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Huang Z, He C, Wang G, Zhu M, Tong X, Feng Y, Zhang C, Dong S, Harim Y, Liu HK, Zhou W, Lan F, Feng W. Mutation of CHD7 impairs the output of neuroepithelium transition that is reversed by the inhibition of EZH2. Mol Psychiatry 2025:10.1038/s41380-025-02990-6. [PMID: 40164694 DOI: 10.1038/s41380-025-02990-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 03/07/2025] [Accepted: 03/25/2025] [Indexed: 04/02/2025]
Abstract
Haploinsufficiency of CHD7 (Chromo-Helicase-DNA binding protein 7) causes a severe congenital disease CHARGE syndrome. Brain anomaly such as microcephaly and olfactory bulb agenesis seen in CHARGE patients have not been mimicked in previous animal models. Here, we uncover an indispensable function of CHD7 in the neuroepithelium (NE) but not in the neural stem cells (NSCs) after NE transition. Loss of Chd7 in mouse NE resulted in CHARGE-like brain anomalies due to reduced proliferation and differentiation of neural stem and progenitor cells, which were recapitulated in CHD7 KO human forebrain organoids. Mechanistically, we find that CHD7 activates neural transcription factors by removing the repressive histone mark H3K27me3 and promoting chromatin accessibility. Importantly, neurodevelopmental defects caused by CHD7 loss in human brain organoids and mice were ameliorated by the inhibition of H3K27me3 methyltransferase EZH2. Altogether, by implementing appropriate experimental models, we uncover the pathogenesis of CHD7-associated neurodevelopmental diseases, and identify a potential therapeutic opportunity for CHARGE syndrome.
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Affiliation(s)
- Zhuxi Huang
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Chenxi He
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Guangfu Wang
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Ming Zhu
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Xiaoyu Tong
- State Key Laboratory of Medical Neurobiology, Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, Fudan Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, China
| | - Yi Feng
- State Key Laboratory of Medical Neurobiology, Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institutes of Brain Science, Brain Science Collaborative Innovation Center, Fudan Institutes of Integrative Medicine, Fudan University, Shanghai, 200032, China
| | - Chenyang Zhang
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Shuhua Dong
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Yassin Harim
- Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, 69120, Germany
| | - Hai-Kun Liu
- Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, 69120, Germany
| | - Wenhao Zhou
- Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China
| | - Fei Lan
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Liver Cancer Institute, Zhongshan Hospital, Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
| | - Weijun Feng
- Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
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Akbari A, Kasak L, Laan M. Introduction to androgenetics: terminology, approaches, and impactful studies across 60 years. Andrology 2025. [PMID: 39780503 DOI: 10.1111/andr.13835] [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: 05/28/2024] [Revised: 11/15/2024] [Accepted: 12/19/2024] [Indexed: 01/11/2025]
Abstract
Across six decades, androgenetics has consistently concentrated on discovering genetic causes and enhancing the molecular diagnostics of male infertility, disorders of sex development, and their broader implications on health, such as cancer and other comorbidities. Despite vast clinical knowledge, the training of andrologists often lacks fundamental basics in medical genetics. This work, as part of the Special Issue of Andrology "Genetics in Andrology", provides the core terminology in medical genetics and technological advancements in genomics, required to understand the ever-progressing research in the field. It also gives an overview of study designs and approaches that have frequently led to discoveries in androgenetics. The rapid progress in the methodological toolbox in human genetics is illustrated by numerous examples of impactful androgenetic studies over 60 years, and their clinical implications.
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Affiliation(s)
- Arvand Akbari
- Center for Embryonic Cell & Gene Therapy, Oregon Health & Science University, Portland, Oregon, USA
| | - Laura Kasak
- Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Maris Laan
- Chair of Human Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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Carriço JN, Gonçalves CI, Aragüés JM, Lemos MC. Kallmann Syndrome: Functional Analysis of a CHD7 Missense Variant Shows Aberrant RNA Splicing. Int J Mol Sci 2024; 25:12061. [PMID: 39596130 PMCID: PMC11594180 DOI: 10.3390/ijms252212061] [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: 10/17/2024] [Revised: 11/03/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Kallmann syndrome is a rare disorder characterized by hypogonadotropic hypogonadism and an impaired sense of smell (anosmia or hyposmia) caused by congenital defects in the development of the gonadotropin-releasing hormone (GnRH) and olfactory neurons. Mutations in several genes have been associated with Kallmann syndrome. However, genetic testing of this disorder often reveals variants of uncertain significance (VUS) that remain uninterpreted without experimental validation. The aim of this study was to analyze the functional consequences of a heterozygous missense VUS in the CHD7 gene (c.4354G>T, p.Val1452Leu), in a patient with Kallmann syndrome with reversal of hypogonadism. The variant, located in the first nucleotide of exon 19, was analyzed using minigene assays to determine its effect on ribonucleic acid (RNA) splicing. These showed that the variant generates two different transcripts: a full-length transcript with the missense change (p.Val1452Leu), and an abnormally spliced transcript lacking exon 19. The latter results in an in-frame deletion (p.Val1452_Lys1511del) that disrupts the helicase C-terminal domain of the CHD7 protein. The variant was reclassified as likely pathogenic. These findings demonstrate that missense variants can exert more extensive effects beyond simple amino acid substitutions and underscore the critical role of functional analyses in VUS reclassification and genetic diagnosis.
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Affiliation(s)
- Josianne Nunes Carriço
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal
| | - Catarina Inês Gonçalves
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal
| | - José Maria Aragüés
- Serviço de Endocrinologia, Diabetes e Metabolismo, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, 1649-028 Lisboa, Portugal
| | - Manuel Carlos Lemos
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506 Covilhã, Portugal
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Hendricks EL, Linskey N, Smith IR, Liebl FLW. Kismet/CHD7/CHD8 and Amyloid Precursor Protein-like Regulate Synaptic Levels of Rab11 at the Drosophila Neuromuscular Junction. Int J Mol Sci 2024; 25:8429. [PMID: 39125997 PMCID: PMC11313043 DOI: 10.3390/ijms25158429] [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: 07/07/2024] [Revised: 07/27/2024] [Accepted: 07/31/2024] [Indexed: 08/12/2024] Open
Abstract
The transmembrane protein β-amyloid precursor protein (APP) is central to the pathophysiology of Alzheimer's disease (AD). The β-amyloid hypothesis posits that aberrant processing of APP forms neurotoxic β-amyloid aggregates, which lead to the cognitive impairments observed in AD. Although numerous additional factors contribute to AD, there is a need to better understand the synaptic function of APP. We have found that Drosophila APP-like (APPL) has both shared and non-shared roles at the synapse with Kismet (Kis), a chromatin helicase binding domain (CHD) protein. Kis is the homolog of CHD7 and CHD8, both of which are implicated in neurodevelopmental disorders including CHARGE Syndrome and autism spectrum disorders, respectively. Loss of function mutations in kis and animals expressing human APP and BACE in their central nervous system show reductions in the glutamate receptor subunit, GluRIIC, the GTPase Rab11, and the bone morphogenetic protein (BMP), pMad, at the Drosophila larval neuromuscular junction (NMJ). Similarly, processes like endocytosis, larval locomotion, and neurotransmission are deficient in these animals. Our pharmacological and epistasis experiments indicate that there is a functional relationship between Kis and APPL, but Kis does not regulate appl expression at the larval NMJ. Instead, Kis likely influences the synaptic localization of APPL, possibly by promoting rab11 transcription. These data identify a potential mechanistic connection between chromatin remodeling proteins and aberrant synaptic function in AD.
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Affiliation(s)
| | | | | | - Faith L. W. Liebl
- Department of Biological Sciences, Southern Illinois University Edwardsville, Edwardsville, IL 62026, USA
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Poch A, Dougherty MP, Roman RA, Chorich L, Hawkins Z, Kim SH, Kim HG, Layman LC. Prevalence of pathogenic variants and digenic disease in patients diagnosed with normosmic hypogonadotropic hypogonadism/Kallmann Syndrome. Mol Cell Endocrinol 2024; 589:112224. [PMID: 38593951 DOI: 10.1016/j.mce.2024.112224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/26/2024] [Accepted: 03/29/2024] [Indexed: 04/11/2024]
Abstract
BACKGROUND Hypogonadotropic hypogonadism (HH) is due to impaired gonadotropin releasing hormone (GnRH) action resulting in absent puberty and infertility. At least 44 genes have been identified to possess genetic variants in 40-50% of nHH/KS, and 2-20% have presumed digenic disease, but not all variants have been characterized in vitro. HYPOTHESIS The prevalence of pathogenic (P)/likely pathogenic (LP) variants in monogenic and digenic nHH/KS is lower than reported. DESIGN Cross-sectional study. SETTING University Research Laboratory. SUBJECTS 158 patients with nHH/KS. METHODS Exome sequencing (ES) was performed and variants were filtered for 44 known genes using Varsome and confirmed by Sanger Sequencing. MAIN OUTCOME MEASURES P/LP variants in nHH/KS genes. RESULTS ES resulted in >370,000 variants, from which variants in 44 genes were filtered. Thirty-one confirmed P/LP variants in 10 genes (ANOS1, CHD7, DUSP6, FGFR1, HS6ST1, KISS1, PROKR2, SEMA3A, SEMA3E, TACR3), sufficient to cause disease, were identified in 30/158 (19%) patients. Only 2/158 (1.2%) patients had digenic variant combinations: a male with hemizygous ANOS1 and heterozygous TACR3 variants and a male with heterozygous SEMA3A and SEMA3E variants. Two patients (1.2%) had compound heterozygous GNRHR (autosomal recessive) variants-one P and one variant of uncertain significance (VUS). Five patients (3.2%) had heterozygous P/LP variants in either GNRHR or TACR3 (both autosomal recessive), but no second variant. CONCLUSION Our prevalence of P/LP variants in nHH/KS was 19%, and digenicity was observed in 1.2%. These findings are less than those previously reported, and probably represent a more accurate estimation since VUS are not included.
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Affiliation(s)
- Alexandra Poch
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA.
| | - Michael P Dougherty
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Robert A Roman
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Lynn Chorich
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Zoe Hawkins
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Soo-Hyun Kim
- Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
| | - Hyung-Goo Kim
- Neurological Disorders Research Center, Qatar Biomedical Research Center, Hamad Bin Khalifa University, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Lawrence C Layman
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Medical College of Georgia at Augusta University, Augusta, GA, USA; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia at Augusta University, Augusta, GA, USA; Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, USA
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Shan Y, Yao L, Li L, Gao X, Jiang J. A novel CHD7 variant in a chinese family with CHARGE syndrome. Genes Genomics 2024; 46:379-387. [PMID: 37273125 DOI: 10.1007/s13258-023-01411-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 05/29/2023] [Indexed: 06/06/2023]
Abstract
OBJECTIVE CHARGE syndrome is a rare autosomal dominant (AD) multi-system disorder with a broad and variable clinical manifestation and occurs in approximately 1/10,000 newborns in the world. Mutations in the CHD7 gene are the genetic cause of over 90% of patients with typical CHARGE syndrome. The present study reported a novel variant in the CHD7 gene in a Chinese family with an abnormal fetus. METHODS Routine prenatal ultrasound screening showed fetal heart abnormality and left foot varus. Chromosomal microarray analysis (CMA) and fetus-parent whole-exome sequencing (trio-WES) were performed to determine the genetic cause of the fetus. The candidate variant was further verified using Sanger sequencing. RESULTS CMA analysis revealed normal results. However, WES analysis identified a de novo heterozygous variant of c.2919_2922del (NM_017780.4) on exon 11 of CHD7 gene, resulting in a premature truncation of the CHD7 protein (p.Gly975*). The variant was classified as Pathogenic (PVS1 + PS2_Moderate + PM2_Supporting) based on the ACMG guidelines. Combined with the clinical phenotype of fetal heart abnormalities, it was confirmed CHARGE syndrome. CONCLUSION We identified a novel heterozygous variant c.2919_2922del in CHD7 of a Chinese fetus with CHARGE syndrome, enriching the genotype-phenotype spectrum of CHD7. These results suggest that genetic testing could help facilitate prenatal diagnosis of CHARGE syndrome, thus promoting the appropriate genetic counseling.
