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Bayam E, Tilly P, Collins SC, Rivera Alvarez J, Kannan M, Tonneau L, Brivio E, Rinaldi B, Lecat R, Schwaller N, Cotellessa L, Maddirevula S, Monteiro F, Guardia CM, Kitajima JP, Kok F, Kato M, Hamed AAA, Salih MA, Al Tala S, Hashem MO, Tada H, Saitsu H, Stabile M, Giacobini P, Friant S, Yüksel Z, Nakashima M, Alkuraya FS, Yalcin B, Godin JD. Bi-allelic variants in WDR47 cause a complex neurodevelopmental syndrome. EMBO Mol Med 2025; 17:129-168. [PMID: 39609633 PMCID: PMC11730659 DOI: 10.1038/s44321-024-00178-z] [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: 01/09/2024] [Revised: 11/13/2024] [Accepted: 11/13/2024] [Indexed: 11/30/2024] Open
Abstract
Brain development requires the coordinated growth of structures and cues that are essential for forming neural circuits and cognitive functions. The corpus callosum, the largest interhemispheric connection, is formed by the axons of callosal projection neurons through a series of tightly regulated cellular events, including neuronal specification, migration, axon extension and branching. Defects in any of those steps can lead to a range of disorders known as syndromic corpus callosum dysgenesis (CCD). We report five unrelated families carrying bi-allelic variants in WDR47 presenting with CCD together with other neuroanatomical phenotypes such as microcephaly and enlarged ventricles. Using in vitro and in vivo mouse models and complementation assays, we show that WDR47 is required for survival of callosal neurons by contributing to the maintenance of mitochondrial and microtubule homeostasis. We further propose that severity of the CCD phenotype is determined by the degree of the loss of function caused by the human variants. Taken together, we identify WDR47 as a causative gene of a new neurodevelopmental syndrome characterized by corpus callosum abnormalities and other neuroanatomical malformations.
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Affiliation(s)
- Efil Bayam
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France.
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France.
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France.
- Université de Strasbourg, Strasbourg, F-67000, France.
| | - Peggy Tilly
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
| | - Stephan C Collins
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
- Université de Bourgogne, INSERM UMR1231, 21000, Dijon, France
| | - José Rivera Alvarez
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
| | - Meghna Kannan
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
| | - Lucile Tonneau
- Université de Bourgogne, INSERM UMR1231, 21000, Dijon, France
| | - Elena Brivio
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
| | - Bruno Rinaldi
- Université de Strasbourg, CNRS, GMGM UMR7156, F-67000, Strasbourg, France
- INSERM, U1112, CRBS (Centre de recherche en biomédecine de Strasbourg), Université de Strasbourg, Strasbourg, F-67000, France
| | - Romain Lecat
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
| | - Noémie Schwaller
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France
- Université de Strasbourg, Strasbourg, F-67000, France
| | - Ludovica Cotellessa
- Université de Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, Lille, France
| | - Sateesh Maddirevula
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | | | - Carlos M Guardia
- Placental Cell Biology Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, 27709, USA
| | | | - Fernando Kok
- Mendelics Análise Genomica SA, CEP 02511-000, Sao Paulo, Brazil
- Department of Neurology, University of Sao Paulo School of Medicine, 01246-903, Sao Paulo, Brazil
| | - Mitsuhiro Kato
- Department of Pediatrics, Showa University School of Medicine, Tokyo, 142-8555, Japan
| | - Ahlam A A Hamed
- Department of Pediatric and Child Health, Faculty of Medicine University of Khartoum, Khartoum, Sudan
| | - Mustafa A Salih
- Health Sector, King Abdulaziz City for Science and Technology, Riyadh, 11442, Saudi Arabia
| | - Saeed Al Tala
- Department of Pediatrics, Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia
| | - Mais O Hashem
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hiroko Tada
- Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, 156-0057, Japan
- Division of Pediatrics, Chibaken Saiseikai Narashino Hospital, Chiba, 275-8580, Japan
| | - Hirotomo Saitsu
- Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuuo-ku, Hamamatsu, 431-3192, Japan
| | - Mariano Stabile
- Center of Genetics and Prenatal Diagnosis "Zygote", 84131, Salerno, Italy
| | - Paolo Giacobini
- Université de Lille, INSERM, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition UMR-S 1172, Lille, France
| | - Sylvie Friant
- Université de Strasbourg, CNRS, GMGM UMR7156, F-67000, Strasbourg, France
- PCBIS-IMPReSs, Plateforme de Chimie Biologique Intégrative de Strasbourg, UAR 3286 CNRS/Université de Strasbourg, 67400, Illkirch, France
| | - Zafer Yüksel
- Human Genetics, Bioscientia GmbH, Ingelheim, Germany
| | - Mitsuko Nakashima
- Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Chuuo-ku, Hamamatsu, 431-3192, Japan
| | - Fowzan S Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Binnaz Yalcin
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France.
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France.
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France.
- Université de Strasbourg, Strasbourg, F-67000, France.
- INSERM UMR1231, Université de Bourgogne, 21000, Dijon, France.
| | - Juliette D Godin
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, IGBMC, Illkirch, F-67404, France.
- Centre National de la Recherche Scientifique, CNRS, UMR7104, Illkirch, F-67404, France.
- Institut National de la Santé et de la Recherche Médicale, INSERM, U1258, Illkirch, F-67404, France.
- Université de Strasbourg, Strasbourg, F-67000, France.
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2
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Chen J, Lewis MA, Wai A, Yin L, Dawson SJ, Ingham NJ, Steel KP. A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential. Hear Res 2024; 451:109091. [PMID: 39067415 DOI: 10.1016/j.heares.2024.109091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/04/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.
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Affiliation(s)
- Jing Chen
- Wolfson Sensory, Pain and Regeneration Centre, King's College London, London SE1 1UL, United Kingdom
| | - Morag A Lewis
- Wolfson Sensory, Pain and Regeneration Centre, King's College London, London SE1 1UL, United Kingdom
| | - Alisa Wai
- Wolfson Sensory, Pain and Regeneration Centre, King's College London, London SE1 1UL, United Kingdom
| | - Lucia Yin
- Wolfson Sensory, Pain and Regeneration Centre, King's College London, London SE1 1UL, United Kingdom
| | - Sally J Dawson
- UCL Ear Institute, University College London, London WC1X 8EE, United Kingdom
| | - Neil J Ingham
- Wolfson Sensory, Pain and Regeneration Centre, King's College London, London SE1 1UL, United Kingdom
| | - Karen P Steel
- Wolfson Sensory, Pain and Regeneration Centre, King's College London, London SE1 1UL, United Kingdom.
