrome. Thus, anophthalmia/microphthalmia is the primary indication for targeted, "phenotype first" analyses of SOX2. However, SOX2 mutations are also associated with a wide range of non-ocular abnormalities, such as postnatal growth retardation, structural brain anomalies, hypogenitalism, and developmental delay. The present report describes three patients without anophthalmia/microphthalmia and loss-of-function mutations or microdeletions of SOX2 who had been investigated in a "genotype first" manner due to intellectual disability/developmental delay using whole exome sequencing or chromosomal microarray analyses. This result prompted us to perform SOX2 Sanger sequencing in 192 developmental delay/intellectual disability patients without anophthalmia or microphthalmia. No additional SOX2 loss-of-function mutations were detected in this cohort, showing that SOX2 is clearly not a major cause of intellectual disability without anophthalmia/microphthalmia. In our three patients and four further, reported "genotype first" SOX2 microdeletion patients, anophthalmia/microphthalmia was present in less than half of the patients. Thus, SOX2 is another example of a gene whose clinical spectrum is broadened by the generation of "genotype first" findings using hypothesis-free, genome-wide methods. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nicola Dennert
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Hartmut Engels
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Kirsten Cremer
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Jessica Becker
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Eva Wohlleber
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Beate Albrecht
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Julia K Ehret
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Hermann-Josef Lüdecke
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.,Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Mohnish Suri
- Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, United Kingdom
| | | | | | - Guido M Kukuk
- Department of Radiology, University of Bonn, Bonn, Germany
| | - Thomas Wieland
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Joris Andrieux
- Laboratory of Medical Genetics, Hôpital Jeanne de Flandre University Hospital, Lille, France
| | - Tim M Strom
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Dagmar Wieczorek
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.,Institute of Human Genetics, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Anne Dieux-Coëslier
- Clinical Genetics, Hôpital Jeanne de France University Hospital, Lille, France
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50
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Doan RN, Bae BI, Cubelos B, Chang C, Hossain AA, Al-Saad S, Mukaddes NM, Oner O, Al-Saffar M, Balkhy S, Gascon GG, Nieto M, Walsh CA. Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior. Cell 2016; 167:341-354.e12. [PMID: 27667684 PMCID: PMC5063026 DOI: 10.1016/j.cell.2016.08.071] [Citation(s) in RCA: 228] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Revised: 05/18/2016] [Accepted: 08/26/2016] [Indexed: 12/15/2022]
Abstract
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.
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Affiliation(s)
- Ryan N Doan
- Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA
| | - Byoung-Il Bae
- Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA
| | - Beatriz Cubelos
- Department of Molecular Biology, Centro de Biología Molecular 'Severo Ochoa', Universidad Autonoma de Madrid, UAM-CSIC, Nicolas Cabrera 1, 28049 Madrid, Spain; Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CNB-CSIC, Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain
| | - Cindy Chang
- Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA
| | - Amer A Hossain
- Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA
| | | | - Nahit M Mukaddes
- Istanbul Institute of Child and Adolescent Psychiatry, 34365 Istanbul, Turkey
| | - Ozgur Oner
- Department of Child and Adolescent Psychiatry, Bahcesehir University School of Medicine, 34353 Istanbul, Turkey
| | - Muna Al-Saffar
- Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 17666, Al-Ain, United Arab Emirates
| | - Soher Balkhy
- Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah 21499, Kingdom of Saudi Arabia
| | - Generoso G Gascon
- Department of Neurology (Pediatric Neurology), Massachusetts General Hospital, Boston, MA 02114, USA
| | - Marta Nieto
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CNB-CSIC, Darwin 3, Campus de Cantoblanco, 28049 Madrid, Spain
| | - Christopher A Walsh
- Division of Genetics and Genomics, Manton Center for Orphan Disease Research, and Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.
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