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)
1
CHU Nantes -
Centre hospitalier universitaire de Nantes
2 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
3 University of Exeter
4 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
5 The Greenwood Genetic Center
6 GeneDx [Gaithersburg, MD, USA]
7 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
8 CHU Pitié-Salpêtrière [AP-HP]
9 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
10 CHU Poitiers - Centre hospitalier universitaire de Poitiers
11 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital
13 IGDR - Institut de Génétique et Développement de Rennes
14 iBrain - UMR 1253 iBrain Imagerie et cerveau
15 UNIGE - Université de Genève = University of Geneva
16 YSM - Yale School of Medicine [New Haven, Connecticut]
2 ITX-lab - ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291
3 University of Exeter
4 MITOVASC - MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale
5 The Greenwood Genetic Center
6 GeneDx [Gaithersburg, MD, USA]
7 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
8 CHU Pitié-Salpêtrière [AP-HP]
9 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
10 CHU Poitiers - Centre hospitalier universitaire de Poitiers
11 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital
13 IGDR - Institut de Génétique et Développement de Rennes
14 iBrain - UMR 1253 iBrain Imagerie et cerveau
15 UNIGE - Université de Genève = University of Geneva
16 YSM - Yale School of Medicine [New Haven, Connecticut]
Sébastien Küry
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 1033186
Connectez-vous pour contacter l'auteur
Alfonso Caro-Llopis
- Function : Author
Xue Zeng
- Function : Author
Stephanie Robert
- Function : Author
Sunday Josiah
- Function : Author
Emre Kiziltug
- Function : Author
Adam Kundishora
- Function : Author
Le Hao
- Function : Author
Hong Li
- Function : Author
Roger Stevenson
- Function : Author
Wallid Deb
- Function : Author
F Lucy Raymond
- Function : Author
Farrah Rajabi
- Function : Author
Emmanuelle Ranza
- Function : Author
Detelina Grozeva
- Function : Author
Stephanie Coury
- Function : Author
Xavier Blanc
- Function : Author
Katrin Õunap
- Function : Author
Karit Reinson
- Function : Author
Pilvi Ilves
- Function : Author
Ingrid Wentzensen
- Function : Author
Eileen Barr
- Function : Author
Perrine Charles
- Function : Author
Eleanor Seaby
- Function : Author
Kristin Monaghan
- Function : Author
Yolande van Bever
- Function : Author
Marjon van Slegtenhorst
- Function : Author
Wendy Chung
- Function : Author
Ashley Wilson
- Function : Author
Flora Bréhéret
- Function : Author
Kyle Retterer
- Function : Author
Pierre Lindenbaum
- Function : Author
Emmanuel Scalais
- Function : Author
Lindsay Rhodes
- Function : Author
Katrien Stouffs
- Function : Author
Elaine Pereira
- Function : Author
Sara Berger
- Function : Author
Sarah Milla
- Function : Author
Ankita Jaykumar
- Function : Author
Melanie Cobb
- Function : Author
Shreyas Panchagnula
- Function : Author
Phan Duy
- Function : Author
Marie Vincent
- Function : Author
Arjan Bouman
- Function : Author
Jill Rosenfeld
- Function : Author
Michael Friez
- Function : Author
Helena Pérez-Peña
- Function : Author
Syed Raza Akhtar Rizvi
- Function : Author
Shozeb Haider
- Function : Author
Francisco Martínez
- Function : Author
Kristopher Kahle
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 1168363
Connectez-vous pour contacter l'auteur
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.