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Rare pathogenic variants in WNK3 cause X-linked intellectual disability
- Source :
- Genetics in Medicine, 24(9), 1941-1951. Lippincott Williams & Wilkins, GENETICS IN MEDICINE, r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe, instname, Genetics in Medicine, Genetics in Medicine, 2022, 24 (9), pp.1941-1951. ⟨10.1016/j.gim.2022.05.009⟩
- 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. 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 identifier 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 identifier with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
- Subjects :
- MESH: Symporters
Exome sequencing
Male
KCC2
Mutation, Missense
MESH: Catalytic Domain
Neurodevelopmental disease
Protein Serine-Threonine Kinases
X-linked intellectual disability
MESH: Brain
WNK3
SDG 3 - Good Health and Well-being
Loss of Function Mutation
Catalytic Domain
MESH: Mental Retardation, X-Linked
Humans
Phosphorylation
MESH: Hemizygote
Genetics (clinical)
Hemizygote
MESH: Mutation, Missense
[SDV.GEN]Life Sciences [q-bio]/Genetics
MESH: Humans
MESH: Phosphorylation
Symporters
Brain
MESH: Loss of Function Mutation
MESH: Protein Serine-Threonine Kinases
MESH: Male
Mental Retardation, X-Linked
Maternal Inheritance
MESH: Maternal Inheritance
Subjects
Details
- Language :
- English
- ISSN :
- 10983600 and 15300366
- Volume :
- 24
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....711e752a43d1442b0a91b2645fc1747e