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Affiliation(s)
- Yanhong Shan
- Department of Obstetrics, the First Hospital of Jilin University, Changchun, Jilin, 130061, China
| | - LingFang Yao
- Department of Obstetrics, Huangshi love and health hospital, Huangshi, Hubei, 435002, China.
| | - Linli Li
- Department of Obstetrics, the First Hospital of Jilin University, Changchun, Jilin, 130061, China
| | - Xueping Gao
- Yinfeng Gene Technology Co., Ltd, Jinan, Shandong, 250000, China
| | - Jinghan Jiang
- Yinfeng Gene Technology Co., Ltd, Jinan, Shandong, 250000, China
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Wang T, Ren W, Fu F, Wang H, Li Y, Duan J. Digenic CHD7 and SMCHD1 inheritance Unveils phenotypic variability in a family mainly presenting with hypogonadotropic hypogonadism. Heliyon 2024; 10:e23272. [PMID: 38148819 PMCID: PMC10750161 DOI: 10.1016/j.heliyon.2023.e23272] [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: 09/20/2023] [Revised: 11/27/2023] [Accepted: 11/29/2023] [Indexed: 12/28/2023] Open
Abstract
Objectives CHARGE syndrome is a congenital hereditary condition involving multiple systems. Patients are easily misdiagnosed with idiopathic hypogonadotropic hypogonadism (IHH) due to the overlap of clinical manifestations. An accurate clinical diagnosis remains challenging when the predominant clinical manifestation resembles hypogonadotropic hypogonadism. Methods This original research is conducted based on the genetic finding and analysis of clinical cases. Whole-exome sequencing (WES) and in-silico analyse were performed on two sisters to investigate the pathogenesis in this family. Homology modelling was conducted to evaluate structural changes in the variants. Results WES and Sanger sequencing revealed two siblings carrying a nonsense mutation (NM_017780.4: c.115C > T) in exon 2 of CHD7 inherited from a mildly affected mother and a missense mutation (NM_015295.3: c.2582T > C) in exon 20 of SMCHD1 inherited from an asymptomatic father. The nonsense mutation in CHD7 was predicted to generate nonsense-mediated decay, whereas the missense mutation in SMCHD1 decreased protein stability. Conclusions We identified digenic CHD7 and SMCHD1 mutations in IHH-associated diseases for the first time and verified the synergistic role of oligogenic inheritance. It was also determined that WES is an effective tool for distinguishing diseases with overlapping features and establishing a molecular diagnosis for cases with digenic or oligogenic hereditary disorders, which is beneficial for timely treatment, and family genetic counseling.
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Affiliation(s)
- Tian Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wu Ren
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Fangfang Fu
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Hairong Wang
- Wuhan KDWS Biological Technology Co.,Ltd, Wuhan, 430000, China
| | - Yan Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Jie Duan
- Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, China
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Emmanouilidou E, Kosmara D, Papadaki E, Mastorodemos V, Constantoulakis P, Repa A, Christopoulou G, Kalpadakis C, Avgoustidis N, Thomas K, Boumpas D, Sidiropoulos P, Bertsias G. Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus: A Consequence of Patient-Intrinsic or -Extrinsic Factors? J Clin Med 2023; 12:6945. [PMID: 37959410 PMCID: PMC10647998 DOI: 10.3390/jcm12216945] [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: 10/04/2023] [Revised: 11/03/2023] [Accepted: 11/04/2023] [Indexed: 11/15/2023] Open
Abstract
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.
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Affiliation(s)
- Evgenia Emmanouilidou
- Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece; (E.E.); (D.K.)
| | - Despoina Kosmara
- Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece; (E.E.); (D.K.)
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology—Hellas, 71110 Heraklion, Greece
| | - Efrosini Papadaki
- Department of Radiology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece
- Computational Bio-Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology—Hellas, 71110 Heraklion, Greece
| | | | | | - Argyro Repa
- Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece; (E.E.); (D.K.)
| | | | - Christina Kalpadakis
- Department of Laboratory Hematology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece
| | - Nestor Avgoustidis
- Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece; (E.E.); (D.K.)
| | - Konstantinos Thomas
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Attikon University General Hospital, 12462 Chaidari, Greece
| | - Dimitrios Boumpas
- 4th Department of Internal Medicine, National and Kapodistrian University of Athens School of Medicine, Attikon University General Hospital, 12462 Chaidari, Greece
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Prodromos Sidiropoulos
- Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece; (E.E.); (D.K.)
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology—Hellas, 71110 Heraklion, Greece
| | - George Bertsias
- Rheumatology and Clinical Immunology, University Hospital of Heraklion and University of Crete Medical School, 71500 Heraklion, Greece; (E.E.); (D.K.)
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology—Hellas, 71110 Heraklion, Greece
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Roux I, Fenollar-Ferrer C, Lee HJ, Chattaraj P, Lopez IA, Han K, Honda K, Brewer CC, Butman JA, Morell RJ, Martin DM, Griffith AJ. CHD7 variants associated with hearing loss and enlargement of the vestibular aqueduct. Hum Genet 2023; 142:1499-1517. [PMID: 37668839 PMCID: PMC10511616 DOI: 10.1007/s00439-023-02581-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 06/20/2023] [Indexed: 09/06/2023]
Abstract
Enlargement of the endolymphatic sac, duct, and vestibular aqueduct (EVA) is the most common inner ear malformation identified in patients with sensorineural hearing loss. EVA is associated with pathogenic variants in SLC26A4. However, in European-Caucasian populations, about 50% of patients with EVA carry no pathogenic alleles of SLC26A4. We tested for the presence of variants in CHD7, a gene known to be associated with CHARGE syndrome, Kallmann syndrome, and hypogonadotropic hypogonadism, in a cohort of 34 families with EVA subjects without pathogenic alleles of SLC26A4. In two families, NM_017780.4: c.3553A > G [p.(Met1185Val)] and c.5390G > C [p.(Gly1797Ala)] were detected as monoallelic CHD7 variants in patients with EVA. At least one subject from each family had additional signs or potential signs of CHARGE syndrome but did not meet diagnostic criteria for CHARGE. In silico modeling of these two missense substitutions predicted detrimental effects upon CHD7 protein structure. Consistent with a role of CHD7 in this tissue, Chd7 transcript and protein were detected in all epithelial cells of the endolymphatic duct and sac of the developing mouse inner ear. These results suggest that some CHD7 variants can cause nonsyndromic hearing loss and EVA. CHD7 should be included in DNA sequence analyses to detect pathogenic variants in EVA patients. Chd7 expression and mutant phenotype data in mice suggest that CHD7 contributes to the formation or function of the endolymphatic sac and duct.
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Affiliation(s)
- Isabelle Roux
- Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA.
| | - Cristina Fenollar-Ferrer
- Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
- Laboratory of Molecular Genetics, NIDCD, NIH, Bethesda, MD, 20892, USA
| | - Hyun Jae Lee
- Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Parna Chattaraj
- Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - Ivan A Lopez
- The NIDCD National Temporal Laboratory at UCLA, Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA
| | - Kyungreem Han
- Laboratory of Membrane Biophysics, NHLBI, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Keiji Honda
- Department of Otorhinolaryngology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
| | - Carmen C Brewer
- Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
| | - John A Butman
- Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, 20892, USA
| | - Robert J Morell
- Genomics and Computational Biology Core, NIDCD, NIH, Bethesda, MD, 20892, USA
| | - Donna M Martin
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Andrew J Griffith
- Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, 20892, USA
- Department of Otolaryngology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
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10
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Kim HG. Editorial for the IJMS Special Issue on "Molecular Genetics of Autism and Intellectual Disability". Int J Mol Sci 2023; 24:10394. [PMID: 37373542 DOI: 10.3390/ijms241210394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Autism spectrum disorder (ASD), a neurodevelopmental illness that affects children at an early age with a global prevalence of 1%, is diagnosed based on clinical features such as social impairment, repetitive behaviors, and restricted interests [...].
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Affiliation(s)
- Hyung-Goo Kim
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
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11
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Obata Y, Takayama K, Nishikubo H, Tobimatsu A, Matsuda I, Uehara Y, Maruo Y, Sho H, Kosugi M, Yasuda T. Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report. BMC Endocr Disord 2023; 23:118. [PMID: 37231428 DOI: 10.1186/s12902-023-01373-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 05/14/2023] [Indexed: 05/27/2023] Open
Abstract
BACKGROUND Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. CASE PRESENTATION A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. CONCLUSIONS We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.
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Affiliation(s)
- Yoshinari Obata
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Kana Takayama
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Hideyuki Nishikubo
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Aoki Tobimatsu
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Izumi Matsuda
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Yuhei Uehara
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Yumiko Maruo
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Hiroyuki Sho
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Motohiro Kosugi
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan
| | - Tetsuyuki Yasuda
- Department of Diabetes and Endocrinology, Osaka Police Hospital, 10-31 Kitayama-Cho, Tennojiku, Osaka, 543-0035, Japan.
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12
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Cannarella R, Gusmano C, Condorelli RA, Bernini A, Kaftalli J, Maltese PE, Paolacci S, Dautaj A, Marceddu G, Bertelli M, La Vignera S, Calogero AE. Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series. Int J Mol Sci 2023; 24:ijms24087428. [PMID: 37108593 PMCID: PMC10138801 DOI: 10.3390/ijms24087428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/15/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Congenital hypogonadotropic hypogonadism (cHH)/Kallmann syndrome (KS) is a rare genetic disorder with variable penetrance and a complex inheritance pattern. Consequently, it does not always follow Mendelian laws. More recently, digenic and oligogenic transmission has been recognized in 1.5-15% of cases. We report the results of a clinical and genetic investigation of five unrelated patients with cHH/KS analyzed using a customized gene panel. Patients were diagnosed according to the clinical, hormonal, and radiological criteria of the European Consensus Statement. DNA was analyzed using next-generation sequencing with a customized panel that included 31 genes. When available, first-degree relatives of the probands were also analyzed to assess genotype-phenotype segregation. The consequences of the identified variants on gene function were evaluated by analyzing the conservation of amino acids across species and by using molecular modeling. We found one new pathogenic variant of the CHD7 gene (c.576T>A, p.Tyr1928) and three new variants of unknown significance (VUSs) in IL17RD (c.960G>A, p.Met320Ile), FGF17 (c.208G>A, p.Gly70Arg), and DUSP6 (c.434T>G, p.Leu145Arg). All were present in the heterozygous state. Previously reported heterozygous variants were also found in the PROK2 (c.163del, p.Ile55*), CHD7 (c.c.2750C>T, p.Thr917Met and c.7891C>T, p.Arg2631*), FLRT3 (c.1106C>T, p.Ala369Val), and CCDC103 (c.461A>C, p.His154Pro) genes. Molecular modeling, molecular dynamics, and conservation analyses were performed on three out of the nine variants identified in our patients, namely, FGF17 (p.Gly70Arg), DUSP6 (p.Leu145Arg), and CHD7 p.(Thr917Met). Except for DUSP6, where the L145R variant was shown to disrupt the interaction between β6 and β3, needed for extracellular signal-regulated kinase 2 (ERK2) binding and recognition, no significant changes were identified between the wild-types and mutants of the other proteins. We found a new pathogenic variant of the CHD7 gene. The molecular modeling results suggest that the VUS of the DUSP6 (c.434T>G, p.Leu145Arg) gene may play a role in the pathogenesis of cHH. However, our analysis indicates that it is unlikely that the VUSs for the IL17RD (c.960G>A, p.Met320Ile) and FGF17 (c.208G>A, p.Gly70Arg) genes are involved in the pathogenesis of cHH. Functional studies are needed to confirm this hypothesis.
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Affiliation(s)
- Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, Italy
| | - Carmelo Gusmano
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, Italy
| | - Rosita A Condorelli
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, Italy
| | - Andrea Bernini
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | | | | | | | | | | | - Matteo Bertelli
- Diagnostics Unit, MAGI EUREGIO, 39100 Bolzano, Italy
- Diagnostics Unit, MAGI'S LAB, 38068 Rovereto, Italy
| | - Sandro La Vignera
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, Italy
| | - Aldo E Calogero
- Department of Clinical and Experimental Medicine, University of Catania, Via S. Sofia 78, 95123 Catania, Italy
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13
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Vezzoli V, Hrvat F, Goggi G, Federici S, Cangiano B, Quinton R, Persani L, Bonomi M. Genetic architecture of self-limited delayed puberty and congenital hypogonadotropic hypogonadism. Front Endocrinol (Lausanne) 2023; 13:1069741. [PMID: 36726466 PMCID: PMC9884699 DOI: 10.3389/fendo.2022.1069741] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/09/2022] [Indexed: 01/18/2023] Open
Abstract
Distinguishing between self limited delayed puberty (SLDP) and congenital hypogonadotropic hypogonadism (CHH) may be tricky as they share clinical and biochemical characteristics. and appear to lie within the same clinical spectrum. However, one is classically transient (SDLP) while the second is typically a lifetime condition (CHH). The natural history and long-term outcomes of these two conditions differ significantly and thus command distinctive approaches and management. Because the first presentation of SDLP and CHH is very similar (delayed puberty with low LH and FSH and low sex hormones), the scientific community is scrambling to identify diagnostic tests that can allow a correct differential diagnosis among these two conditions, without having to rely on the presence or absence of phenotypic red flags for CHH that clinicians anyway seem to find hard to process. Despite the heterogeneity of genetic defects so far reported in DP, genetic analysis through next-generation sequencing technology (NGS) had the potential to contribute to the differential diagnostic process between SLDP and CHH. In this review we will provide an up-to-date overview of the genetic architecture of these two conditions and debate the benefits and the bias of performing genetic analysis seeking to effectively differentiate between these two conditions.