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3
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Mi D, Yanatori I, Zheng H, Kong Y, Hirayama T, Toyokuni S. Association of poly( rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. Free Radic Res 2024; 58:261-275. [PMID: 38599240 DOI: 10.1080/10715762.2024.2340711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/15/2024] [Indexed: 04/12/2024]
Abstract
Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here, we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Although direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.
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Affiliation(s)
- Danyang Mi
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Izumi Yanatori
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hao Zheng
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yingyi Kong
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tasuku Hirayama
- Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Gifu, Japan
| | - Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan
- Center for Integrated Sciences of Low-temperature Plasma Core Research (iPlasma Core), Tokai National Higher Education and Research System, Nagoya, Japan
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4
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Kretz PF, Wagner C, Mikhaleva A, Montillot C, Hugel S, Morella I, Kannan M, Fischer MC, Milhau M, Yalcin I, Brambilla R, Selloum M, Herault Y, Reymond A, Collins SC, Yalcin B. Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein. Genome Biol 2023; 24:261. [PMID: 37968726 PMCID: PMC10647150 DOI: 10.1186/s13059-023-03092-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 10/18/2023] [Indexed: 11/17/2023] Open
Abstract
BACKGROUND Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus. RESULTS We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes. In male mice, among the 13 genes associated with neuroanatomical defects (Mvp, Ppp4c, Zg16, Taok2, Slx1b, Maz, Fam57b, Bola2, Tbx6, Qprt, Spn, Hirip3, and Doc2a), Mvp is the top driver implicated in phenotypes pertaining to brain, cortex, hippocampus, ventricles, and corpus callosum sizes. The major vault protein (MVP), the main component of the vault organelle, is a conserved protein found in eukaryotic cells, yet its function is not understood. Here, we find MVP expression highly specific to the limbic system and show that Mvp regulates neuronal morphology, postnatally and specifically in males. We also recapitulate a previously reported genetic interaction and show that Mvp+/-;Mapk3+/- mice exhibit behavioral deficits, notably decreased anxiety-like traits detected in the elevated plus maze and open field paradigms. CONCLUSIONS Our study highlights multiple gene drivers in neuroanatomical phenotypes, interacting with each other through complex relationships. It also provides the first evidence for the involvement of the major vault protein in the regulation of brain size and neuroanatomy, specifically in male mice.
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Affiliation(s)
- Perrine F Kretz
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
| | - Christel Wagner
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
| | - Anna Mikhaleva
- Center for Integrative Genomics, University of Lausanne, CH-1015, Lausanne, Switzerland
| | | | - Sylvain Hugel
- Institute of Cellular and Integrative neuroscience, CNRS, UPR321267000, Strasbourg, France
| | - Ilaria Morella
- School of Biosciences, Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, CF24 4HQ, UK
| | - Meghna Kannan
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
| | - Marie-Christine Fischer
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
| | - Maxence Milhau
- Inserm UMR1231, Université de Bourgogne, 21000, Dijon, France
| | - Ipek Yalcin
- Institute of Cellular and Integrative neuroscience, CNRS, UPR321267000, Strasbourg, France
| | - Riccardo Brambilla
- School of Biosciences, Neuroscience and Mental Health Innovation Institute, Cardiff University, Cardiff, CF24 4HQ, UK
- Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani", Università degli Studi di Pavia, Pavia, Italy
| | - Mohammed Selloum
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
- University of Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, ICS, 67400, Illkirch, France
| | - Yann Herault
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
- University of Strasbourg, CNRS, INSERM, CELPHEDIA, PHENOMIN, ICS, 67400, Illkirch, France
| | - Alexandre Reymond
- Center for Integrative Genomics, University of Lausanne, CH-1015, Lausanne, Switzerland
| | - Stephan C Collins
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France
- Current address: Université de Bourgogne, Inserm UMR1231, 21000, Dijon, France
| | - Binnaz Yalcin
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, University of Strasbourg, CNRS, INSERM, IGBMC, U964, 67400, Illkirch, France.
- Current address: Université de Bourgogne, Inserm UMR1231, 21000, Dijon, France.
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5
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Levitin MO, Rawlins LE, Sanchez-Andrade G, Arshad OA, Collins SC, Sawiak SJ, Iffland PH, Andersson MHL, Bupp C, Cambridge EL, Coomber EL, Ellis I, Herkert JC, Ironfield H, Jory L, Kretz PF, Kant SG, Neaverson A, Nibbeling E, Rowley C, Relton E, Sanderson M, Scott EM, Stewart H, Shuen AY, Schreiber J, Tuck L, Tonks J, Terkelsen T, van Ravenswaaij-Arts C, Vasudevan P, Wenger O, Wright M, Day A, Hunter A, Patel M, Lelliott CJ, Crino PB, Yalcin B, Crosby AH, Baple EL, Logan DW, Hurles ME, Gerety SS. Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes. Brain 2023; 146:4766-4783. [PMID: 37437211 PMCID: PMC10629792 DOI: 10.1093/brain/awad231] [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: 11/02/2022] [Revised: 05/31/2023] [Accepted: 06/18/2023] [Indexed: 07/14/2023] Open
Abstract
KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.
