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Rare pathogenic variants in WNK3 cause X-linked intellectual disability.
- Source :
-
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2022 Sep; Vol. 24 (9), pp. 1941-1951. Date of Electronic Publication: 2022 Jun 09. - Publication Year :
- 2022
-
Abstract
- Purpose: WNK3 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.<br />Method: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).<br />Results: We 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.<br />Conclusion: Pathogenic 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.<br />Competing Interests: Conflict of Interest E.T., K.M., K.R., I.M.W., K.G.M., and L.R. are employees of GeneDx, LLC. K.R. is a shareholder of OPKO Health, Inc. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics Laboratories. All other authors declare no conflicts of interest.<br /> (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Brain abnormalities
Catalytic Domain genetics
Hemizygote
Humans
Loss of Function Mutation
Male
Maternal Inheritance genetics
Mutation, Missense
Phosphorylation
Mental Retardation, X-Linked genetics
Protein Serine-Threonine Kinases chemistry
Protein Serine-Threonine Kinases genetics
Symporters metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0366
- Volume :
- 24
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 35678782
- Full Text :
- https://doi.org/10.1016/j.gim.2022.05.009