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Affiliation(s)
- Valeria Vezzoli
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Faris Hrvat
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Giovanni Goggi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Silvia Federici
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Biagio Cangiano
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Richard Quinton
- Department of Endocrinology, Diabetes & Metabolism, Newcastle-upon-Tyne Hospitals, Newcastle-upon-Tyne, United Kingdom
- Translational & Clinical Research Institute, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne, United Kingdom
| | - Luca Persani
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Marco Bonomi
- Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano, Milan, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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14
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Al Sayed Y, Howard SR. Panel testing for the molecular genetic diagnosis of congenital hypogonadotropic hypogonadism – a clinical perspective. Eur J Hum Genet 2022; 31:387-394. [PMID: 36517585 PMCID: PMC10133250 DOI: 10.1038/s41431-022-01261-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/16/2022] Open
Abstract
AbstractCongenital hypogonadotropic hypogonadism (CHH) is a rare endocrine disorder that results in reproductive hormone deficiency and reduced potential for fertility in adult life. Discoveries of the genetic aetiology of CHH have advanced dramatically in the past 30 years, with currently over 40 genes recognised to cause or contribute to the development of this condition. The genetic complexity of CHH is further increased by the observation of di- and oligogenic, as well as classic monogenic, inheritance and incomplete penetrance. Very recently in the UK, a panel of 14 genes has been curated for the genetic diagnosis of CHH within the NHS Genomic Medicine Service programme. The aim of this review is to appraise the advantages and potential pitfalls of the use of a CHH panel in clinical endocrine diagnostics, and to consider the future avenues for developing this panel including the potential of whole exome or whole genome sequencing data analysis in this condition.
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15
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Nie J, Ueda Y, Solivais AJ, Hashino E. CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids. Nat Commun 2022; 13:7053. [PMID: 36396635 PMCID: PMC9672366 DOI: 10.1038/s41467-022-34759-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 11/07/2022] [Indexed: 11/19/2022] Open
Abstract
Mutations in CHD7 cause CHARGE syndrome, affecting multiple organs including the inner ear in humans. We investigate how CHD7 mutations affect inner ear development using human pluripotent stem cell-derived organoids as a model system. We find that loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors. Further analysis of the mutant otic progenitors suggests that CHD7 can regulate otic genes through a chromatin remodeling-independent mechanism. Results from transcriptome profiling of hair cells reveal disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss. Notably, co-differentiating CHD7 knockout and wild-type cells in chimeric organoids partially rescues mutant phenotypes by restoring otherwise severely dysregulated otic genes. Taken together, our results suggest that CHD7 plays a critical role in regulating human otic lineage specification and hair cell differentiation.
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Affiliation(s)
- Jing Nie
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yoshitomo Ueda
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Alexander J Solivais
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Eri Hashino
- Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
- Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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16
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Saengkaew T, Howard SR. Genetics of pubertal delay. Clin Endocrinol (Oxf) 2022; 97:473-482. [PMID: 34617615 PMCID: PMC9543006 DOI: 10.1111/cen.14606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/29/2021] [Accepted: 10/04/2021] [Indexed: 12/23/2022]
Abstract
The timing of pubertal development is strongly influenced by the genetic background, and clinical presentations of delayed puberty are often found within families with clear patterns of inheritance. The discovery of the underlying genetic regulators of such conditions, in recent years through next generation sequencing, has advanced the understanding of the pathogenesis of disorders of pubertal timing and the potential for genetic testing to assist diagnosis for patients with these conditions. This review covers the significant advances in the understanding of the biological mechanisms of delayed puberty that have occurred in the last two decades.
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Affiliation(s)
- Tansit Saengkaew
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
- Endocrinology Unit, Department of Paediatrics, Faculty of MedicinePrince of Songkla UniversitySongkhlaThailand
| | - Sasha R. Howard
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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17
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The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism. JOURNAL OF ONCOLOGY 2022; 2022:7973726. [PMID: 36245975 PMCID: PMC9553531 DOI: 10.1155/2022/7973726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022]
Abstract
Background. Idiopathic hypogonadotropin hypogonadism (IHH) is caused by hypothalamic-pituitary-gonadal axis dysfunction. This is divided into Kallmann syndrome which has an impaired sense of smell and hypogonadotropin hypogonadism with normal olfactory (nIHH sense. Approximately 60% of patients are associated with Kallmann syndrome, whereas there are approximately 40% with hypogonadotropin hypogonadism (nIHH). This disease is associated with various variants in genes along with different phenotypic characteristics, and even those gene variations could also lead to the cancer formation in patients. So, current study has been designed to investigate and to better understand the characteristics of various IHH-associated genes and the correlation between IHH genes and phenotype. Methods. The cohort included 14 children with IHH (6 patients of KS and 8 patients of IHH), including 13 boys and 1 girl. Exclusion criteria are as follows: diagnosis of secondary hypogonadotropin hypogonadism due to tumor, trauma, drugs, or other systemic diseases. Clinical data and genetic results were analyzed. Results. Almost all male patients showed micropenis (12/13, 92.3%), and few of them had cryptorchidism (5/13, 41.7%). A total of 6 genes, CHD7, PROKR2, ANOS1, FGFR1, SEMA3A, and NDNF, were detected. CHD7 was the most common (11/17, 64.7%), and the main mutation type was missense mutation (14/16, 87.5%). Six reported variants and 10 new variants (5 genes, including entire ANSO1 duplicates) were found. Neonatal variation was detected in 3 patients with IHH. Eight patients inherited the variation from their father, while five patients inherited it from their mother. One patient had both FGFR1 and SEMA3A gene variants, while the other had two different CHD7 gene variants and entire ANSO1 repeats. According to ACMG criteria, 4 variants were pathogenic (P), 2 were possibly pathogenic (LP), and 8 had uncertain significance (US). In patients with P or LP (5/6, 83.3%), we found that extragonadal symptoms were more common. Conclusions. It was concluded that variations in the studied genes could lead to the IHH. Ten new variants have been reported which may lead to different symptoms of IHH. For CHD7 variants, the rare sequencing variants (RSVs) of P or LP showed commonly associated with CHARGE syndrome. Findings of the current study may help for the better diagnosis and treatment of IHH.
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18
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Liu Y, Zhi X. Advances in Genetic Diagnosis of Kallmann Syndrome and Genetic Interruption. Reprod Sci 2022; 29:1697-1709. [PMID: 34231173 PMCID: PMC9110439 DOI: 10.1007/s43032-021-00638-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/25/2021] [Indexed: 11/30/2022]
Abstract
Kallmann syndrome (KS) is a rare hereditary disease with high phenotypic and genetic heterogeneity. Congenital hypogonadotropic hypogonadism and hyposmia/anosmia are the two major characterized phenotypes of KS. Besides, mirror movements, dental agenesis, digital bone abnormalities, unilateral renal agenesis, midline facial defects, hearing loss, and eye movement abnormalities can also be observed in KS patients. Because of the phenotypic heterogeneity, genetic diagnosis become increasingly valuable to distinguish KS from other disorders including normosmic congenital hypogonadotropic hypogonadism, constitutional delay of growth and puberty, CHARGE syndrome, and functional hypogonadotropic hypogonadism. Application of next-generation sequencing has promoted the discovery of novel pathogenic genes in KS pedigrees. Prenatal diagnosis is an effective method in clinical settings to decrease birth defects and block transmission of genetic disorders. However, pregnant women may suffer from physical and psychological distress when fetuses are diagnosed with congenital defects. Preimplantation genetic testing (PGT) is a prospective approach during the in vitro fertilization process that helps to interrupt transmission of hereditary diseases to offspring at an early stage. Thus, genetic testing and counseling are recommended to KS patients with family histories, prenatal diagnosis and PGT are considered to be useful options.
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Affiliation(s)
- Yujun Liu
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China
- Key Laboratory of Assisted Reproduction (Peking University, Ministry of Education, Beijing, 100191, China
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China
| | - Xu Zhi
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China.
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China.
- Key Laboratory of Assisted Reproduction (Peking University, Ministry of Education, Beijing, 100191, China.
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, 100191, China.
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19
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Sánchez-Garrido MA, García-Galiano D, Tena-Sempere M. Early programming of reproductive health and fertility: novel neuroendocrine mechanisms and implications in reproductive medicine. Hum Reprod Update 2022; 28:346-375. [PMID: 35187579 PMCID: PMC9071071 DOI: 10.1093/humupd/dmac005] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/29/2021] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, environmental changes taking place during early maturational periods may alter normal development and predispose to the occurrence of diverse pathologies later in life. Indeed, adverse conditions during these critical developmental windows of high plasticity have been reported to alter the offspring developmental trajectory, causing permanent functional and structural perturbations that in the long term may enhance disease susceptibility. However, while solid evidence has documented that fluctuations in environmental factors, ranging from nutrient availability to chemicals, in early developmental stages (including the peri-conceptional period) have discernible programming effects that increase vulnerability to develop metabolic perturbations, the impact and eventual mechanisms involved, of such developmental alterations on the reproductive phenotype of offspring have received less attention. OBJECTIVE AND RATIONALE This review will summarize recent advances in basic and clinical research that support the concept of DOHaD in the context of the impact of nutritional and hormonal perturbations, occurring during the periconceptional, fetal and early postnatal stages, on different aspects of reproductive function in both sexes. Special emphasis will be given to the effects of early nutritional stress on the timing of puberty and adult gonadotropic function, and to address the underlying neuroendocrine pathways, with particular attention to involvement of the Kiss1 system in these reproductive perturbations. The implications of such phenomena in terms of reproductive medicine will also be considered. SEARCH METHODS A comprehensive MEDLINE search, using PubMed as main interface, of research articles and reviews, published mainly between 2006 and 2021, has been carried out. Search was implemented using multiple terms, focusing on clinical and preclinical data from DOHaD studies, addressing periconceptional, gestational and perinatal programming of reproduction. Selected studies addressing early programming of metabolic function have also been considered, when relevant. OUTCOMES A solid body of evidence, from clinical and preclinical studies, has documented the impact of nutritional and hormonal fluctuations during the periconceptional, prenatal and early postnatal periods on pubertal maturation, as well as adult gonadotropic function and fertility. Furthermore, exposure to environmental chemicals, such as bisphenol A, and maternal stress has been shown to negatively influence pubertal development and gonadotropic function in adulthood. The underlying neuroendocrine pathways and mechanisms involved have been also addressed, mainly by preclinical studies, which have identified an, as yet incomplete, array of molecular and neurohormonal effectors. These include, prominently, epigenetic regulatory mechanisms and the hypothalamic Kiss1 system, which likely contribute to the generation of reproductive alterations in conditions of early nutritional and/or metabolic stress. In addition to the Kiss1 system, other major hypothalamic regulators of GnRH neurosecretion, such as γ-aminobutyric acid and glutamate, may be targets of developmental programming. WIDER IMPLICATIONS This review addresses an underdeveloped area of reproductive biology and medicine that may help to improve our understanding of human reproductive disorders and stresses the importance, and eventual pathogenic impact, of early determinants of puberty, adult reproductive function and fertility.