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Affiliation(s)
- Maria O Levitin
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Evox Therapeutics Limited, Oxford OX4 4HG, UK
| | - Lettie E Rawlins
- RILD Wellcome Wolfson Medical Research Centre, University of Exeter, Exeter EX2 5DW, UK
- Peninsula Clinical Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter EX1 2ED, UK
| | | | - Osama A Arshad
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Stephan C Collins
- INSERM Unit 1231, Université de Bourgogne Franche-Comté, Dijon 21078, France
| | - Stephen J Sawiak
- Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK
- Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Phillip H Iffland
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Malin H L Andersson
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Caleb Bupp
- Spectrum Health, Helen DeVos Children’s Hospital, Grand Rapids, MI 49503, USA
| | - Emma L Cambridge
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Eve L Coomber
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Ian Ellis
- Department of Clinical Genetics, Alder Hey Children’s Hospital, Liverpool L14 5AB, UK
| | - Johanna C Herkert
- Department of Genetics, University Medical Centre, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Holly Ironfield
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Logan Jory
- Haven Clinical Psychology Practice Ltd, Bude, Cornwall EX23 9HP, UK
| | | | - Sarina G Kant
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden 2300 RC, The Netherlands
| | - Alexandra Neaverson
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK
| | - Esther Nibbeling
- Laboratory for Diagnostic Genome Analysis, Department of Clinical Genetics, Leiden University Medical Center, Leiden 3015 GD, The Netherlands
| | - Christine Rowley
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Institute of Metabolic Science, Cambridge University, Cambridge CB2 0QQ, UK
| | - Emily Relton
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Faculty of Health and Medical Science, University of Surrey, Guildford GU2 7YH, UK
| | - Mark Sanderson
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Ethan M Scott
- New Leaf Center, Clinic for Special Children, Mount Eaton, OH 44659, USA
| | - Helen Stewart
- Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford OX3 7HE, UK
| | - Andrew Y Shuen
- London Health Sciences Centre, London, ON N6A 5W9, Canada
- Division of Medical Genetics, Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5W9, Canada
| | - John Schreiber
- Department of Neurology, Children’s National Medical Center, Washington DC 20007, USA
| | - Liz Tuck
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - James Tonks
- Haven Clinical Psychology Practice Ltd, Bude, Cornwall EX23 9HP, UK
| | - Thorkild Terkelsen
- Department of Clinical Genetics, Aarhus University Hospital, Aarhus DK-8200, Denmark
| | - Conny van Ravenswaaij-Arts
- Department of Genetics, University Medical Centre, University of Groningen, Groningen 9713 GZ, The Netherlands
| | - Pradeep Vasudevan
- Department of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 7RH, UK
| | - Olivia Wenger
- New Leaf Center, Clinic for Special Children, Mount Eaton, OH 44659, USA
| | - Michael Wright
- Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne NE1 7RU, UK
| | - Andrew Day
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Qkine Ltd., Cambridge CB5 8HW, UK
| | - Adam Hunter
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Minal Patel
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Christopher J Lelliott
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Institute of Metabolic Science, Cambridge University, Cambridge CB2 0QQ, UK
| | - Peter B Crino
- Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Binnaz Yalcin
- INSERM Unit 1231, Université de Bourgogne Franche-Comté, Dijon 21078, France
| | - Andrew H Crosby
- RILD Wellcome Wolfson Medical Research Centre, University of Exeter, Exeter EX2 5DW, UK
| | - Emma L Baple
- RILD Wellcome Wolfson Medical Research Centre, University of Exeter, Exeter EX2 5DW, UK
- Peninsula Clinical Genetics Service, Royal Devon University Healthcare NHS Foundation Trust, Exeter EX1 2ED, UK
| | - Darren W Logan
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Waltham Petcare Science Institute, Waltham on the Wolds LE14 4RT, UK
| | - Matthew E Hurles
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Sebastian S Gerety
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
- Open Targets, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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张 竞, 何 静, 米 晓, 许 贤, 田 英, 燕 茹. [High homocysteine level promotes autophagy and apoptosis of mouse hippocampal HT22 cells through the Notch1/Hes1 signaling pathway]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:1796-1803. [PMID: 37933657 PMCID: PMC10630217 DOI: 10.12122/j.issn.1673-4254.2023.10.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Indexed: 11/08/2023]
Abstract
OBJECTIVE To explore the mechanism of neuronal injury caused by hyperhomocysteinemia. METHODS Mouse hippocampal HT22 cells were treated with homocysteine (Hcy, 100 μmol/L), Hcy+folic acid+vitamin B12 (100+fv group) or folic acid+vitamin B12 (0+fv group), and the changes in cell autophagy and apoptosis were detected using transmission electron microscope (TEM) and flow cytometry. The expressions of Hes1, Hes5, Notch1, Jagged1, Bcl-2, Bax, P62 and LC3 in the treated cells were detected with Western blotting and real-time PCR. RESULTS Treatment with Hcy for 48 h significantly increased the number of dead cells in HT22 cell cultures. Flow cytometry showed that the percentage of apoptotic cells was significantly higher in cells treated with Hcy alone than in other treatment groups (P<0.05). TEM revealed obvious mitochondrial swelling and vacuolation and increased autophagy in Hcy-treated cells. Western blotting showed that the Bax/Bcl-2 ratio was significantly higher in Hcy-treated cells than in the blank control cells and cells in 100+fv group (P<0.05). The Hcy-treated cells showed a significantly lower relative expression of P62 than the blank control cells (P<0.05), a higher LC3II/LC3I ratio than the cells in the blank control and 100+fv groups (P<0.05), and lower expressions of HES1, HES5, Notch1 and Jagged1 proteins than the blank control cells (P<0.05). Interference with Hes1 siRNA significantly lowered the expression levels of Hes1 and Jagged1 without obviously affecting Notch1 expression in HT22 cells (P>0.05). CONCLUSION High Hcy levels promote autophagy and apoptosis and down-regulate Hes1 and Jagged1 expressions in HT22 cells.
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Affiliation(s)
- 竞文 张
- 宁夏医科大学基础医学院//国家卫生健康委员会代谢性心血管疾病研究重点实验室, 宁夏 银川 750004School of Basic Medical Sciences, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, University, Yinchuan 750004, China Yinchuan 750004, China
| | - 静 何
- 宁夏医科大学总医院, 宁夏 银川 750004General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - 晓娟 米
- 宁夏医科大学基础医学院//国家卫生健康委员会代谢性心血管疾病研究重点实验室, 宁夏 银川 750004School of Basic Medical Sciences, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, University, Yinchuan 750004, China Yinchuan 750004, China
| | - 贤瑞 许
- 宁夏医科大学总医院, 宁夏 银川 750004General Hospital of Ningxia Medical University, Yinchuan 750004, China
| | - 英 田
- 宁夏医科大学基础医学院//国家卫生健康委员会代谢性心血管疾病研究重点实验室, 宁夏 银川 750004School of Basic Medical Sciences, NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, University, Yinchuan 750004, China Yinchuan 750004, China
| | - 茹 燕
- 宁夏医科大学总医院, 宁夏 银川 750004General Hospital of Ningxia Medical University, Yinchuan 750004, China
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7
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Montillot C, Skutunova E, Ayushma, Dubied M, Lahmar A, Nguyen S, Peerally B, Prin F, Duffourd Y, Thauvin-Robinet C, Duplomb L, Wang H, Ansar M, Faivre L, Navarro N, Minocha S, Collins SC, Yalcin B. Characterization of Vps13b-mutant mice reveals neuroanatomical and behavioral phenotypes with females less affected. Neurobiol Dis 2023; 185:106259. [PMID: 37573958 DOI: 10.1016/j.nbd.2023.106259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/26/2023] [Accepted: 08/11/2023] [Indexed: 08/15/2023] Open
Abstract
The vacuolar protein sorting-associated protein 13B (VPS13B) is a large and highly conserved protein. Disruption of VPS13B causes the autosomal recessive Cohen syndrome, a rare disorder characterized by microcephaly and intellectual disability among other features, including developmental delay, hypotonia, and friendly-personality. However, the underlying mechanisms by which VPS13B disruption leads to brain dysfunction still remain unexplained. To gain insights into the neuropathogenesis of Cohen syndrome, we systematically characterized brain changes in Vps13b-mutant mice and compared murine findings to 235 previously published and 17 new patients diagnosed with VPS13B-related Cohen syndrome. We showed that Vps13b is differentially expressed across brain regions with the highest expression in the cerebellum, the hippocampus and the cortex with postnatal peak. Half of the Vps13b-/- mice die during the first week of life. The remaining mice have a normal lifespan and display the core phenotypes of the human disease, including microcephaly, growth delay, hypotonia, altered memory, and enhanced sociability. Systematic 2D and 3D brain histo-morphological analyses reveal specific structural changes in the brain starting after birth. The dentate gyrus is the brain region with the most prominent reduction in size, while the motor cortex is specifically thinner in layer VI. The fornix, the fasciculus retroflexus, and the cingulate cortex remain unaffected. Interestingly, these neuroanatomical changes implicate an increase of neuronal death during infantile stages with no progression in adulthood suggesting that VPS13B promotes neuronal survival early in life. Importantly, whilst both sexes were affected, some neuroanatomical and behavioral phenotypes were less pronounced or even absent in females. We evaluate sex differences in Cohen patients and conclude that females are less affected both in mice and patients. Our findings provide new insights about the neurobiology of VPS13B and highlight previously unreported brain phenotypes while defining Cohen syndrome as a likely new entity of non-progressive infantile neurodegeneration.
