Skip to Main content Skip to Navigation
New interface
Journal articles

Rare pathogenic variants in WNK3 cause X-linked intellectual disability

Sébastien Küry 1, 2, * Jinwei Zhang 3 Thomas Besnard 1, 2 Alfonso Caro-Llopis Xue Zeng Stephanie Robert Sunday Josiah Emre Kiziltug Anne-Sophie Denommé-Pichon 4 Benjamin Cogné 1, 2 Adam Kundishora Le Hao Hong Li Roger Stevenson Raymond Louie 5 Wallid Deb Erin Torti 6 Virginie Vignard 2 Kirsty Mcwalter 6 F Lucy Raymond Farrah Rajabi Emmanuelle Ranza Detelina Grozeva Stephanie Coury Xavier Blanc Elise Brischoux-Boucher 7 Boris Keren 8 Katrin Õunap Karit Reinson Pilvi Ilves Ingrid Wentzensen Eileen Barr Solveig Heide Guihard 8 Perrine Charles Eleanor Seaby Kristin Monaghan Marlène Rio 9 Yolande van Bever Marjon van Slegtenhorst Wendy Chung Ashley Wilson Delphine Quinquis 1 Flora Bréhéret Kyle Retterer Pierre Lindenbaum Emmanuel Scalais Lindsay Rhodes Katrien Stouffs Elaine Pereira Sara Berger Sarah Milla Ankita Jaykumar Melanie Cobb Shreyas Panchagnula Phan Duy Marie Vincent Sandra Mercier 2 Brigitte Gilbert-Dussardier 10 Xavier Le Guillou 10 Séverine Audebert-Bellanger 11 Sylvie Odent 12, 13 Sébastien Schmitt 1 Pierre Boisseau 1 Dominique Bonneau 4 Annick Toutain 14 Estelle Colin 4 Laurent Pasquier 12, 13 Richard Redon 2 Arjan Bouman Jill Rosenfeld Michael Friez Helena Pérez-Peña Syed Raza Akhtar Rizvi Shozeb Haider Stylianos Antonarakis 15 Charles Schwartz 5 Francisco Martínez Stéphane Bézieau 2 Kristopher Kahle 16, * Bertrand Isidor 2 
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.
Document type :
Journal articles
Complete list of metadata
Contributor : Laurent Jonchère Connect in order to contact the contributor
Submitted on : Wednesday, September 28, 2022 - 1:57:09 PM
Last modification on : Tuesday, November 22, 2022 - 2:32:29 PM



Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, et al.. Rare pathogenic variants in WNK3 cause X-linked intellectual disability. Genetics in Medicine, 2022, 24 (9), pp.1941-1951. ⟨10.1016/j.gim.2022.05.009⟩. ⟨hal-03790515⟩



Record views