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Genet Med ; 24(9): 1941-1951, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35678782

RESUMEN

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.


Asunto(s)
Discapacidad Intelectual Ligada al Cromosoma X , Proteínas Serina-Treonina Quinasas , Simportadores , Encéfalo/anomalías , Dominio Catalítico/genética , Hemicigoto , Humanos , Mutación con Pérdida de Función , Masculino , Herencia Materna/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Mutación Missense , Fosforilación , Proteínas Serina-Treonina Quinasas/química , Proteínas Serina-Treonina Quinasas/genética , Simportadores/metabolismo
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