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Affiliation(s)
- Miguel Angel Sánchez-Garrido
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
- Hospital Universitario Reina Sofia, Cordoba, Spain
| | - David García-Galiano
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
- Hospital Universitario Reina Sofia, Cordoba, Spain
| | - Manuel Tena-Sempere
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), Cordoba, Spain
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain
- Hospital Universitario Reina Sofia, Cordoba, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Cordoba, Spain
- Institute of Biomedicine, University of Turku, Turku, Finland
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20
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Liu C, Xiong Q, Li Q, Lin W, Jiang S, Zhang D, Wang Y, Duan X, Gong P, Kang N. CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling. Nat Commun 2022; 13:1989. [PMID: 35418650 PMCID: PMC9007978 DOI: 10.1038/s41467-022-29633-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 03/23/2022] [Indexed: 02/08/2023] Open
Abstract
Chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent eukaryotic chromatin remodeling enzyme, is essential for the development of organs. The mutation of CHD7 is the main cause of CHARGE syndrome, but its function and mechanism in skeletal system remain unclear. Here, we show conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and preosteoblasts leads to a pathological phenotype manifested as low bone mass and severely high marrow adiposity. Mechanistically, we identify enhancement of the peroxisome proliferator-activated receptor (PPAR) signaling in Chd7-deficient MSCs. Loss of Chd7 reduces the restriction of PPAR-γ and then PPAR-γ associates with trimethylated histone H3 at lysine 4 (H3K4me3), which subsequently activates the transcription of downstream adipogenic genes and disrupts the balance between osteogenic and adipogenic differentiation. Our data illustrate the pathological manifestations of Chd7 mutation in MSCs and reveal an epigenetic mechanism in skeletal health and diseases. CHD7 is chromatin remodeler and mutations of CHD7 are the main cause of CHARGE syndrome. Here the authors show that conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and pre-osteoblasts leads to a skeletal system development disorder in mice and upregulated PPAR signaling, disrupting the balance between osteogenic and adipogenic differentiation.
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Affiliation(s)
- Caojie Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Qiuchan Xiong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Qiwen Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Weimin Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Shuang Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Danting Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Yuan Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Xiaobo Duan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China.
| | - Ning Kang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, PR China.
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21
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Jofré DM, Hoffman DK, Cervino AS, Hahn GM, Grundy M, Yun S, Amrit FRG, Stolz DB, Godoy LF, Salvatore E, Rossi FA, Ghazi A, Cirio MC, Yanowitz JL, Hochbaum D. The CHARGE syndrome ortholog CHD-7 regulates TGF-β pathways in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2022; 119:e2109508119. [PMID: 35394881 PMCID: PMC9169646 DOI: 10.1073/pnas.2109508119] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 02/24/2022] [Indexed: 11/18/2022] Open
Abstract
CHARGE syndrome is a complex developmental disorder caused by mutations in the chromodomain helicase DNA-binding protein-7 (CHD7) and characterized by retarded growth and malformations in the heart and nervous system. Despite the public health relevance of this disorder, relevant cellular pathways and targets of CHD7 that relate to disease pathology are still poorly understood. Here we report that chd-7, the nematode ortholog of Chd7, is required for dauer morphogenesis, lifespan determination, stress response, and body size determination. Consistent with our discoveries, we found chd-7 to be allelic to scd-3, a previously identified dauer suppressor from the DAF-7/ tumor growth factor-β (TGF-β) pathway. Epistatic analysis places CHD-7 at the level of the DAF-3/DAF-5 complex, but we found that CHD-7 also directly impacts the expression of multiple components of this pathway. Transcriptomic analysis revealed that chd-7 mutants fail to repress daf-9 for execution of the dauer program. In addition, CHD-7 regulates the DBL-1/BMP pathway components and shares roles in male tail development and cuticle synthesis. To explore a potential conserved function for chd-7 in vertebrates, we used Xenopus laevis embryos, an established model to study craniofacial development. Morpholino-mediated knockdown of Chd7 led to a reduction in col2a1 messenger RNA (mRNA) levels, a collagen whose expression depends on TGF-β signaling. Both embryonic lethality and craniofacial defects in Chd7-depleted tadpoles were partially rescued by overexpression of col2a1 mRNA. We suggest that Chd7 has conserved roles in regulation of the TGF-β signaling pathway and pathogenic Chd7 could lead to a defective extracellular matrix deposition.
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Affiliation(s)
- Diego M. Jofré
- Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1053 Buenos Aires, Argentina
| | | | - Ailen S. Cervino
- Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1053 Buenos Aires, Argentina
| | - Gabriella M. Hahn
- Interdisciplinary Biomedical Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | | | - Sijung Yun
- Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20814
| | - Francis R. G. Amrit
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - Donna B. Stolz
- Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA 15213
| | - Luciana F. Godoy
- Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1053 Buenos Aires, Argentina
| | - Esteban Salvatore
- Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1053 Buenos Aires, Argentina
| | - Fabiana A. Rossi
- Instituto de Investigaciones en Medicina Traslacional, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Universidad Austral, B1630 Pilar, Argentina
| | - Arjumand Ghazi
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
- Department of Cell Biology & Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213
| | - M. Cecilia Cirio
- Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1053 Buenos Aires, Argentina
| | - Judith L. Yanowitz
- Magee-Womens Research Institute, Pittsburgh, PA 15213
- Department of Obstetrics, Gynecology & Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213
| | - Daniel Hochbaum
- Departamento de Biodiversidad y Biología Experimental, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1053 Buenos Aires, Argentina
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Sobrino V, Avendaño MS, Perdices-López C, Jimenez-Puyer M, Tena-Sempere M. Kisspeptins and the neuroendocrine control of reproduction: Recent progress and new frontiers in kisspeptin research. Front Neuroendocrinol 2022; 65:100977. [PMID: 34999056 DOI: 10.1016/j.yfrne.2021.100977] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/18/2021] [Accepted: 12/22/2021] [Indexed: 12/31/2022]
Abstract
In late 2003, a major breakthrough in our understanding of the mechanisms that govern reproduction occurred with the identification of the reproductive roles of kisspeptins, encoded by the Kiss1 gene, and their receptor, Gpr54 (aka, Kiss1R). The discovery of this unsuspected reproductive facet attracted an extraordinary interest and boosted an intense research activity, in human and model species, that, in a relatively short period, established a series of basic concepts on the physiological roles of kisspeptins. Such fundamental knowledge, gathered in these early years of kisspeptin research, set the scene for the more recent in-depth dissection of the intimacies of the neuronal networks involving Kiss1 neurons, their precise mechanisms of regulation and the molecular underpinnings of the function of kisspeptins as pivotal regulators of all key aspects of reproductive function, from puberty onset to pulsatile gonadotropin secretion and the metabolic control of fertility. While no clear temporal boundaries between these two periods can be defined, in this review we will summarize the most prominent advances in kisspeptin research occurred in the last ten years, as a means to provide an up-dated view of the state of the art and potential paths of future progress in this dynamic, and ever growing domain of Neuroendocrinology.
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Affiliation(s)
- Veronica Sobrino
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain; Hospital Universitario Reina Sofia, 14004 Cordoba, Spain
| | - Maria Soledad Avendaño
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain; Hospital Universitario Reina Sofia, 14004 Cordoba, Spain
| | - Cecilia Perdices-López
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain; Hospital Universitario Reina Sofia, 14004 Cordoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Cordoba, Spain
| | - Manuel Jimenez-Puyer
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain; Hospital Universitario Reina Sofia, 14004 Cordoba, Spain
| | - Manuel Tena-Sempere
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain; Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain; Hospital Universitario Reina Sofia, 14004 Cordoba, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Cordoba, Spain; Institute of Biomedicine, University of Turku, FIN-20520 Turku, Finland.
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23
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Kim JH, Choi Y, Hwang S, Kim GH, Yoo HW, Choi JH. Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings. Endocr Connect 2022; 11:e210522. [PMID: 35015700 PMCID: PMC8859950 DOI: 10.1530/ec-21-0522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 01/11/2022] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Heterozygous CHD7 mutations cause a broad spectrum of clinical phenotypes ranging from typical CHARGE syndrome to self-limited delayed puberty. This study aimed to investigate the clinical characteristics of endocrine dysfunction in patients with CHD7 mutations. METHODS The clinical features and endocrine findings from 30 patients with CHD7 variants were retrospectively reviewed. A diagnosis of CHARGE syndrome was based on the Verloes diagnostic criteria. RESULTS Seventeen patients fulfilled the criteria for typical CHARGE syndrome, one patient for partial/incomplete CHARGE, and the remaining eleven patients had atypical CHARGE syndrome. One patient was diagnosed with Kallmann syndrome and unilateral deafness. The most frequently observed features were inner ear anomalies (80.0%), intellectual disability (76.7%), and external ear anomalies (73.3%). The mean height and weight SDSs at diagnosis were -2.6 ± 1.3 and -2.2 ± 1.8, respectively. Short stature was apparent in 18 patients (60%), and 1 patient was diagnosed with growth hormone deficiency. Seventeen males showed genital hypoplasia, including micropenis, cryptorchidism, or both. Seven patients after pubertal age had hypogonadotropic hypogonadism with hyposmia/anosmia and olfactory bulb hypoplasia. Truncating CHD7 mutations were the most common (n = 22), followed by missense variants (n = 3), splice-site variants (n = 2), and large deletion (n = 2). CONCLUSIONS A diverse phenotypic spectrum was observed in patients with CHD7 variants, and endocrine defects such as short stature and delayed puberty occurred in most patients. Endocrine evaluation, especially for growth and pubertal impairment, should be performed during diagnosis and follow-up to improve the patient's quality of life.
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Affiliation(s)
- Ja Hye Kim
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Yunha Choi
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Soojin Hwang
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Gu-Hwan Kim
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin-Ho Choi
- Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea
- Correspondence should be addressed to J-H Choi:
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Liu Q, Yin X, Li P. Clinical, hormonal, and genetic characteristics of 25 Chinese patients with idiopathic hypogonadotropic hypogonadism. BMC Endocr Disord 2022; 22:30. [PMID: 35090434 PMCID: PMC8796337 DOI: 10.1186/s12902-022-00940-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 01/19/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Idiopathic hypogonadotropic hypogonadism (IHH) is a type of congenital disease caused by a variety of gene variants leading to dysfunction in the secretion of hypothalamic gonadotropin-releasing hormones (GnRHs). Clinically, IHH can be divided into Kallmann syndrome (KS) with dysosmia and normosmic idiopathic hypogonadotropic hypogonadism (nIHH) according to the presence or absence of an olfactory disorder. METHODS We retrospectively evaluated 25 IHH patients (8 KS and 17 nIHH) who were diagnosed at the Department of Endocrinology of Shanghai Children's Hospital from 2015 to 2021. We analysed the patients' clinical data, including their hormone levels and gene sequences. RESULTS All male patients exhibited small phalli, and 35% of them exhibited cryptorchidism. A significant difference was observed in the levels of dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation (P = 0.028) between the KS group and the nIHH group. Missense variants were the major cause of IHH, and the main pathogenic genes were FGFR1, PROKR2/PROK2, and KAl1. Nine reported and 13 novel variants of six genes were identified. De novo variants were detected in 16 IHH patients; eight patients inherited the variants from their mothers, while only three patients inherited variants from their fathers. One patient had both KAl1 and PROKR2 gene variants, and another patient had two different PROKR2 gene variants. These two patients both had the hot spot variant c.533G > C (p. Trp178Ser) of the PROKR2 gene. CONCLUSION IHH should be highly suspected in patients with a small phallus and cryptorchidism. Compared with nIHH patients, KS patients exhibited a higher level of DHT after HCG stimulation. Missense variants were the major cause of IHH, and most of the inherited variants were from their mothers who exhibited no obvious clinical symptoms. We identified 9 reported variants and 13 novel variants that led to IHH. A small proportion of patients were at risk of inheriting either the oligogenic variant or the compound heterozygous variant. The hot spot variant c.533G > C (p. Trp178Ser) of PROKR2 might be involved in oligogenic inheritance and compound heterozygous inheritance. These findings provide deeper insight into the diagnosis and classification of IHH and will contribute to its clinical assessment.
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Affiliation(s)
- Qingxu Liu
- Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China
| | - Xiaoqin Yin
- Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China
| | - Pin Li
- Department of Endocrinology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, People's Republic of China.
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25
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Wang S, Lin Y, Liang P, Li Q, Li W, Wang Z, Wang J, Chen J, Zha D. De novo Splice Site Mutation of the CHD7 Gene in a Chinese Patient with Typical CHARGE Syndrome. ORL J Otorhinolaryngol Relat Spec 2022; 84:417-424. [PMID: 35078197 DOI: 10.1159/000520376] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 08/26/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION CHARGE syndrome (CS, OMIM 214800) is a rare genetic disease characterized by multiple congenital abnormalities, including coloboma, heart defect, atresia of the choanae, retardation of development, genital anomalies, and ear anomalies/deafness. The syndrome is mainly caused by a heterozygous variant in the chromodomain helicase DNA-binding protein 7 (CHD7) gene that encodes the CHD7 protein, involved in the ATP-dependent remodeling of chromatin. METHODS In this study, the next-generation sequencing targeted panel was used to detect a de novo variant c.3523-2A>G in the CHD7 gene in a patient with severe CS, congenital heart disease, left coloboma of the choroid, cryptorchidism, and congenital deafness. The Sanger sequencing confirmed the variant and clarified it as de novo variant by short tandem repeat analysis in the patient family. We analyzed the effect of a variant by Minigene assay to evaluate the pathogenicity of the variant. RESULTS In summary, cDNA analysis confirmed that c.3523-2A>G variant activates a cryptic splice site, resulting in 172 base pair missing in exon 15, leading to the premature truncation of the CHD7 protein (p.V1175Afs*11). CONCLUSION The present study functionally characterized the novel c.3523-2A>G variant in CHD7, providing further confirmatory evidence that it is associated with CS.