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Affiliation(s)
- Charlotte Montillot
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Emilia Skutunova
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Ayushma
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi (IITD), Hauz Khas, New Delhi 110016, India
| | - Morgane Dubied
- Biogéosciences, UMR 6282 CNRS, EPHE, Université de Bourgogne, 21000 Dijon, France
| | - Adam Lahmar
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Sylvie Nguyen
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Benazir Peerally
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Fabrice Prin
- Crick Advanced Light Microscopy Facility, The Francis Crick Institute, London NW1 1AT, UK
| | - Yannis Duffourd
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, Dijon University Hospital, 21000 Dijon, France
| | - Christel Thauvin-Robinet
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, Dijon University Hospital, 21000 Dijon, France; Reference Center for Rare Diseases "Déficiences intellectuelles de causes rares", Dijon University Hospital, 21000 Dijon, France
| | - Laurence Duplomb
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Heng Wang
- DDC Clinic for Special Needs Children, Middlefield, OH 44062, USA
| | - Muhammad Ansar
- Jules Gonin Eye Hospital, University of Lausanne, CH-1015 Lausanne, Switzerland; Advanced Molecular Genetics and Genomics Disease Research and Treatment Centre, Dow University of Health Sciences, Karachi, Pakistan
| | - Laurence Faivre
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France; Reference Center for Rare Diseases "Anomalies du Développement et syndromes malformatifs", Dijon University Hospital, 21000 Dijon, France
| | - Nicolas Navarro
- Biogéosciences, UMR 6282 CNRS, EPHE, Université de Bourgogne, 21000 Dijon, France; EPHE, PSL University, Paris 75014, France
| | - Shilpi Minocha
- Kusuma School of Biological Sciences, Indian Institute of Technology Delhi (IITD), Hauz Khas, New Delhi 110016, India
| | - Stephan C Collins
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France
| | - Binnaz Yalcin
- Université de Bourgogne, 21000 Dijon, France; Inserm Unit 1231, 21000 Dijon, France.
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8
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Denommé-Pichon AS, Collins SC, Bruel AL, Mikhaleva A, Wagner C, Vancollie VE, Thomas Q, Chevarin M, Weber M, Prada CE, Overs A, Palomares-Bralo M, Santos-Simarro F, Pacio-Míguez M, Busa T, Legius E, Bacino CA, Rosenfeld JA, Le Guyader G, Egloff M, Le Guillou X, Mencarelli MA, Renieri A, Grosso S, Levy J, Dozières B, Desguerre I, Vitobello A, Duffourd Y, Lelliott CJ, Thauvin-Robinet C, Philippe C, Faivre L, Yalcin B. YWHAE loss of function causes a rare neurodevelopmental disease with brain abnormalities in human and mouse. Genet Med 2023; 25:100835. [PMID: 36999555 DOI: 10.1016/j.gim.2023.100835] [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: 10/10/2022] [Revised: 03/20/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
PURPOSE Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. METHODS Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. RESULTS We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. CONCLUSION This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.
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Affiliation(s)
- Anne-Sophie Denommé-Pichon
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France; European Reference Network, ERN-ITHACA.
| | - Stephan C Collins
- UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France
| | - Ange-Line Bruel
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France
| | - Anna Mikhaleva
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | | | | | - Quentin Thomas
- UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France; Department of Neurology, Dijon Bourgogne University Hospital, Dijon, France
| | - Martin Chevarin
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France
| | - Mathys Weber
- UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France; Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France
| | - Carlos E Prada
- Division of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Alexis Overs
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France
| | - María Palomares-Bralo
- European Reference Network, ERN-ITHACA; Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, IdiPAZ, Madrid, Spain; Rare Diseases Networking Biomedical Research Centre (CIBERER), Carlos III Institute, Madrid, Spain
| | - Fernando Santos-Simarro
- European Reference Network, ERN-ITHACA; Institute of Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Autonomous University of Madrid, IdiPAZ, Madrid, Spain; Rare Diseases Networking Biomedical Research Centre (CIBERER), Carlos III Institute, Madrid, Spain
| | - Marta Pacio-Míguez
- Rare Diseases Networking Biomedical Research Centre (CIBERER), Carlos III Institute, Madrid, Spain
| | - Tiffany Busa
- Department of Medical Genetics, CHU Timone Enfants, AP-HM, Marseille, France
| | - Eric Legius
- Laboratory for Neurofibromatosis Research, Department of Human Genetics, KU Leuven University Hospital, Belgium
| | - Carlos A Bacino
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Jill A Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Baylor Genetics Laboratories, Houston, TX
| | - Gwenaël Le Guyader
- Genetics Department, Poitiers University Hospital, Poitiers, France; University of Poitiers, Poitiers, France
| | - Matthieu Egloff
- Genetics Department, Poitiers University Hospital, Poitiers, France; University of Poitiers, Poitiers, France; Experimental and Clinical Neurosciences Laboratory, INSERM, University of Poitiers, Poitiers, France
| | - Xavier Le Guillou
- Genetics Department, Poitiers University Hospital, Poitiers, France; University of Poitiers, Poitiers, France
| | | | - Alessandra Renieri
- Medical Genetics, Azienda Ospedaliero-Universitaria Senese, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
| | - Salvatore Grosso
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy; U.O.C. Pediatria, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Jonathan Levy
- Genetics Department, Robert-Debré University Hospital, APHP, Paris, France
| | - Blandine Dozières
- Department of Pediatric Neurology and Metabolic Diseases, Robert Debré University Hospital, APHP, Paris, France
| | - Isabelle Desguerre
- Departments of Pediatric Neurology and Medical Genetics, Hôpital Necker-Enfants Malades, Université Paris Cité, Paris, France
| | - Antonio Vitobello
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France; European Reference Network, ERN-ITHACA
| | - Yannis Duffourd
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France
| | | | - Christel Thauvin-Robinet
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France; Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France
| | - Christophe Philippe
- Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France; UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France
| | - Laurence Faivre
- UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France; European Reference Network, ERN-ITHACA; Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France
| | - Binnaz Yalcin
- UMR1231 GAD "Génétique des Anomalies du Développement", INSERM, FHU-TRANSLAD, University of Burgundy, Dijon, France.
