Rare pathogenic variants in WNK3 cause X-linked intellectual disability.
Publication/Presentation Date
9-1-2022
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.
METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).
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.
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.
Volume
24
Issue
9
First Page
1941
Last Page
1951
ISSN
1530-0366
Published In/Presented At
Küry, S., Zhang, J., Besnard, T., Caro-Llopis, A., Zeng, X., Robert, S. M., Josiah, S. S., Kiziltug, E., Denommé-Pichon, A. S., Cogné, B., Kundishora, A. J., Hao, L. T., Li, H., Stevenson, R. E., Louie, R. J., Deb, W., Torti, E., Vignard, V., McWalter, K., Raymond, F. L., … Isidor, B. (2022). Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genetics in medicine : official journal of the American College of Medical Genetics, 24(9), 1941–1951. https://doi.org/10.1016/j.gim.2022.05.009
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
35678782
Department(s)
Administration and Leadership
Document Type
Article