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Affiliation(s)
- Shujuan Wang
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China,
| | - Ying Lin
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Pengfei Liang
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Qiong Li
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Wei Li
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Zhaoxia Wang
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Jian Wang
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Jun Chen
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
| | - Dingjun Zha
- Department of Otolaryngology and Head and Neck Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
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Sun B, Wang X, Mao J, Zhao Z, Zhang W, Nie M, Wu X. Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics. Front Genet 2022; 12:770680. [PMID: 35047002 PMCID: PMC8762265 DOI: 10.3389/fgene.2021.770680] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Accepted: 11/24/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose:CHD7 rare variants can cause congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome. We aimed to summarize the genotype and phenotype characteristics of CHH patients with CHD7 rare variants. Methods: Rare sequencing variants (RSVs) were detected by Sanger sequencing in a series of 327 CHH patients and were interpreted and grouped according to the American College of Medical Genetics and Genomics (ACMG) guideline. Detailed phenotyping and genotype-phenotype correlation were analyzed. Results: The RSV detection rate was 11.01% (36/327) in the CHH patients. We identified 30 RSVs and 19 of them were novel. Following ACMG criteria, three variants were pathogenic (P), 4 were likely pathogenic (LP), 3 were of uncertain significance with paradoxical evidence (US1), and 20 were of uncertain significance without enough evidence (US2). All patients (4/4, 100%) with P or LP variants manifested extragonadal symptoms. Conclusion: Addition of 19 novel CHD7 variants expanded the spectrum of variants, and pathogenic or likely pathogenic RSVs were more likely to cause syndromic CHH. For CHH patients carrying CHD7 RSVs, detailed genotyping and phenotyping can facilitate clinical diagnosis and therapy.
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Affiliation(s)
- Bang Sun
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Wang
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiangfeng Mao
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhiyuan Zhao
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Zhang
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Nie
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xueyan Wu
- NHC Key Laboratory of Endocrinology (Peking Union Medical College Hospital), Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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27
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Jie H, Xu Z, Gao J, Li F, Chen Y, Zeng D, Zhao G, Li D. Differential expression profiles of microRNAs in musk gland of unmated and mated forest musk deer ( Moschus berezovskii). PeerJ 2022; 9:e12710. [PMID: 35036174 PMCID: PMC8710055 DOI: 10.7717/peerj.12710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 12/08/2021] [Indexed: 11/26/2022] Open
Abstract
Background The formation of musk is a complex biophysical and biochemical process that change with the rut of male forest musk deer. We have reported that the mating status of male forest musk deer might result to the variations of chemical composition and microbiota of musk and its yields. Critical roles for microRNAs (miRNAs) of multi-tissues were profiled in our previous study; however, the role for miRNAs of the musk gland remains unclear in this species. Methods In this study, we used Illumina deep sequencing technology to sequence the small RNA transcriptome of unmated male (UM) and mated male (UM) of Chinese forest musk deer. Results We identified 1,652 known miRNAs and 45 novel miRNAs, of which there were 174 differentially expressed miRNAs between UM and MM. chi-miR-21-5p, ipu-miR-99b and bta-miR-26a were up-regulated in UM among the 10 most differentially expressed miRNAs. Functional enrichment of the target genes showed that monosaccharide biosynthetic process, protein targeting, cellular protein catabolic process enriched higher in MM. Meanwhile, structural molecule activity, secretion by cell, regulated exocytosis and circulatory system process enriched more in UM, hinting that the formation of musk in UM was mediated by target genes related to exocytosis. The miRNA-mRNA pairs such as miR-21: CHD7, miR143: HSD17B7, miR-141/200a: Noc2 might involve in musk gland development and musk secretion, which need to be verified in future study.
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Affiliation(s)
- Hang Jie
- Chongqing Institute of Medicinal Plant Cultivation, Bio-resource Research and Utilization joint key laboratory of Sichuan and Chongqing, Nanchuan, Chongqing, China
| | - Zhongxian Xu
- Sichuan Agricultural University, Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Chengdu, Sichuan, China.,China West Normal University, Key Laboratory of Southwest China Wildlife Resources Conservation (Ministry of Education), Nanchong, Sichuan, China
| | - Jian Gao
- Sichuan Agricultural University, Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Chengdu, Sichuan, China
| | - Feng Li
- Sichuan Agricultural University, Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Chengdu, Sichuan, China.,China West Normal University, Key Laboratory of Southwest China Wildlife Resources Conservation (Ministry of Education), Nanchong, Sichuan, China
| | - Yinglian Chen
- Chongqing Institute of Medicinal Plant Cultivation, Bio-resource Research and Utilization joint key laboratory of Sichuan and Chongqing, Nanchuan, Chongqing, China
| | - Dejun Zeng
- Chongqing Institute of Medicinal Plant Cultivation, Bio-resource Research and Utilization joint key laboratory of Sichuan and Chongqing, Nanchuan, Chongqing, China
| | - Guijun Zhao
- Chongqing Institute of Medicinal Plant Cultivation, Bio-resource Research and Utilization joint key laboratory of Sichuan and Chongqing, Nanchuan, Chongqing, China
| | - Diyan Li
- Sichuan Agricultural University, Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Chengdu, Sichuan, China
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Deller M, Gellrich J, Lohrer EC, Schriever VA. Genetics of congenital olfactory dysfunction: a systematic review of the literature. Chem Senses 2022; 47:6847567. [PMID: 36433800 DOI: 10.1093/chemse/bjac028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Olfaction, as one of our 5 senses, plays an important role in our daily lives. It is connected to proper nutrition, social interaction, and protection mechanisms. Disorders affecting this sense consequently also affect the patients' general quality of life. Because the underlying genetics of congenital olfactory disorders (COD) have not been thoroughly investigated yet, this systematic review aimed at providing information on genes that have previously been reported to be mutated in patients suffering from COD. This was achieved by systematically reviewing existing literature on 3 databases, namely PubMed, Ovid Medline, and ISI Web of Science. Genes and the type of disorder, that is, isolated and/or syndromic COD were included in this study, as were the patients' associated abnormal features, which were categorized according to the affected organ(-system). Our research yielded 82 candidate genes/chromosome loci for isolated and/or syndromic COD. Our results revealed that the majority of these are implicated in syndromic COD, a few accounted for syndromic and isolated COD, and the least underly isolated COD. Most commonly, structures of the central nervous system displayed abnormalities. This study is meant to assist clinicians in determining the type of COD and detecting potentially abnormal features in patients with confirmed genetic variations. Future research will hopefully expand this list and thereby further improve our understanding of COD.
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Affiliation(s)
- Matthias Deller
- Charité-Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany
| | - Janine Gellrich
- Abteilung Neuropädiatrie Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Elisabeth C Lohrer
- Abteilung Neuropädiatrie Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany
| | - Valentin A Schriever
- Charité-Universitätsmedizin Berlin, Department of Pediatric Neurology, Berlin, Germany.,Abteilung Neuropädiatrie Medizinische Fakultät Carl Gustav Carus, Technische Universität, Dresden, Germany.,Charité-Universitätsmedizin Berlin, Center for Chronically Sick Children (Sozialpädiatrisches Zentrum, SPZ), Berlin, Germany
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29
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Gach A, Pinkier I, Wysocka U, Sałacińska K, Salachna D, Szarras-Czapnik M, Pietrzyk A, Sakowicz A, Nykel A, Rutkowska L, Rybak-Krzyszkowska M, Socha M, Jamsheer A, Jakubowski L. New findings in oligogenic inheritance of congenital hypogonadotropic hypogonadism. Arch Med Sci 2022; 18:353-364. [PMID: 35316923 PMCID: PMC8924836 DOI: 10.5114/aoms.2020.98909] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 08/11/2020] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Congenital hypogonadotropic hypogonadism results from a dysfunction of the hypothalamic-pituitary-gonadal axis, which is essential for the development and function of the reproductive system. It may be associated with anosmia, referred to as Kallmann syndrome, or a normal sense of smell. Numerous studies have proven that hypogonadotropic hypogonadism is not simply a monogenic Mendelian disease, but that more than one gene may be involved in its pathogenesis in a single patient. The oligogenic complex architecture underlying the disease is still largely unknown. MATERIAL AND METHODS Targeted next-generation sequencing (NGS) was used to screen for DNA variants in a cohort of 47 patients with congenital hypogonadotropic hypogonadism. The NGS panel consists of over 50 well-known and candidate genes, associated with hypogonadotropic state. RESULTS Here we report the identification of new oligogenic variants in SPRY4/SEMA3A, SRA1/SEMA7A, CHD7/SEMA7A, CCDC141/POLR3B/POLR3B, and PROKR2/SPRY4/NSMF. These genes are known to contribute to the phenotype of hypogonadotropic hypogonadism, yet our results point to potential new "partners" underlying digenic and trigenic patterns. CONCLUSIONS The finding supports the importance of oligogenic inheritance and demonstrates the complexity of genetic architecture in hypogonadotropic hypogonadism. It also underlines the necessity for developing fine-tuned guidelines to provide a tool for adequate and precise sequence variant classification in non-Mendelian conditions.
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Affiliation(s)
- Agnieszka Gach
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Iwona Pinkier
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Urszula Wysocka
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Kinga Sałacińska
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Dominik Salachna
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Maria Szarras-Czapnik
- Department of Endocrinology and Diabetology, Children’s Memorial Health Institute, Warsaw, Poland
| | - Aleksandra Pietrzyk
- Department of Genetics and Pathomorphology, Faculty of Medicine and Health Sciences, University of Zielona Gora, Poland
| | - Agata Sakowicz
- Department of Medical Biotechnology, Medical University of Lodz, Lodz, Poland
| | - Anna Nykel
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | - Lena Rutkowska
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
| | | | - Magda Socha
- Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Aleksander Jamsheer
- Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland
| | - Lucjusz Jakubowski
- Department of Genetics, Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
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Abstract
The diagnostic suspicion of congenital central hypogonadism is based on clinical signs. Biochemical confirmation is challenging, especially after the postnatal activation stage of the hypothalamic-pituitary-testicular axis. Sertoli cell markers, like AMH and inhibin B, have become useful tools for the diagnosis of male central hypogonadism during childhood. Different mechanisms can participate in the aetiopathogenesis of central hypogonadism, leading to a deficiency in the production of gonadotrophins. Advances in genetic studies, mainly next generation sequencing techniques, have allowed the discovery of a large number of genes related to central hypogonadism. However, a causal variant is found in approximately half of the patients. Central hypogonadism has been classically described as a pathology with variable expressivity and incomplete penetrance. Currently, these characteristics are known to be partially explained by the presence of oligogenicity, that is the participation of variants in more than one gene in the aetiology of central hypogonadism in the same patient.
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Affiliation(s)
- Romina P Grinspon
- Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET - FEI - División de, Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD, Buenos Aires, Argentina.
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31
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Abstract
Idiopathic hypogonadotropic hypogonadism (IHH) is a group of rare developmental disorders characterized by low gonadotropin levels in the face of low sex steroid hormone concentrations. IHH is practically divided into two major groups according to the olfactory function: normal sense of smell (normosmia) nIHH, and reduced sense of smell (hyposmia/anosmia) Kallmann syndrome (KS). Although mutations in more than 50 genes have been associated with IHH so far, only half of those cases were explained by gene mutations. Various combinations of deleterious variants in different genes as causes of IHH have been increasingly recognized (Oligogenic etiology). In addition to the complexity of inheritance patterns, the spontaneous or sex steroid-induced clinical recovery from IHH, which is seen in approximately 10–20% of cases, blurs further the phenotype/genotype relationship in IHH, and poses challenging steps in new IHH gene discovery. Beyond helping for clinical diagnostics, identification of the genetic mutations in the pathophysiology of IHH is hoped to shed light on the central governance of the hypothalamo-pituitary-gonadal axis through life stages. This review aims to summarize the genetic etiology of IHH and discuss the clinical and physiological ramifications of the gene mutations.