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9
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Pretzsch CM, Ecker C. Structural neuroimaging phenotypes and associated molecular and genomic underpinnings in autism: a review. Front Neurosci 2023; 17:1172779. [PMID: 37457001 PMCID: PMC10347684 DOI: 10.3389/fnins.2023.1172779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 06/09/2023] [Indexed: 07/18/2023] Open
Abstract
Autism has been associated with differences in the developmental trajectories of multiple neuroanatomical features, including cortical thickness, surface area, cortical volume, measures of gyrification, and the gray-white matter tissue contrast. These neuroimaging features have been proposed as intermediate phenotypes on the gradient from genomic variation to behavioral symptoms. Hence, examining what these proxy markers represent, i.e., disentangling their associated molecular and genomic underpinnings, could provide crucial insights into the etiology and pathophysiology of autism. In line with this, an increasing number of studies are exploring the association between neuroanatomical, cellular/molecular, and (epi)genetic variation in autism, both indirectly and directly in vivo and across age. In this review, we aim to summarize the existing literature in autism (and neurotypicals) to chart a putative pathway from (i) imaging-derived neuroanatomical cortical phenotypes to (ii) underlying (neuropathological) biological processes, and (iii) associated genomic variation.
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Affiliation(s)
- Charlotte M. Pretzsch
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom
| | - Christine Ecker
- Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
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10
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Groza T, Gomez FL, Mashhadi HH, Muñoz-Fuentes V, Gunes O, Wilson R, Cacheiro P, Frost A, Keskivali-Bond P, Vardal B, McCoy A, Cheng TK, Santos L, Wells S, Smedley D, Mallon AM, Parkinson H. The International Mouse Phenotyping Consortium: comprehensive knockout phenotyping underpinning the study of human disease. Nucleic Acids Res 2023; 51:D1038-D1045. [PMID: 36305825 PMCID: PMC9825559 DOI: 10.1093/nar/gkac972] [Citation(s) in RCA: 217] [Impact Index Per Article: 108.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/05/2022] [Accepted: 10/14/2022] [Indexed: 01/30/2023] Open
Abstract
The International Mouse Phenotyping Consortium (IMPC; https://www.mousephenotype.org/) web portal makes available curated, integrated and analysed knockout mouse phenotyping data generated by the IMPC project consisting of 85M data points and over 95,000 statistically significant phenotype hits mapped to human diseases. The IMPC portal delivers a substantial reference dataset that supports the enrichment of various domain-specific projects and databases, as well as the wider research and clinical community, where the IMPC genotype-phenotype knowledge contributes to the molecular diagnosis of patients affected by rare disorders. Data from 9,000 mouse lines and 750 000 images provides vital resources enabling the interpretation of the ignorome, and advancing our knowledge on mammalian gene function and the mechanisms underlying phenotypes associated with human diseases. The resource is widely integrated and the lines have been used in over 4,600 publications indicating the value of the data and the materials.
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Affiliation(s)
- Tudor Groza
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
| | - Federico Lopez Gomez
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
| | - Hamed Haseli Mashhadi
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
| | - Violeta Muñoz-Fuentes
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
| | - Osman Gunes
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
| | - Robert Wilson
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
| | - Pilar Cacheiro
- William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Anthony Frost
- Mary Lyon Centre at MRC Harwell, Harwell Campus OX11 7UE, UK
| | | | - Bora Vardal
- Mary Lyon Centre at MRC Harwell, Harwell Campus OX11 7UE, UK
| | - Aaron McCoy
- Mary Lyon Centre at MRC Harwell, Harwell Campus OX11 7UE, UK
| | - Tsz Kwan Cheng
- Mary Lyon Centre at MRC Harwell, Harwell Campus OX11 7UE, UK
| | - Luis Santos
- Research Data Team, The Turing Institute, 96 Euston Rd, London NW1 2DB, UK
| | - Sara Wells
- Mary Lyon Centre at MRC Harwell, Harwell Campus OX11 7UE, UK
| | - Damian Smedley
- William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Ann-Marie Mallon
- Research Data Team, The Turing Institute, 96 Euston Rd, London NW1 2DB, UK
| | - Helen Parkinson
- European Bioinformatics Institute, European Molecular Biology Laboratory, Welcome Genome Campus, Hinxton CB10 1SD, UK
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11
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Collins SC, Vancollie VE, Mikhaleva A, Wagner C, Balz R, Lelliott CJ, Yalcin B. Characterization of Two Mouse Chd7 Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome. Int J Mol Sci 2022; 23:11509. [PMID: 36232804 PMCID: PMC9569499 DOI: 10.3390/ijms231911509] [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] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.
