Rare pathogenic variants in WNK3 cause X-linked intellectual disability |
| |
| Affiliation: | 1. Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France;2. Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax, Nantes, France;3. Hatherly Laboratories, The Institute of Biomedical and Clinical Sciences, College of Medicine and Health, University of Exeter, Exeter, United Kingdom;4. Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT;5. State Key Laboratory of Bio-Organic and Natural Products Chemistry, Research Center of Chemical Kinomics, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China;6. Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain;7. Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT;8. Département de Biochimie et Génétique, Centre Hospitalier Universitaire Angers, Angers, France;9. UMR CNRS 6214, INSERM 1083, Université d’Angers, Angers, France;10. Departments of Human Genetics and Pediatrics, School of Medicine, Emory University, Atlanta, GA;11. Greenwood Genetic Center, Greenwood, SC;12. GeneDx, Gaithersburg, MD;13. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Biomedical Campus Cambridge, Cambridge, United Kingdom;14. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA;15. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;16. Centre for Trials Research, Cardiff University, Cardiff, United Kingdom;17. Centre de Génétique Humaine, CHU de Besançon, Université de Bourgogne Franche-Comté, Besançon, France;18. Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France;19. Department of Clinical Genetics, Genetics and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia;20. Department of Clinical Genetics, Institute of Clinical Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;21. Department of Radiology, Tartu University Hospital, Tartu, Estonia;22. Groupe de Recherche Clinique, Déficience Intellectuelle et Autisme, Sorbonne University, Paris, France;23. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA;24. Genomic Informatics Group, University of Southampton, Southampton, United Kingdom;25. Developmental Brain Disorders laboratory, INSERM UMR 1163, Imagine Institute, University of Paris, Paris, France;26. Department of Genetics, Centre de Référence Déficiences Intellectuelles de Causes Rares, Necker Enfants Malades Hospital, APHP, Paris, France;27. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, the Netherlands;28. Departments of Pediatrics and Medicine, Columbia University Irving Medical Center, Columbia University New York, NY;29. Division of Clinical Genetics, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children’s Hospital, New York, NY;30. Division of Pediatric Neurology, Department of Pediatrics, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg;31. Neurogenetics Research Group, Reproduction and Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Laarbeeklaan, Brussels, Belgium;32. Department of Radiology and Imaging Sciences, School of Medicine, Emory University, Atlanta, GA;33. Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX;34. Service de Génétique, CHU Poitiers, Poitiers, France;35. Génétique Médicale, CHRU Brest, Brest, France;36. Service de Génétique Clinique, ERN ITHACA, CHU Rennes, Rennes, France;37. Institut de Génétique et Développement de Rennes, IGDR UMR 6290 CNRS, INSERM, IGDR Univ Rennes, Rennes, France;38. Unité de Génétique Médicale, Centre Hospitalier Régional Universitaire de Tours, France;39. Unité Mixte de Recherche 1253, iBrain, Université de Tours, Institut National de la Santé et de la Recherche Médicale, Tours, France;40. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;41. Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, University College London, London, United Kingdom;42. Centre for Advanced Research Computing, University College London, London, United Kingdom;43. Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland;44. iGE3, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva, Switzerland;45. Department of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT;46. NIH-Yale Centers for Mendelian Genomics, Yale School of Medicine, Yale University, New Haven, CT;47. Yale Stem Cell Center, Yale School of Medicine, Yale University, New Haven, CT;1. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada;2. Genomics Health Services and Policy Research Program, Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;3. Lunenfeld Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada;4. Pathology and Laboratory Medicine, Mount Sinai Hospital, Sinai Health, Toronto, Ontario, Canada;5. Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;6. Li Ka Shing Knowledge Institute, St. Michael''s Hospital, Unity Health Toronto, Toronto, Ontario, Canada;7. Department of Surgery, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada;8. Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia;9. Ontario Institute for Cancer Research, Toronto, Ontario, Canada;1. National Center for Tumor Diseases (NCT), Heidelberg, Germany;2. Memorial Sloan Kettering Cancer Center, New York, NY;3. National Cancer Institute, Rockville, MD;1. Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada;2. Children''s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada;1. Morgan & Mendel Genomics, Inc, Bronx, NY;2. Albert Einstein College of Medicine, Bronx, NY;3. Fred Hutchinson Cancer Center, Seattle, WA;4. Mayo Clinic, Scottsdale, AZ;5. The University of Melbourne, Melbourne, Victoria, Australia;6. Ontario Institute of Cancer Research, Toronto, Ontario, Canada;7. Montefiore Medical Center, Bronx, NY;1. Department of Genetics, Cell Biology, and Development, College of Biological Sciences, University of Minnesota, Minneapolis, MN;2. Department of Biology, Macalester College, Saint Paul, MN;3. Libraries, University of Minnesota, Minneapolis, MN;1. Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany;2. Institute of Human Genetics, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany |
| |
| Abstract: | ![]()
PurposeWNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.MethodWe ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).ResultsWe identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.ConclusionPathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism. |
| |
| Keywords: | Exome sequencing KCC2 Neurodevelopmental disease X-linked intellectual disability |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