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32
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Adeyemo A, Faridi R, Chattaraj P, Yousaf R, Tona R, Okorie S, Bharadwaj T, Nouel-Saied LM, Acharya A, Schrauwen I, Morell RJ, Leal SM, Friedman TB, Griffith AJ, Roux I. Genomic analysis of childhood hearing loss in the Yoruba population of Nigeria. Eur J Hum Genet 2021; 30:42-52. [PMID: 34837038 PMCID: PMC8738750 DOI: 10.1038/s41431-021-00984-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/02/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022] Open
Abstract
Although variant alleles of hundreds of genes are associated with sensorineural deafness in children, the genes and alleles involved remain largely unknown in the Sub-Saharan regions of Africa. We ascertained 56 small families mainly of Yoruba ethno-lingual ancestry in or near Ibadan, Nigeria, that had at least one individual with nonsyndromic, severe-to-profound, prelingual-onset, bilateral hearing loss not attributed to nongenetic factors. We performed a combination of exome and Sanger sequencing analyses to evaluate both nuclear and mitochondrial genomes. No biallelic pathogenic variants were identified in GJB2, a common cause of deafness in many populations. Potential causative variants were identified in genes associated with nonsyndromic hearing loss (CIB2, COL11A1, ILDR1, MYO15A, TMPRSS3, and WFS1), nonsyndromic hearing loss or Usher syndrome (CDH23, MYO7A, PCDH15, and USH2A), and other syndromic forms of hearing loss (CHD7, OPA1, and SPTLC1). Several rare mitochondrial variants, including m.1555A>G, were detected in the gene MT-RNR1 but not in control Yoruba samples. Overall, 20 (33%) of 60 independent cases of hearing loss in this cohort of families were associated with likely causal variants in genes reported to underlie deafness in other populations. None of these likely causal variants were present in more than one family, most were detected as compound heterozygotes, and 77% had not been previously associated with hearing loss. These results indicate an unusually high level of genetic heterogeneity of hearing loss in Ibadan, Nigeria and point to challenges for molecular genetic screening, counseling, and early intervention in this population.
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Affiliation(s)
- Adebolajo Adeyemo
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.
| | - Rabia Faridi
- Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, 20892, USA
| | - Parna Chattaraj
- Otolaryngology Branch, NIDCD, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Rizwan Yousaf
- Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, 20892, USA
| | - Risa Tona
- Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, 20892, USA
| | - Samuel Okorie
- Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria
| | - Thashi Bharadwaj
- Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA
| | - Liz M Nouel-Saied
- Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA
| | - Anushree Acharya
- Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA
| | - Isabelle Schrauwen
- Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA
| | - Robert J Morell
- Genomics and Computational Biology Core, NIDCD, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Suzanne M Leal
- Center for Statistical Genetics, Gertrude H. Sergievsky Center, Department of Neurology, Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA.,Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 630 W 168th St, New York, NY, 10032, USA
| | - Thomas B Friedman
- Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health, Bethesda, MD, 20892, USA
| | - Andrew J Griffith
- Otolaryngology Branch, NIDCD, National Institutes of Health, Bethesda, MD, 20892, USA.,Department of Otolaryngology, College of Medicine, University of Tennessee Health Science Center, 910 Madison Avenue, Memphis, TN, 38163, USA
| | - Isabelle Roux
- Otolaryngology Branch, NIDCD, National Institutes of Health, Bethesda, MD, 20892, USA.
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Cardoso AR, Lopes-Marques M, Oliveira M, Amorim A, Prata MJ, Azevedo L. Genetic Variability of the Functional Domains of Chromodomains Helicase DNA-Binding (CHD) Proteins. Genes (Basel) 2021; 12:genes12111827. [PMID: 34828433 PMCID: PMC8623811 DOI: 10.3390/genes12111827] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 11/30/2022] Open
Abstract
In the past few years, there has been an increasing neuroscientific interest in understanding the function of mammalian chromodomains helicase DNA-binding (CHD) proteins due to their association with severe developmental syndromes. Mammalian CHDs include nine members (CHD1 to CHD9), grouped into subfamilies according to the presence of specific functional domains, generally highly conserved in evolutionary terms. Mutations affecting these domains hold great potential to disrupt protein function, leading to meaningful pathogenic scenarios, such as embryonic defects incompatible with life. Here, we analysed the evolution of CHD proteins by performing a comparative study of the functional domains of CHD proteins between orthologous and paralogous protein sequences. Our findings show that the highest degree of inter-species conservation was observed at Group II (CHD3, CHD4, and CHD5) and that most of the pathological variations documented in humans involve amino acid residues that are conserved not only between species but also between paralogs. The parallel analysis of both orthologous and paralogous proteins, in cases where gene duplications have occurred, provided extra information showing patterns of flexibility as well as interchangeability between amino acid positions. This added complexity needs to be considered when the impact of novel mutations is assessed in terms of evolutionary conservation.
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Affiliation(s)
- Ana R. Cardoso
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.R.C.); (M.L.-M.); (M.O.); (A.A.); (M.J.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FCUP—Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Mónica Lopes-Marques
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.R.C.); (M.L.-M.); (M.O.); (A.A.); (M.J.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FCUP—Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Manuela Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.R.C.); (M.L.-M.); (M.O.); (A.A.); (M.J.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FCUP—Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - António Amorim
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.R.C.); (M.L.-M.); (M.O.); (A.A.); (M.J.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FCUP—Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Maria J. Prata
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.R.C.); (M.L.-M.); (M.O.); (A.A.); (M.J.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FCUP—Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
| | - Luísa Azevedo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (A.R.C.); (M.L.-M.); (M.O.); (A.A.); (M.J.P.)
- IPATIMUP—Institute of Molecular Pathology and Immunology, University of Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal
- FCUP—Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre, s/n, 4169-007 Porto, Portugal
- Correspondence:
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Vazquez MJ, Daza-Dueñas S, Tena-Sempere M. Emerging Roles of Epigenetics in the Control of Reproductive Function: Focus on Central Neuroendocrine Mechanisms. J Endocr Soc 2021; 5:bvab152. [PMID: 34703958 PMCID: PMC8533971 DOI: 10.1210/jendso/bvab152] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Indexed: 12/11/2022] Open
Abstract
Reproduction is an essential function for perpetuation of the species. As such, it is controlled by sophisticated regulatory mechanisms that allow a perfect match between environmental conditions and internal cues to ensure adequate pubertal maturation and achievement of reproductive capacity. Besides classical genetic regulatory events, mounting evidence has documented that different epigenetic mechanisms operate at different levels of the reproductive axis to finely tune the development and function of this complex neuroendocrine system along the lifespan. In this mini-review, we summarize recent evidence on the role of epigenetics in the control of reproduction, with special focus on the modulation of the central components of this axis. Particular attention will be paid to the epigenetic control of puberty and Kiss1 neurons because major developments have taken place in this domain recently. In addition, the putative role of central epigenetic mechanisms in mediating the influence of nutritional and environmental cues on reproductive function will be discussed.
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Affiliation(s)
- Maria Jesus Vazquez
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Hospital Universitario Reina Sofia, 14004 Cordoba, Spain
| | - Silvia Daza-Dueñas
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain
| | - Manuel Tena-Sempere
- Instituto Maimónides de Investigación Biomédica de Cordoba (IMIBIC), 14004 Cordoba, Spain.,Department of Cell Biology, Physiology and Immunology, University of Cordoba, 14004 Cordoba, Spain.,Hospital Universitario Reina Sofia, 14004 Cordoba, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, 14004 Cordoba, Spain.,Institute of Biomedicine, University of Turku, FIN-20520 Turku, Finland
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35
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Howard SR. Interpretation of reproductive hormones before, during and after the pubertal transition-Identifying health and disordered puberty. Clin Endocrinol (Oxf) 2021; 95:702-715. [PMID: 34368982 PMCID: PMC9291332 DOI: 10.1111/cen.14578] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 11/28/2022]
Abstract
Puberty is a process of transition from childhood to adult reproductive capacity, governed by the reactivation of the hypothalamic-pituitary-gonadal axis after a long period of dormancy in mid-childhood. As such, the reproductive hormones are in a state of flux during the adolescent years, and interpretation of both the onset of healthy, concordant puberty and the differentiation of precocious, delayed or disordered puberty, can be challenging. This review is focused on the description of the endocrine axes in healthy puberty and the markers of disorders of puberty that can aid diagnosis and management for patients with these conditions. It will cover the hypothalamic, pituitary and gonadal hormone systems, the dynamic changes that occur during puberty, conditions leading to precocious, delayed or absent puberty and other syndromes with disordered puberty, and the biochemical diagnosis of these different disorders of puberty.
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Affiliation(s)
- Sasha R. Howard
- Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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36
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Liu C, Kang N, Guo Y, Gong P. Advances in Chromodomain Helicase DNA-Binding (CHD) Proteins Regulating Stem Cell Differentiation and Human Diseases. Front Cell Dev Biol 2021; 9:710203. [PMID: 34616726 PMCID: PMC8488160 DOI: 10.3389/fcell.2021.710203] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Regulation of gene expression is critical for stem cell differentiation, tissue development, and human health maintenance. Recently, epigenetic modifications of histone and chromatin remodeling have been verified as key controllers of gene expression and human diseases. Objective: In this study, we review the role of chromodomain helicase DNA-binding (CHD) proteins in stem cell differentiation, cell fate decision, and several known human developmental disorders and cancers. Conclusion: CHD proteins play a crucial role in stem cell differentiation and human diseases.
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Affiliation(s)
- Caojie Liu
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Ning Kang
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Yuchen Guo
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
| | - Ping Gong
- State Key Laboratory of Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, China
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Xu W, Zhou W, Lin H, Ye D, Chen G, Dong F, Shen J. A novel heterozygous mutation of CHD7 gene in a Chinese patient with Kallmann syndrome: a case report. BMC Endocr Disord 2021; 21:193. [PMID: 34563184 PMCID: PMC8465769 DOI: 10.1186/s12902-021-00836-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 08/05/2021] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Variants of chromodomain helicase DNA binding protein 7 (CHD7) gene are commonly associated with Kallmann syndrome (KS) and account for 5-6% of idiopathic hypogonadotropic hypogonadism (IHH) cases. Here we report a novel mutation of CHD7 gene in a patient with KS, which may contribute to the better understanding of KS. CASE PRESENTATION A 29-year-old male patient with KS and a chief complaint of delayed puberty for 13 years (Tanner B Stage< 4) was admitted to the Department of Endocrinology of the First Affiliated Hospital of Zhejiang University (Hangzhou, China) in September 2019. Dual-energy X-ray absorptiometry (DEXA) showed low bone density in both lumbar spine (L1 ~ L5 mean Z-score - 3.0) and femoral neck (Z-score - 2.7). Dynamic contrast-enhanced magnetic resonance imaging (MRI) of pituitary and contrast-enhanced computed tomography (CT) showed no abnormal findings. Ophthalmological evaluation showed that his both eyes showed exotropia, and no sight loss was noted. Heterozygous c.1619G > T mutation of TCD7 gene (p.G4856V) was detected, whereas none of his family members had this mutation. Human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG) were injected for three times/week to treat idiopathic hypogonadotropic hypogonadism (IHH). After several months of therapy, the patient's health condition improved. His testicles became larger, and his secondary sexual characteristics improved after treatment. CONCLUSION Exploration of the novel splice-site mutation of CHD7 may further our current understanding of KS.
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Affiliation(s)
- Weiwei Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital, School of Medicine, Zhejiang University, No.79, Qing-Chun Road, Zhejiang, 310003, Hangzhou, China
| | - Weibin Zhou
- Department of Endocrinology and Metabolism, First Affiliated Hospital, School of Medicine, Zhejiang University, No.79, Qing-Chun Road, Zhejiang, 310003, Hangzhou, China
| | - Haiyang Lin
- Department of Endocrinology, the Affiliated Wenling Hospital, Wenzhou Medical University, #333, S Chuan'an Road, Wenling, Zhejiang, 317500, China
| | - Dan Ye
- Department of Endocrinology and Metabolism, First Affiliated Hospital, School of Medicine, Zhejiang University, No.79, Qing-Chun Road, Zhejiang, 310003, Hangzhou, China
| | - Guoping Chen
- Department of Endocrinology and Metabolism, First Affiliated Hospital, School of Medicine, Zhejiang University, No.79, Qing-Chun Road, Zhejiang, 310003, Hangzhou, China
| | - Fengqin Dong
- Department of Endocrinology and Metabolism, First Affiliated Hospital, School of Medicine, Zhejiang University, No.79, Qing-Chun Road, Zhejiang, 310003, Hangzhou, China
| | - Jianguo Shen
- Department of Endocrinology and Metabolism, First Affiliated Hospital, School of Medicine, Zhejiang University, No.79, Qing-Chun Road, Zhejiang, 310003, Hangzhou, China.