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Affiliation(s)
- Stephan C. Collins
- Inserm UMR1231, University of Burgundy Franche-Comté, 15 Boulevard Maréchal de Lattre de Tassigny, 21070 Dijon, France
| | | | - Anna Mikhaleva
- Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
| | - Christel Wagner
- Institute of Genetics and Molecular and Cellular Biology, UMR7104, 67400 Illkirch, France
| | - Rebecca Balz
- Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
| | | | - Binnaz Yalcin
- Inserm UMR1231, University of Burgundy Franche-Comté, 15 Boulevard Maréchal de Lattre de Tassigny, 21070 Dijon, France
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12
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Klöckner C, Fernández-Murray JP, Tavasoli M, Sticht H, Stoltenburg-Didinger G, Scholle LM, Bakhtiari S, Kruer MC, Darvish H, Firouzabadi SG, Pagnozzi A, Shukla A, Girisha KM, Narayanan DL, Kaur P, Maroofian R, Zaki MS, Noureldeen MM, Merkenschlager A, Gburek-Augustat J, Cali E, Banu S, Nahar K, Efthymiou S, Houlden H, Jamra RA, Williams J, McMaster CR, Platzer K. Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly. Brain 2022; 145:1916-1923. [PMID: 35202461 PMCID: PMC9630884 DOI: 10.1093/brain/awac074] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/15/2021] [Accepted: 02/06/2022] [Indexed: 11/14/2022] Open
Abstract
The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.
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Affiliation(s)
- Chiara Klöckner
- Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | | | - Mahtab Tavasoli
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3N 0A1, Canada
| | - Heinrich Sticht
- Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
| | | | | | - Somayeh Bakhtiari
- Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, Arizona 85004, USA
- Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, Arizona 85004, USA
| | - Michael C Kruer
- Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, Arizona 85004, USA
- Departments of Child Health, Neurology, Cellular & Molecular Medicine and Program in Genetics, University of Arizona College of Medicine, Phoenix, Arizona 85004, USA
| | - Hossein Darvish
- Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | | | - Alex Pagnozzi
- CSIRO Health and Biosecurity, The Australian e-Health Research Centre, Brisbane, QLD 4029, Australia
| | - Anju Shukla
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
| | - Katta Mohan Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
| | - Dhanya Lakshmi Narayanan
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
| | - Parneet Kaur
- Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
| | - Reza Maroofian
- Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
| | - Maha S Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
| | - Mahmoud M Noureldeen
- Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Andreas Merkenschlager
- Division of Neuropaediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Janina Gburek-Augustat
- Division of Neuropaediatrics, Hospital for Children and Adolescents, University Hospital Leipzig, 04103 Leipzig, Germany
| | - Elisa Cali
- Department of Pediatric Neurology, Dr. M.R. Khan Shishu (Children) Hospital and ICH, Mirpur, Dhaka, Bangladesh
| | - Selina Banu
- Department of Pediatric Neurology, Dr. M.R. Khan Shishu (Children) Hospital and ICH, Mirpur, Dhaka, Bangladesh
| | - Kamrun Nahar
- Department of Pediatric Neurology, Dr. M.R. Khan Shishu (Children) Hospital and ICH, Mirpur, Dhaka, Bangladesh
| | - Stephanie Efthymiou
- Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
| | - Henry Houlden
- Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK
| | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
| | - Jason Williams
- Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia B3N 0A1, Canada
| | | | - Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany
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13
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Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development. Nat Commun 2022; 13:2746. [PMID: 35585091 PMCID: PMC9117333 DOI: 10.1038/s41467-022-30443-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 04/29/2022] [Indexed: 11/08/2022] Open
Abstract
Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
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14
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Rawlins LE, Almousa H, Khan S, Collins SC, Milev MP, Leslie J, Saint-Dic D, Khan V, Hincapie AM, Day JO, McGavin L, Rowley C, Harlalka GV, Vancollie VE, Ahmad W, Lelliott CJ, Gul A, Yalcin B, Crosby AH, Sacher M, Baple EL. Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice. PLoS Genet 2022; 18:e1010114. [PMID: 35298461 PMCID: PMC8963566 DOI: 10.1371/journal.pgen.1010114] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 03/29/2022] [Accepted: 02/20/2022] [Indexed: 11/25/2022] Open
Abstract
The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice. Microcephalic neurodevelopmental disorders are a group of conditions that are often inherited in families, involving small head size and abnormal brain development and function. This often results in delayed development of an affected child, affecting their movement, language and/or non-verbal communication and learning, as well as seizures and neuropsychiatric problems. A group of proteins called the transport protein particles (TRAPPs) are important for the transport of cargos inside cells. Alterations within a number of the TRAPP proteins have previously been associated with human inherited diseases called the ‘TRAPPopathies’, which involve neurodevelopmental and skeletal abnormalities. Here we show that TRAPPC10 gene alterations cause a new TRAPPopathy microcephalic neurodevelopmental disorder, and we provide a detailed clinical description of the condition termed ‘TRAPPC10-related disorder’. Our studies in mice lacking the TRAPPC10 gene identified similar features to those of affected humans, including small brain size and skeletal abnormalities. Our molecular studies showed that an affected individual with an alteration in the TRAPPC10 gene has no functional TRAPPC10 protein in their cells, which in turn causes a reduction in levels of another important TRAPP molecule, TRAPPC9. Cells lacking TRAPPC10 also display abnormalities in cellular transport processes. Together our data confirm alterations in TRAPPC10 as a cause of a microcephalic neurodevelopmental disorder in both humans and mice.
