The p190 RhoGAPs,ARHGAP35, and ARHGAP5 are implicated in GnRH neuronal development: Evidence from patients with idiopathic hypogonadotropic hypogonadism,zebrafish, and in vitro GAP activity assay |
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| Institution: | 1. Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, MA;2. Department of Pediatrics and Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL;3. Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL;4. Cancer Research Program, Research Institute of the McGill University Health Centre, Department of Anatomy and Cell Biology, McGill University, Montréal, Quebec, Canada;5. Center for Human Disease Modeling, Duke University Medical Center, Durham, NC;6. Intramural Research Program, National Institutes of Health, Bethesda, MD;7. Division of Endocrinology-Department of Internal Medicine, University of Patras School of Health Sciences, Rio-Patras, Greece;8. Instituto de Investigaciones Materno Infantil (IDIMI), University of Chile, Santiago, Chile;9. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom;10. Functional Unit 6254 Innovation in Genomic Diagnosis of Rare Diseases, CHU Dijon Bourgogne, Dijon, France;11. Centre de Référence Maladies Rares « Anomalies du Développement Et Syndrome Malformatifs » de L’Est, Hôpital D’Enfants, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France;12. Department of Clinical Genetics, Birmingham Women''s and Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom;13. Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;14. Medical Genetic Department for Rare Diseases and Personalized Medicine, Reference Center AD SOOR, AnDDI-RARE, Groupe DI, Inserm U1298, INM, Montpellier University, Centre Hospitalier Universitaire de Montpellier, Montpellier, France;15. The Endocrine Unit, Massachusetts General Hospital, Boston, MA;1. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN;2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN;1. Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, United Kingdom;2. North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, United Kingdom;3. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Uunited Kingdom;4. Division of Gynaecology, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom;5. Clinical Genetics Service, Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom;6. Prevention Breast Cancer Centre and Nightingale Breast Screening Centre, University Hospital of South Manchester, Manchester, United Kingdom;7. The Christie NHS Foundation Trust, Manchester, United Kingdom;8. Manchester Breast Centre, Manchester Cancer Research Centre, University of Manchester, United Kingdom;1. Division of Biomedical Informatics, Cincinnati Children’s Hospital Medical Center, Cincinnati Children''s Research Foundation, Cincinnati, OH;2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH;3. Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH;4. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH;1. Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD;1. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;2. Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;3. Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA;1. Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetric and Gynecologic Diseases, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;3. Medical Scientist Training Program, Baylor College of Medicine, Houston, TX;4. Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;5. Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China;6. Department of Gynecology and Obstetrics, Research Centre for Women''s Health, Tübingen University Hospital, Tübingen, Germany;7. Department of Orthopedic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China;8. Department of Obstetrics and Gynecology, The 3rd Affiliated Hospital of Shenzhen University, Luohu Hospital, Shenzhen, Guangdong, China;9. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland;10. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;11. Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;12. Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;13. Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China;14. Center for Adolescent Medicine and UNESCO Chair in Adolescent Health Care, First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Aghia Sophia Children''s Hospital, Athens, Greece;15. Division of Pediatric-Adolescent Gynecology and Reconstructive Surgery, 2nd Department of Obstetrics and Gynecology, School of Medicine, National and Kapodistrian University of Athens, Aretaieion Hospital, Athens, Greece;16. Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of Sao Paulo, Sao Paulo, Brazil;17. Department of Pediatrics, Baylor College of Medicine, Houston, TX;18. Department of Obstetrics and Gynecology, Texas Children''s Hospital and Baylor College of Medicine, Houston, TX;19. Texas Children''s Hospital, Houston, TX;20. Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Vari, Athens, Greece;21. Baylor Genetics, Houston, TX;22. Institute of Genetics and Genomics in Geneva, University of Geneva, Geneva, Switzerland |
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| Abstract: | PurposeThe study aimed to identify novel genes for idiopathic hypogonadotropic hypogonadism (IHH).MethodsA cohort of 1387 probands with IHH underwent exome sequencing and de novo, familial, and cohort-wide investigations. Functional studies were performed on 2 p190 Rho GTPase–activating proteins (p190 RhoGAP), ARHGAP35 and ARHGAP5, which involved in vivo modeling in larval zebrafish and an in vitro p190A-GAP activity assay.ResultsRare protein-truncating variants (PTVs; n = 5) and missense variants in the RhoGAP domain (n = 7) in ARHGAP35 were identified in IHH cases (rare variant enrichment: PTV unadjusted P = 3.1E-06] and missense adjusted P = 4.9E-03] vs controls). Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a, the predominant ARHGAP35 paralog in the zebrafish brain, display decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant ARHGAP35 p.(Arg1284Trp)] had decreased GAP activity. Rare PTVs (n = 2) also were discovered in ARHGAP5, a paralog of ARHGAP35; however, arhgap5 zebrafish mutants did not display significant GnRH3-GFP+ abnormalities.ConclusionThis study identified ARHGAP35 as a new autosomal dominant genetic driver for IHH and ARHGAP5 as a candidate gene for IHH. These observations suggest a novel role for the p190 RhoGAP proteins in GnRH neuronal development and integrity. |
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| Keywords: | Developmental disorder Idiopathic hypogonadotropic hypogonadism Intellectual disability Puberty Rho GTPase–activating protein |
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