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Oleari R, Massa V, Cariboni A, Lettieri A. The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency. Int J Mol Sci 2021; 22:9425. [PMID: 34502334 PMCID: PMC8431607 DOI: 10.3390/ijms22179425] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/27/2021] [Accepted: 08/28/2021] [Indexed: 01/19/2023] Open
Abstract
Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.
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Affiliation(s)
- Roberto Oleari
- Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milano, Italy;
| | - Valentina Massa
- Department of Health Sciences, University of Milan, 20142 Milano, Italy;
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milano, Italy
| | - Anna Cariboni
- Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milano, Italy;
| | - Antonella Lettieri
- Department of Health Sciences, University of Milan, 20142 Milano, Italy;
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Department of Health Sciences, University of Milan, 20142 Milano, Italy
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Louden ED, Poch A, Kim HG, Ben-Mahmoud A, Kim SH, Layman LC. Genetics of hypogonadotropic Hypogonadism-Human and mouse genes, inheritance, oligogenicity, and genetic counseling. Mol Cell Endocrinol 2021; 534:111334. [PMID: 34062169 DOI: 10.1016/j.mce.2021.111334] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 05/12/2021] [Accepted: 05/24/2021] [Indexed: 12/14/2022]
Abstract
Hypogonadotropic hypogonadism, which may be normosmic (nHH) or anosmic/hyposmic, known as Kallmann syndrome (KS), is due to gonadotropin-releasing hormone deficiency, which results in absent puberty and infertility. Investigation of the genetic basis of nHH/KS over the past 35 years has yielded a substantial increase in our understanding, as variants in 44 genes in OMIM account for ~50% of cases. The first genes for KS (ANOS1) and nHH (GNRHR) were followed by the discovery that FGFR1 variants may cause either nHH or KS. Associated anomalies include midline facial defects, neurologic deficits, cardiac anomalies, and renal agenesis, among others. Mouse models for all but one gene (ANOS1) generally support findings in humans. About half of the known genes implicated in nHH/KS are inherited as autosomal dominant and half are autosomal recessive, whereas only 7% are X-linked recessive. Digenic and oligogenic inheritance has been reported in 2-20% of patients, most commonly with variants in genes that may result in either nHH or KS inherited in an autosomal dominant fashion. In vitro analyses have only been conducted for both gene variants in eight cases and for one gene variant in 20 cases. Rigorous confirmation that two gene variants in the same individual cause the nHH/KS phenotype is lacking for most. Clinical diagnosis is probably best accomplished by targeted next generation sequencing of the known candidate genes with confirmation by Sanger sequencing. Elucidation of the genetic basis of nHH/KS has resulted in an enhanced understanding of this disorder, as well as normal puberty, which makes genetic diagnosis clinically relevant.
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Affiliation(s)
- Erica D Louden
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Department of Neuroscience & Regenerative Medicine, Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA
| | - Alexandra Poch
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Department of Neuroscience & Regenerative Medicine, Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA
| | - Hyung-Goo Kim
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Afif Ben-Mahmoud
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
| | - Soo-Hyun Kim
- Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
| | - Lawrence C Layman
- Section of Reproductive Endocrinology, Infertility, & Genetics, Department of Obstetrics & Gynecology, Department of Neuroscience & Regenerative Medicine, Department of Physiology, Medical College of Georgia at Augusta University, Augusta, GA, 30912, USA.
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Кокорева КД, Чугунов ИС, Безлепкина ОБ. [Molecular genetics and phenotypic features of congenital isolated hypogonadotropic hypogonadism]. PROBLEMY ENDOKRINOLOGII 2021; 67:46-56. [PMID: 34533013 PMCID: PMC9112933 DOI: 10.14341/probl12787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/16/2022]
Abstract
Congenital isolated hypogonadotropic hypogonadism includes a group of diseases related to the defects of secretion and action of gonadotropin-releasing hormone (GNRH) and gonadotropins. In a half of cases congenital hypogonadism is associated with an impaired sense of smell. It's named Kallmann syndrome. Now 40 genes are known to be associated with function of hypothalamus pituitary gland and gonads. Phenotypic features of hypogonadism and therapy effectiveness are related to different molecular defects. However clinical signs may vary even within the same family with the same molecular genetic defect. Genotype phenotype correlation in patients with congenital malformations prioritizes the search for mutations in candidate genes. There are data of significant contribution of oligogenicity into the phenotype of the disease are presented in the review. Moreover, an issue of current isolated hypogonadotropic hypogonadism definition and classification revision is raised in the review due to hypogonadotropic hypogonadism development while there are mutations in genes not associated with GNRH neurons secretion and function.
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Affiliation(s)
- К. Д. Кокорева
- Национальный медицинский исследовательский центр эндокринологии
| | - И. С. Чугунов
- Национальный медицинский исследовательский центр эндокринологии
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Lee E, Kang C, Purhonen P, Hebert H, Bouazoune K, Hohng S, Song JJ. A Novel N-terminal Region to Chromodomain in CHD7 is Required for the Efficient Remodeling Activity. J Mol Biol 2021; 433:167114. [PMID: 34161779 DOI: 10.1016/j.jmb.2021.167114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/15/2021] [Indexed: 10/21/2022]
Abstract
Chromodomain-Helicase DNA binding protein 7 (CHD7) is an ATP dependent chromatin remodeler involved in maintaining open chromatin structure. Mutations of CHD7 gene causes multiple developmental disorders, notably CHARGE syndrome. However, there is not much known about the molecular mechanism by which CHD7 remodels nucleosomes. Here, we performed biochemical and biophysical analysis on CHD7 chromatin remodeler and uncover that N-terminal to the Chromodomain (N-CRD) interacts with nucleosome and contains a high conserved arginine stretch, which is reminiscent of arginine anchor. Importantly, this region is required for efficient ATPase stimulation and nucleosome remodeling activity of CHD7. Furthermore, smFRET analysis shows the mutations in the N-CRD causes the defects in remodeling activity. Collectively, our results uncover the functional importance of a previously unidentified N-terminal region in CHD7 and implicate that the multiple domains in chromatin remodelers are involved in regulating their activities.
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Affiliation(s)
- Eunhye Lee
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), KAIST Institute of BioCentury, Daejeon 34141, Korea
| | - Chanshin Kang
- Department of Physics and Astronomy, Institute of Applied Physics, Seoul National University, Seoul 08826, Korea
| | - Pasi Purhonen
- School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Biomedical Engineering and Health Systems, KTH Royal Institute of Technology, S-141 52 Huddinge, Sweden
| | - Hans Hebert
- School of Engineering Sciences in Chemistry, Biotechnology and Health, Department of Biomedical Engineering and Health Systems, KTH Royal Institute of Technology, S-141 52 Huddinge, Sweden
| | - Karim Bouazoune
- Institut für Molekularbiologie und Tumorforschung (IMT), Biomedizinisches Forschungszentrum, Philipps-Universität Marburg, Marburg 35043, Germany
| | - Sungchul Hohng
- Department of Physics and Astronomy, Institute of Applied Physics, Seoul National University, Seoul 08826, Korea.
| | - Ji-Joon Song
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), KAIST Institute of BioCentury, Daejeon 34141, Korea.
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Defects in GnRH Neuron Migration/Development and Hypothalamic-Pituitary Signaling Impact Clinical Variability of Kallmann Syndrome. Genes (Basel) 2021; 12:genes12060868. [PMID: 34198905 PMCID: PMC8229512 DOI: 10.3390/genes12060868] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/30/2021] [Accepted: 06/03/2021] [Indexed: 11/16/2022] Open
Abstract
Kallmann syndrome (KS) is a combination of isolated hypogonadotropic hypogonadism (IHH) with olfactory dysfunction, representing a heterogeneous disorder with a broad phenotypic spectrum. The genetic background of KS has not yet been fully established. This study was conducted on 46 Polish KS subjects (41 males, 5 females; average age: 29 years old). The studied KS patients were screened for defects in a 38-gene panel with next-generation sequencing (NGS) technology. The analysis revealed 27 pathogenic and likely pathogenic (P/LP) variants, and 21 variants of uncertain significance (VUS). The P/LP variants were detected in 20 patients (43.5%). The prevalence of oligogenic P/LP defects in selected genes among KS patients was 26% (12/46), whereas the co-occurrence of other variants was detected in 43% (20 probands). The examined KS patients showed substantial genotypic and phenotypic variability. A marked difference in non-reproductive phenotypes, involving defects in genes responsible for GnRH neuron development/migration and genes contributing to pituitary development and signaling, was observed. A comprehensive gene panel for IHH testing enabled the detection of clinically relevant variants in the majority of KS patients, which makes targeted NGS an effective molecular tool. The significance of oligogenicity and the high incidence of alterations in selected genes should be further elucidated.
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Lettieri A, Oleari R, Paganoni AJJ, Gervasini C, Massa V, Fantin A, Cariboni A. Semaphorin Regulation by the Chromatin Remodeler CHD7: An Emerging Genetic Interaction Shaping Neural Cells and Neural Crest in Development and Cancer. Front Cell Dev Biol 2021; 9:638674. [PMID: 33869187 PMCID: PMC8047133 DOI: 10.3389/fcell.2021.638674] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
CHD7 is a chromatin remodeler protein that controls gene expression via the formation of multi-protein complexes with specific transcription factors. During development, CHD7 controls several differentiation programs, mainly by acting on neural progenitors and neural crest (NC) cells. Thus, its roles range from the central nervous system to the peripheral nervous system and the organs colonized by NC cells, including the heart. Accordingly, mutated CHD7 is linked to CHARGE syndrome, which is characterized by several neuronal dysfunctions and by malformations of NC-derived/populated organs. Altered CHD7 has also been associated with different neoplastic transformations. Interestingly, recent evidence revealed that semaphorins, a class of molecules involved in developmental and pathological processes similar to those controlled by CHD7, are regulated by CHD7 in a context-specific manner. In this article, we will review the recent insights that support the existence of genetic interactions between these pathways, both during developmental processes and cancer progression.
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Affiliation(s)
- Antonella Lettieri
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Roberto Oleari
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alyssa J J Paganoni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Cristina Gervasini
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Valentina Massa
- CRC Aldo Ravelli for Neurotechnology and Experimental Brain Therapeutics, Università degli Studi di Milano, Milan, Italy.,Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Alessandro Fantin
- Department of Biosciences, Università degli Studi di Milano, Milan, Italy
| | - Anna Cariboni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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Cho CY, Tsai WY, Lee CT, Liu SY, Huang SY, Chien YH, Hwu WL, Lee NC, Tung YC. Clinical and molecular features of idiopathic hypogonadotropic hypogonadism in Taiwan: A single center experience. J Formos Med Assoc 2021; 121:218-226. [PMID: 33775534 DOI: 10.1016/j.jfma.2021.03.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 01/08/2021] [Accepted: 03/08/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Idiopathic (isolated) hypogonadotropic hypogonadism (IHH) is a rare disease that can be classified as Kallmann syndrome (KS) or normosmic IHH (nIHH). This study investigated the phenotype and genotype of IHH in Taiwanese patients. METHODS Twenty-six unrelated IHH patients were included in this study and their clinical, hormonal, and radiological findings were analyzed retrospectively. Whole exome sequencing (WES) was performed to identify the etiology. RESULTS The 26 patients (M:F = 19:7) were divided into a KS group (n = 11) and a nIHH group (n = 15). The diagnosis was earlier in boys than in girls. Fifteen patients were found to have pathogenic/likely pathogenic (P/LP) variants of IHH-associated genes, and the mutation detection rate was 58%. CHD7, FGFR1, and ANOS1 were the most common genetic etiologies identified in this group. Two patients with nIHH were found to have de novo SOX11 mutations and Coffin-Siris syndrome features. After treatment, the height outcomes and secondary sexual characteristics were significantly improved. There were no obvious differences between the genetically resolved (GR), variants of uncertain significance (VUS) and genetically unresolved groups (GUR). CONCLUSION Whole exome sequencing is useful in patients with IHH, and we identified the SOX11 gene as a causal factor in this study. We described the clinical, hormonal, and molecular characteristics, and the treatment outcomes, of Taiwanese patients with IHH, which should aid therapeutic planning and further research.
