Rare pathogenic variants in WNK3 cause X-linked intellectual disability
dc.contributor.author | Küry, S | |
dc.contributor.author | Zhang, J | |
dc.contributor.author | Besnard, T | |
dc.contributor.author | Caro-Llopis, A | |
dc.contributor.author | Zeng, X | |
dc.contributor.author | Robert, SM | |
dc.contributor.author | Josiah, SS | |
dc.contributor.author | Kiziltug, E | |
dc.contributor.author | Denommé-Pichon, A-S | |
dc.contributor.author | Cogné, B | |
dc.contributor.author | Kundishora, AJ | |
dc.contributor.author | Hao, LT | |
dc.contributor.author | Li, H | |
dc.contributor.author | Stevenson, RE | |
dc.contributor.author | Louie, RJ | |
dc.contributor.author | Deb, W | |
dc.contributor.author | Torti, E | |
dc.contributor.author | Vignard, V | |
dc.contributor.author | McWalter, K | |
dc.contributor.author | Raymond, FL | |
dc.contributor.author | Rajabi, F | |
dc.contributor.author | Ranza, E | |
dc.contributor.author | Grozeva, D | |
dc.contributor.author | Coury, SA | |
dc.contributor.author | Blanc, X | |
dc.contributor.author | Brischoux-Boucher, E | |
dc.contributor.author | Keren, B | |
dc.contributor.author | Õunap, K | |
dc.contributor.author | Reinson, K | |
dc.contributor.author | Ilves, P | |
dc.contributor.author | Wentzensen, IM | |
dc.contributor.author | Barr, EE | |
dc.contributor.author | Guihard, SH | |
dc.contributor.author | Charles, P | |
dc.contributor.author | Seaby, EG | |
dc.contributor.author | Monaghan, KG | |
dc.contributor.author | Rio, M | |
dc.contributor.author | van Bever, Y | |
dc.contributor.author | van Slegtenhorst, M | |
dc.contributor.author | Chung, WK | |
dc.contributor.author | Wilson, A | |
dc.contributor.author | Quinquis, D | |
dc.contributor.author | Bréhéret, F | |
dc.contributor.author | Retterer, K | |
dc.contributor.author | Lindenbaum, P | |
dc.contributor.author | Scalais, E | |
dc.contributor.author | Rhodes, L | |
dc.contributor.author | Stouffs, K | |
dc.contributor.author | Pereira, EM | |
dc.contributor.author | Berger, SM | |
dc.contributor.author | Milla, SS | |
dc.contributor.author | Jaykumar, AB | |
dc.contributor.author | Cobb, MH | |
dc.contributor.author | Panchagnula, S | |
dc.contributor.author | Duy, PQ | |
dc.contributor.author | Vincent, M | |
dc.contributor.author | Mercier, S | |
dc.contributor.author | Gilbert-Dussardier, B | |
dc.contributor.author | Le Guillou, X | |
dc.contributor.author | Audebert-Bellanger, S | |
dc.contributor.author | Odent, S | |
dc.contributor.author | Schmitt, S | |
dc.contributor.author | Boisseau, P | |
dc.contributor.author | Bonneau, D | |
dc.contributor.author | Toutain, A | |
dc.contributor.author | Colin, E | |
dc.contributor.author | Pasquier, L | |
dc.contributor.author | Redon, R | |
dc.contributor.author | Bouman, A | |
dc.contributor.author | Rosenfeld, JA | |
dc.contributor.author | Friez, MJ | |
dc.contributor.author | Pérez-Peña, H | |
dc.contributor.author | Akhtar Rizvi, SR | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Antonarakis, SE | |
dc.contributor.author | Schwartz, CE | |
dc.contributor.author | Martínez, F | |
dc.contributor.author | Bézieau, S | |
dc.contributor.author | Kahle, KT | |
dc.contributor.author | Isidor, B | |
dc.date.accessioned | 2022-06-10T10:31:00Z | |
dc.date.issued | 2022-06-09 | |
dc.date.updated | 2022-06-10T09:33:46Z | |
dc.description.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. | en_GB |
dc.description.sponsorship | Estonian Research Council | en_GB |
dc.description.sponsorship | National Natural Science Foundation of China | en_GB |
dc.description.sponsorship | Royal Society | en_GB |
dc.description.sponsorship | South Carolina Department of Disabilities and Special Needs (SCDDSN) | en_GB |
dc.description.sponsorship | National Institute of Neurological Disorders and Stroke (NINDS) | en_GB |
dc.identifier.citation | Published online 9 June 2022 | en_GB |
dc.identifier.doi | https://doi.org/10.1016/j.gim.2022.05.009 | |
dc.identifier.grantnumber | PRG471 | en_GB |
dc.identifier.grantnumber | 81970238 | en_GB |
dc.identifier.grantnumber | 82170406 | en_GB |
dc.identifier.grantnumber | IEC\NSFC\201094 | en_GB |
dc.identifier.grantnumber | R01NS073854 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/129894 | |
dc.identifier | ORCID: 0000-0001-8683-509X (Zhang, Jinwei) | |
dc.identifier | ScopusID: 24385918800 (Zhang, Jinwei) | |
dc.identifier | ResearcherID: N-8584-2017 (Zhang, Jinwei) | |
dc.language.iso | en | en_GB |
dc.publisher | Elsevier / American College of Medical Genetics and Genomics | en_GB |
dc.rights | © 2022. This version is made available under the CC-BY-NC-ND 4.0 license: https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_GB |
dc.subject | Exome sequencing | en_GB |
dc.subject | KCC2 | en_GB |
dc.subject | Neurodevelopmental disease | en_GB |
dc.subject | WNK3 | en_GB |
dc.subject | X-linked intellectual disability | en_GB |
dc.title | Rare pathogenic variants in WNK3 cause X-linked intellectual disability | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2022-06-10T10:31:00Z | |
dc.identifier.issn | 1098-3600 | |
dc.description | This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record | en_GB |
dc.description | Data availability: All data are available upon request. The sequence variants in WNK3 (NM_004656.3) reported in the paper have been deposited in ClinVar database. Their respective accession numbers (SCV002107163 to SCV002107168) are indicated in Tables 1 and S1. | en_GB |
dc.identifier.journal | Genetics in Medicine | en_GB |
dc.relation.ispartof | Genetics in Medicine | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_GB |
dcterms.dateAccepted | 2022-05-11 | |
rioxxterms.version | AM | en_GB |
rioxxterms.licenseref.startdate | 2022-06-09 | |
rioxxterms.type | Journal Article/Review | en_GB |
refterms.dateFCD | 2022-06-10T10:14:22Z | |
refterms.versionFCD | AM | |
refterms.dateFOA | 2022-06-10T10:33:45Z | |
refterms.panel | A | en_GB |
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