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Affiliation(s)
- Lettie E. Rawlins
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
- Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Exeter, United Kingdom
| | - Hashem Almousa
- Department of Biology, Concordia University, Montreal, Quebec, Canada
| | - Shazia Khan
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| | - Stephan C. Collins
- Institute of Genetics and Molecular and Cellular Biology, Inserm, Illkirch, France
- Inserm, University of Bourgogne Franche-Comté, Dijon, France
| | - Miroslav P. Milev
- Department of Biology, Concordia University, Montreal, Quebec, Canada
| | - Joseph Leslie
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
| | - Djenann Saint-Dic
- Department of Biology, Concordia University, Montreal, Quebec, Canada
| | - Valeed Khan
- Department of Molecular Diagnostics, Rehman Medical Institute, Peshawar, Pakistan
| | | | - Jacob O. Day
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
- Faculty of Health, University of Plymouth, Plymouth, United Kingdom
| | - Lucy McGavin
- University Hospitals Plymouth NHS Trust, Plymouth, United Kingdom
| | | | - Gaurav V. Harlalka
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
- Department of Pharmacology, Rajarshi Shahu College of Pharmacy, Malvihir, Buldana, India
| | | | - Wasim Ahmad
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | | | - Asma Gul
- Department of Biological Sciences, International Islamic University, Islamabad, Pakistan
| | - Binnaz Yalcin
- Institute of Genetics and Molecular and Cellular Biology, Inserm, Illkirch, France
- Inserm, University of Bourgogne Franche-Comté, Dijon, France
| | - Andrew H. Crosby
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
| | - Michael Sacher
- Department of Biology, Concordia University, Montreal, Quebec, Canada
- Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada
| | - Emma L. Baple
- RILD Wellcome Wolfson Medical Research Centre, RD&E (Wonford) NHS Foundation Trust, University of Exeter Medical School, Exeter, United Kingdom
- Peninsula Clinical Genetics Service, Royal Devon & Exeter Hospital (Heavitree), Exeter, United Kingdom
- * E-mail:
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15
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A diffusion MRI-based spatiotemporal continuum of the embryonic mouse brain for probing gene-neuroanatomy connections. Proc Natl Acad Sci U S A 2022; 119:2111869119. [PMID: 35165149 PMCID: PMC8851557 DOI: 10.1073/pnas.2111869119] [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] [Accepted: 12/07/2021] [Indexed: 11/18/2022] Open
Abstract
We established an ultra high-resolution diffusion MRI atlas of the embryonic mouse brains from E10.5 to E15.5, which characterizes the continuous changes of brain morphology and microstructures at mesoscopic scale. By integrating gene-expression data into the spatiotemporal continuum, we can navigate the evolving landscape of gene expression and neuroanatomy across both spatial and temporal dimensions to visualize their interactions in normal and abnormal embryonic brain development. We also identified regional clusters with distinct developmental trajectories and identified gene-expression profiles that matched to these regional domains. The diffusion MRI–based continuum of the embryonic brain and the computational techniques presented in this study offer a valuable tool for systematic study of the genetic control of brain development. The embryonic mouse brain undergoes drastic changes in establishing basic anatomical compartments and laying out major axonal connections of the developing brain. Correlating anatomical changes with gene-expression patterns is an essential step toward understanding the mechanisms regulating brain development. Traditionally, this is done in a cross-sectional manner, but the dynamic nature of development calls for probing gene–neuroanatomy interactions in a combined spatiotemporal domain. Here, we present a four-dimensional (4D) spatiotemporal continuum of the embryonic mouse brain from E10.5 to E15.5 reconstructed from diffusion magnetic resonance microscopy (dMRM) data. This study achieved unprecedented high-definition dMRM at 30- to 35-µm isotropic resolution, and together with computational neuroanatomy techniques, we revealed both morphological and microscopic changes in the developing brain. We transformed selected gene-expression data to this continuum and correlated them with the dMRM-based neuroanatomical changes in embryonic brains. Within the continuum, we identified distinct developmental modes comprising regional clusters that shared developmental trajectories and similar gene-expression profiles. Our results demonstrate how this 4D continuum can be used to examine spatiotemporal gene–neuroanatomical interactions by connecting upstream genetic events with anatomical changes that emerge later in development. This approach would be useful for large-scale analysis of the cooperative roles of key genes in shaping the developing brain.
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16
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Szpak M, Collins SC, Li Y, Liu X, Ayub Q, Fischer MC, Vancollie VE, Lelliott CJ, Xue Y, Yalcin B, Yang H, Tyler-Smith C. A Positively Selected MAGEE2 LoF Allele Is Associated with Sexual Dimorphism in Human Brain Size and Shows Similar Phenotypes in Magee2 Null Mice. Mol Biol Evol 2021; 38:5655-5663. [PMID: 34464968 PMCID: PMC8662591 DOI: 10.1093/molbev/msab243] [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] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
A nonsense allele at rs1343879 in human MAGEE2 on chromosome X has previously been reported as a strong candidate for positive selection in East Asia. This premature stop codon causing ∼80% protein truncation is characterized by a striking geographical pattern of high population differentiation: common in Asia and the Americas (up to 84% in the 1000 Genomes Project East Asians) but rare elsewhere. Here, we generated a Magee2 mouse knockout mimicking the human loss-of-function mutation to study its functional consequences. The Magee2 null mice did not exhibit gross abnormalities apart from enlarged brain structures (13% increased total brain area, P = 0.0022) in hemizygous males. The area of the granular retrosplenial cortex responsible for memory, navigation, and spatial information processing was the most severely affected, exhibiting an enlargement of 34% (P = 3.4×10-6). The brain size in homozygous females showed the opposite trend of reduced brain size, although this did not reach statistical significance. With these insights, we performed human association analyses between brain size measurements and rs1343879 genotypes in 141 Chinese volunteers with brain MRI scans, replicating the sexual dimorphism seen in the knockout mouse model. The derived stop gain allele was significantly associated with a larger volume of gray matter in males (P = 0.00094), and smaller volumes of gray (P = 0.00021) and white (P = 0.0015) matter in females. It is unclear whether or not the observed neuroanatomical phenotypes affect behavior or cognition, but it might have been the driving force underlying the positive selection in humans.
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Affiliation(s)
- Michał Szpak
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Stephan C Collins
- Inserm UMR1231, Genetics of Developmental Disorders Laboratory, University of Bourgogne Franche-Comté, Dijon, France.,IGBMC, UMR7104, Illkirch, Inserm, France
| | - Yan Li
- BGI-Shenzhen, Shenzhen, China
| | - Xiao Liu
- Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, China
| | - Qasim Ayub
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.,Monash University Malaysia Genomics Facility, School of Science, Bandar Sunway, Selangor Darul Ehsan, Malaysia
| | | | | | | | - Yali Xue
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Binnaz Yalcin
- Inserm UMR1231, Genetics of Developmental Disorders Laboratory, University of Bourgogne Franche-Comté, Dijon, France.,IGBMC, UMR7104, Illkirch, Inserm, France
| | | | - Chris Tyler-Smith
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
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17
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Mahallati H, Sotiriadis A, Celestin C, Millischer AE, Sonigo P, Grevent D, O'Gorman N, Bahi-Buisson N, Attié-Bitach T, Ville Y, Salomon LJ. Heterogeneity in defining fetal corpus callosal pathology: systematic review. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2021; 58:11-18. [PMID: 32798278 DOI: 10.1002/uog.22179] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/22/2020] [Accepted: 08/07/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE Fetal anomalies of the corpus callosum (CC) have been reported in the prenatal imaging literature since 1985, and, especially when isolated, pose challenges for both the patient and fetal medicine specialist. The purpose of this study was to review systematically the literature on prenatally diagnosed abnormalities of the CC, focusing on the terminology used to describe abnormalities other than complete agenesis of the CC, and to assess the heterogeneity of the nomenclature and definitions used. METHODS This study was conducted in accordance with the PRISMA statement for reporting systematic reviews. A literature search was performed to identify prospective or retrospective case series or cohort studies, published in English, French, Italian, German or Spanish, reporting fetal imaging findings and describing anomalies of the CC. Quality and risk of bias of the studies were evaluated using the Newcastle-Ottawa scale and a modification of the scale developed by Conde-Agudelo et al. for other fetal imaging studies. The data extracted included the number of patients, the number of different anomalies identified, the descriptive names of the anomalies, and, where applicable, the definitions of the anomalies, the number of cases of each type of anomaly and the biometric charts used. Secondary tests used to confirm the diagnosis, as well as the postnatal or post-termination tests used to ascertain the diagnosis, were also recorded. RESULTS The search identified 998 records, and, after review of titles and abstracts and full review of 45 papers, 27 studies were included initially in the review, of which 24 were included in the final analysis. These 24 studies had a broad range of quality and risk of bias and represented 1135 cases of CC anomalies, of which 49% were complete agenesis and the remainder were described using the term partial agenesis or nine other terms, of which five had more than one definition. CONCLUSIONS In comparison to the postnatal literature, in the prenatal literature there is much greater heterogeneity in the nomenclature and definition of CC anomalies other than complete agenesis. This heterogeneity and lack of standard definitions in the prenatal literature make it difficult to develop large multicenter pooled cohorts of patients who can be followed in order to develop a better understanding of the genetic associations and neurodevelopmental and psychological outcomes of patients with CC anomalies. As this information is important to improve counseling of these patients, a good first step towards this goal would be to develop a simpler categorization of prenatal CC anomalies that matches better the postnatal literature. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.