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Affiliation(s)
- Chih-Yi Cho
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Yu Tsai
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Ting Lee
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Yao Liu
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shu-Yuan Huang
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yin-Hsiu Chien
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Wuh-Liang Hwu
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
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Delaney A, Burkholder AB, Lavender CA, Plummer L, Mericq V, Merino PM, Quinton R, Lewis KL, Meader BN, Albano A, Shaw ND, Welt CK, Martin KA, Seminara SB, Biesecker LG, Bailey-Wilson JE, Hall JE. Increased Burden of Rare Sequence Variants in GnRH-Associated Genes in Women With Hypothalamic Amenorrhea. J Clin Endocrinol Metab 2021; 106:e1441-e1452. [PMID: 32870266 PMCID: PMC7947783 DOI: 10.1210/clinem/dgaa609] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/28/2020] [Indexed: 12/17/2022]
Abstract
CONTEXT Functional hypothalamic amenorrhea (HA) is a common, acquired form of hypogonadotropic hypogonadism that occurs in the setting of energy deficits and/or stress. Variability in individual susceptibility to these stressors, HA heritability, and previous identification of several rare sequence variants (RSVs) in genes associated with the rare disorder, isolated hypogonadotropic hypogonadism (IHH), in individuals with HA suggest a possible genetic contribution to HA susceptibility. OBJECTIVE We sought to determine whether the burden of RSVs in IHH-related genes is greater in women with HA than controls. DESIGN We compared patients with HA to control women. SETTING The study was conducted at secondary referral centers. PATIENTS AND OTHER PARTICIPANTS Women with HA (n = 106) and control women (ClinSeq study; n = 468). INTERVENTIONS We performed exome sequencing in all patients and controls. MAIN OUTCOME MEASURE(S) The frequency of RSVs in 53 IHH-associated genes was determined using rare variant burden and association tests. RESULTS RSVs were overrepresented in women with HA compared with controls (P = .007). Seventy-eight heterozygous RSVs in 33 genes were identified in 58 women with HA (36.8% of alleles) compared to 255 RSVs in 41 genes among 200 control women (27.2%). CONCLUSIONS Women with HA are enriched for RSVs in genes that cause IHH, suggesting that variation in genes associated with gonadotropin-releasing hormone neuronal ontogeny and function may be a major determinant of individual susceptibility to developing HA in the face of diet, exercise, and/or stress.
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Affiliation(s)
- Angela Delaney
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
| | - Adam B Burkholder
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Christopher A Lavender
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Lacey Plummer
- Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Veronica Mericq
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
- Department of Pediatrics, Clínica Las Condes, Santiago, Chile
| | - Paulina M Merino
- Institute of Maternal and Child Research, University of Chile, Santiago, Chile
| | - Richard Quinton
- Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK
| | - Katie L Lewis
- Medical Genomics & Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland
| | - Brooke N Meader
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
| | - Alessandro Albano
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
| | - Natalie D Shaw
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
| | - Corrine K Welt
- Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah
| | - Kathryn A Martin
- Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Stephanie B Seminara
- Harvard Reproductive Sciences Center and Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Leslie G Biesecker
- Medical Genomics & Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland
| | - Joan E Bailey-Wilson
- Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Baltimore, Maryland
| | - Janet E Hall
- National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, North Carolina
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Barraud S, Delemer B, Poirsier-Violle C, Bouligand J, Mérol JC, Grange F, Higel-Chaufour B, Decoudier B, Zalzali M, Dwyer AA, Acierno JS, Pitteloud N, Millar RP, Young J. Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome. Neuroendocrinology 2021; 111:99-114. [PMID: 32074614 DOI: 10.1159/000506640] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 02/18/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs. RESULTS The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met. CONCLUSION This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.
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Affiliation(s)
- Sara Barraud
- Department of Endocrinology, Reims University Hospital, Reims, France
- University of Reims Champagne-Ardenne, Reims, France
| | - Brigitte Delemer
- Department of Endocrinology, Reims University Hospital, Reims, France
- University of Reims Champagne-Ardenne, Reims, France
| | | | - Jérôme Bouligand
- Department of Molecular Genetics, Pharmacogenomics, and Hormonology, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
- University Paris-Saclay, Le Kremlin-Bicêtre, France
- INSERM U1185, Paris Saclay Medical School, Le Kremlin-Bicêtre, France
| | - Jean-Claude Mérol
- Department of Otolaryngology, Reims University Hospital, Reims, France
| | - Florent Grange
- Department of Dermatology, Reims University Hospital, Reims, France
| | | | | | - Mohamad Zalzali
- Department of Endocrinology, Reims University Hospital, Reims, France
| | - Andrew A Dwyer
- Boston College, William F. Connell School of Nursing, Chestnut Hill, Massachusetts, USA
| | - James S Acierno
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Nelly Pitteloud
- Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
| | - Robert P Millar
- Centre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Jacques Young
- University Paris-Saclay, Le Kremlin-Bicêtre, France,
- Department of Reproductive Endocrinology, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France,
- INSERM U1185, Paris Saclay Medical School, Le Kremlin-Bicêtre, France,
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Zhang J, Tang SY, Zhu XB, Li P, Lu JQ, Cong JS, Wang LB, Zhang F, Li Z. Whole exome sequencing and trio analysis to broaden the variant spectrum of genes in idiopathic hypogonadotropic hypogonadism. Asian J Androl 2021; 23:288-293. [PMID: 33208564 PMCID: PMC8152424 DOI: 10.4103/aja.aja_65_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Dozens of genes are associated with idiopathic hypogonadotropic hypogonadism (IHH) and an oligogenic etiology has been suggested. However, the associated genes may account for only approximately 50% cases. In addition, a genomic systematic pedigree analysis is still lacking. Here, we conducted whole exome sequencing (WES) on 18 unrelated men affected by IHH and their corresponding parents. Notably, one reported and 10 novel variants in eight known IHH causative genes (AXL, CCDC141, CHD7, DMXL2, FGFR1, PNPLA6, POLR3A, and PROKR2), nine variants in nine recently reported candidate genes (DCAF17, DCC, EGF, IGSF10, NOTCH1, PDE3A, RELN, SLIT2, and TRAPPC9), and four variants in four novel candidate genes for IHH (CCDC88C, CDON, GADL1, and SPRED3) were identified in 77.8% (14/18) of IHH cases. Among them, eight (8/18, 44.4%) cases carried more than one variant in IHH-related genes, supporting the oligogenic model. Interestingly, we found that those variants tended to be maternally inherited (maternal with n = 17 vs paternal with n = 7; P = 0.028). Our further retrospective investigation of published reports replicated the maternal bias (maternal with n = 46 vs paternal with n = 28; P = 0.024). Our study extended a variant spectrum for IHH and provided thefirst evidence that women are probably more tolerant to variants of IHH-related genes than men.
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Affiliation(s)
- Jian Zhang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Shu-Yan Tang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Xiao-Bin Zhu
- Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Peng Li
- Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Jian-Qi Lu
- Department of Research Institute, Reproduction Medical Center, The first Hospital of Lanzhou University, Lanzhou 730000, China
| | - Jiang-Shan Cong
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Ling-Bo Wang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Feng Zhang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Fudan University, Shanghai 200011, China
| | - Zheng Li
- Department of Andrology, Center for Men's Health, Urologic Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China
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Abstract
Pituitary stalk interruption syndrome (PSIS) is a distinct developmental defect of the pituitary gland identified by magnetic resonance imaging and characterized by a thin, interrupted, attenuated or absent pituitary stalk, hypoplasia or aplasia of the adenohypophysis, and an ectopic posterior pituitary. The precise etiology of PSIS still remains elusive or incompletely confirmed in most cases. Adverse perinatal events, including breech delivery and hypoxia, were initially proposed as the underlying mechanism affecting the hypothalamic-pituitary axis. Nevertheless, recent findings have uncovered a wide variety of PSIS-associated molecular defects in genes involved in pituitary development, holoprosencephaly (HPE), neural development, and other important cellular processes such as cilia function. The application of whole exome sequencing (WES) in relatively large cohorts has identified an expanded pool of potential candidate genes, mostly related to the Wnt, Notch, and sonic hedgehog signaling pathways that regulate pituitary growth and development during embryogenesis. Importantly, WES has revealed coexisting pathogenic variants in a significant number of patients; therefore, pointing to a multigenic origin and inheritance pattern of PSIS. The disorder is characterized by inter- and intrafamilial variability and incomplete or variable penetrance. Overall, PSIS is currently viewed as a mild form of an expanded HPE spectrum. The wide and complex clinical manifestations include evolving pituitary hormone deficiencies (with variable timing of onset and progression) and extrapituitary malformations. Severe and life-threatening symptomatology is observed in a subset of patients with complete pituitary hormone deficiency during the neonatal period. Nevertheless, most patients are referred later in childhood for growth retardation. Prompt and appropriate hormone substitution therapy constitutes the cornerstone of treatment. Further studies are needed to uncover the etiopathogenesis of PSIS.
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Affiliation(s)
- Antonis Voutetakis
- Department of Pediatrics, School of Medicine, Democritus University of Thrace, Alexandroupolis, Thrace, Greece.
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49
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Brauner R, Bignon-Topalovic J, Bashamboo A, McElreavey K. Peripheral Precocious Puberty of Ovarian Origin in a Series of 18 Girls: Exome Study Finds Variants in Genes Responsible for Hypogonadotropic Hypogonadism. Front Pediatr 2021; 9:641397. [PMID: 34055685 PMCID: PMC8149944 DOI: 10.3389/fped.2021.641397] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/16/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Peripheral precocious puberty of ovarian origin is a very rare condition compared to central form. It may be associated with an isolated ovarian cyst (OC). The causes of OC in otherwise healthy prepubertal girls is currently unknown. Methods: Exome sequencing was performed on a cohort of 18 unrelated girls presenting with prenatal and/or prepubertal OC at pelvic ultrasonography. The presenting symptom was prenatal OC in 5, breast development in 7 (with vaginal bleeding in 3) and isolated vaginal bleeding in 6. All had OC ≥ 10 mm. The girls had no other anomalies. Four patients had a familial history of ovarian anomalies and/or infertility. Results: In 9 girls (50%), candidate or known pathogenic variants were identified in genes associated with syndromic and non-syndromic forms of hypogonadotropic hypogonadism including PNPLA6, SEMA3A, TACR3, PROK2, KDM6A, KMT2D, OFD1, GNRH1, GNRHR, GLI3, INSR, CHD7, CDON, RNF216, PROKR2, GLI3, LEPR. Basal plasma concentrations of gonadotropins were undetectable and did not increase after gonadotropin-releasing hormone test in 3 of them whilst 5 had prepubertal values. The plasma estradiol concentrations were prepubertal in 6 girls, high (576 pmol/L) in one and not evaluated in 2 of them. Conclusions: In the first study reporting exome sequencing in prepubertal OC, half of the patients with OC carry either previously reported pathogenic variants or potentially pathogenic variants in genes known to be associated with isolated or syndromic forms of congenital hypogonadotropic hypogonadism. Functional studies and studies of other cohorts are recommended to establish the causality of these variants.
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Affiliation(s)
- Raja Brauner
- Hôpital Fondation Adolphe de Rothschild and Université Paris Descartes, Paris, France
| | | | - Anu Bashamboo
- Human Developmental Genetics Unit, Institut Pasteur, Paris, France
| | - Ken McElreavey
- Human Developmental Genetics Unit, Institut Pasteur, Paris, France
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50
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Brandies PA, Wright BR, Hogg CJ, Grueber CE, Belov K. Characterization of reproductive gene diversity in the endangered Tasmanian devil. Mol Ecol Resour 2020; 21:721-732. [PMID: 33188658 DOI: 10.1111/1755-0998.13295] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/25/2020] [Accepted: 11/05/2020] [Indexed: 01/11/2023]
Abstract
Interindividual variation at genes known to play a role in reproduction may impact reproductive fitness. The Tasmanian devil is an endangered Australian marsupial with low genetic diversity. Recent work has shown concerning declines in productivity in both wild and captive populations over time. Understanding whether functional diversity exists at reproductive genes in the Tasmanian devil is a key first step in identifying genes that may influence productivity. We characterized single nucleotide polymorphisms (SNPs) at 214 genes involved in reproduction in 37 Tasmanian devils. Twenty genes contained nonsynonymous substitutions, with genes involved in embryogenesis, fertilization and hormonal regulation of reproduction displaying greater numbers of nonsynonymous SNPs than synonymous SNPs. Two genes, ADAMTS9 and NANOG, showed putative signatures of balancing selection indicating that natural selection is maintaining diversity at these genes despite the species exhibiting low overall levels of genetic diversity. We will use this information in future to examine the interplay between reproductive gene variation and reproductive fitness in Tasmanian devil populations.
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Affiliation(s)
- Parice A Brandies
- School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW, Australia
| | - Belinda R Wright
- School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW, Australia
| | - Carolyn J Hogg
- School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW, Australia
| | - Catherine E Grueber
- School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW, Australia.,San Diego Zoo Global, San Diego, CA, USA
| | - Katherine Belov
- School of Life and Environmental Sciences, Faculty of Science, University of Sydney, Sydney, NSW, Australia
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