| Title: |
Rare pathogenic variants in WNK3 cause X-linked intellectual disability |
| Authors: |
Küry, S; Zhang, J; Besnard, T; Caro-Llopis, A; Zeng, X; Robert, SM; Josiah, SS; Kiziltug, E; Denommé-Pichon, AS; Cogné, B; Kundishora, AJ; Hao, LT; Li, H; Stevenson, RE; Louie, RJ; Deb, W; Torti, E; Vignard, V; McWalter, K; Raymond, FL; Rajabi, F; Ranza, E; Grozeva, D; Coury, SA; Blanc, X; Brischoux-Boucher, E; Keren, B; Õunap, K; Reinson, K; Ilves, P; Wentzensen, IM; Barr, EE; Guihard, SH; Charles, P; Seaby, EG; Monaghan, KG; Rio, M; van Bever, Y; van Slegtenhorst, M; Chung, WK; Wilson, A; Quinquis, D; Bréhéret, F; Retterer, K; Lindenbaum, P; Scalais, E; Rhodes, L; Stouffs, K; Pereira, EM; Berger, SM; Milla, SS; Jaykumar, AB; Cobb, MH; Panchagnula, S; Duy, PQ; Vincent, M; Mercier, S; Gilbert-Dussardier, B; Le Guillou, X; Audebert-Bellanger, S; Odent, S; Schmitt, S; Boisseau, P; Bonneau, D; Toutain, A; Colin, E; Pasquier, L; Redon, R; Bouman, A; Rosenfeld, JA; Friez, MJ; Pérez-Peña, H; Akhtar Rizvi, SR; Haider, S; Antonarakis, SE; Schwartz, CE; Martínez, F; Bézieau, S; Kahle, KT; Isidor, B |
| Source: |
Genetics in Medicine , 24 (9) pp. 1941-1951. (2022) |
| Publisher Information: |
Elsevier BV |
| Publication Year: |
2022 |
| Collection: |
University College London: UCL Discovery |
| Subject Terms: |
Exome sequencing; KCC2; Neurodevelopmental disease; WNK3; X-linked intellectual disability |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10151159/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10151159/2/Shozeb_Rare%20pathogenic%20variants%20in%20WNK3%20cause%20X-linked%20intellectual%20disability_AAM.pdf; https://discovery.ucl.ac.uk/id/eprint/10151159/ |
| Rights: |
open |
| Accession Number: |
edsbas.E0B4AACD |
| Database: |
BASE |