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Affiliation(s)
- H Mahallati
- Department of Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - A Sotiriadis
- Second Department of Obstetrics and Gynecology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - C Celestin
- Service de Gynécologie-Obstétrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - A E Millischer
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - P Sonigo
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - D Grevent
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Service de Radiologie Pédiatrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - N O'Gorman
- Service de Gynécologie-Obstétrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - N Bahi-Buisson
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Pediatric Neurology Department, University Hospital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - T Attié-Bitach
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Service de Neurologie Pédiatrique, Université Paris Descartes et Inserm U781, Imagine, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - Y Ville
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Service de Gynécologie-Obstétrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
| | - L J Salomon
- Fetus & LUMIERE team, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
- Service de Gynécologie-Obstétrique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France
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18
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Balan S, Ohnishi T, Watanabe A, Ohba H, Iwayama Y, Toyoshima M, Hara T, Hisano Y, Miyasaka Y, Toyota T, Shimamoto-Mitsuyama C, Maekawa M, Numata S, Ohmori T, Shimogori T, Kikkawa Y, Hayashi T, Yoshikawa T. Role of an Atypical Cadherin Gene, Cdh23 in Prepulse Inhibition, and Implication of CDH23 in Schizophrenia. Schizophr Bull 2021; 47:1190-1200. [PMID: 33595068 PMCID: PMC8266601 DOI: 10.1093/schbul/sbab007] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility.
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Affiliation(s)
- Shabeesh Balan
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan,Neuroscience Research Laboratory, Institute of Mental Health and Neurosciences (IMHANS), Kozhikode, Kerala, India
| | - Tetsuo Ohnishi
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Akiko Watanabe
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Hisako Ohba
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Yoshimi Iwayama
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Manabu Toyoshima
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Tomonori Hara
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan,Department of Organ Anatomy, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yasuko Hisano
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Yuki Miyasaka
- Deafness Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan,Division of Experimental Animals, Graduate School of Medicine, Nagoya University, Nagoya, Japan
| | - Tomoko Toyota
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | | | - Motoko Maekawa
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan,Department of Biological Science, Graduate School of Humanities and Science, Ochanomizu University, Tokyo, Japan
| | - Shusuke Numata
- Department of Psychiatry, Institute of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Tetsuro Ohmori
- Department of Psychiatry, Institute of Biomedical Science, Tokushima University Graduate School, Tokushima, Japan
| | - Tomomi Shimogori
- Laboratory for Molecular Mechanisms of Brain Development, RIKEN Center for Brain Science, Wako, Saitama, Japan
| | - Yoshiaki Kikkawa
- Deafness Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan
| | - Takeshi Hayashi
- Agricultural Artificial Intelligence (AI) Research Office, Research Center for Agricultural Information Technology, National Agriculture and Food Research Organization (NARO), Tokyo, Japan
| | - Takeo Yoshikawa
- Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Wako, Saitama, Japan,To whom correspondence should be addressed; 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; tel: +81-48-467-5968, fax: +81-48-467-7462, e-mail:
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A Genetic Screen Links the Disease-Associated Nab2 RNA-Binding Protein to the Planar Cell Polarity Pathway in Drosophila melanogaster. G3-GENES GENOMES GENETICS 2020; 10:3575-3583. [PMID: 32817074 PMCID: PMC7534439 DOI: 10.1534/g3.120.401637] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Mutations in the gene encoding the ubiquitously expressed RNA-binding protein ZC3H14 result in a non-syndromic form of autosomal recessive intellectual disability in humans. Studies in Drosophila have defined roles for the ZC3H14 ortholog, Nab2 (aka Drosophila Nab2 or dNab2), in axon guidance and memory due in part to interaction with a second RNA-binding protein, the fly Fragile X homolog Fmr1, and coregulation of shared Nab2-Fmr1 target mRNAs. Despite these advances, neurodevelopmental mechanisms that underlie defective axonogenesis in Nab2 mutants remain undefined. Nab2 null phenotypes in the brain mushroom bodies (MBs) resemble defects caused by alleles that disrupt the planar cell polarity (PCP) pathway, which regulates planar orientation of static and motile cells via a non-canonical arm of the Wnt/Wg pathway. A kinked bristle phenotype in surviving Nab2 mutant adults additionally suggests a defect in F-actin polymerization and bundling, a PCP-regulated processes. To test for Nab2-PCP genetic interactions, a collection of PCP mutant alleles was screened for modification of a rough-eye phenotype produced by Nab2 overexpression in the eye (GMR> Nab2) and, subsequently, for modification of a viability defect among Nab2 nulls. Multiple PCP alleles dominantly modify GMR> Nab2 eye roughening and a subset rescue low survival and thoracic bristle kinking in Nab2 zygotic nulls. Collectively, these genetic interactions identify the PCP pathway as a potential target of the Nab2 RNA-binding protein in developing eye and wing tissues and suggest that altered PCP signaling could contribute to neurological defects that result from loss of Drosophila Nab2 or its vertebrate ortholog ZC3H14.
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