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KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.

dc.rights.licenseopenen_US
dc.contributor.authorMICELI, Francesco
dc.contributor.authorMILLEVERT, Charissa
dc.contributor.authorSOLDOVIERI, Maria Virginia
dc.contributor.authorMOSCA, Ilaria
dc.contributor.authorAMBROSINO, Paolo
dc.contributor.authorCAROTENUTO, Lidia
dc.contributor.authorSCHRADER, Dewi
dc.contributor.authorLEE, Hyun Kyung
dc.contributor.authorRIVIELLO, James
dc.contributor.authorHONG, William
dc.contributor.authorRISEN, Sarah
dc.contributor.authorEMRICK, Lisa
dc.contributor.authorAMIN, Hitha
dc.contributor.authorVILLE, Dorothee
dc.contributor.authorEDERY, Patrick
dc.contributor.authorDE BELLESCIZE, Julitta
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorMICHAUD, Vincent
dc.contributor.authorVAN-GILS, Julien
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorGOIZET, Cyril
dc.contributor.authorWILLEMSEN, Marjolein H
dc.contributor.authorKLEEFSTRA, Tjitske
dc.contributor.authorMØLLER, Rikke S
dc.contributor.authorDEVINSKY, Orrin
dc.contributor.authorSANDS, Tristan
dc.contributor.authorKORENKE, G Christoph
dc.contributor.authorKLUGER, Gerhard
dc.contributor.authorMEFFORD, Heather C
dc.contributor.authorBRILSTRA, Eva
dc.contributor.authorLESCA, Gaetan
dc.contributor.authorMILH, Mathieu
dc.contributor.authorCOOPER, Edward C
dc.contributor.authorWECKHUYSEN, Sarah
dc.date.accessioned2023-07-05T08:38:40Z
dc.date.available2023-07-05T08:38:40Z
dc.date.issued2022-07-01
dc.identifier.issn2352-3964en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/183301
dc.description.abstractEnPrior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.
dc.language.isoENen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.subject.enAmitriptyline
dc.subject.enAutistic Disorder
dc.subject.enEpilepsy
dc.subject.enGain of Function Mutation
dc.subject.enHumans
dc.subject.enInfant
dc.subject.enNewborn
dc.subject.enInfant
dc.subject.enNewborn
dc.subject.enDiseases
dc.subject.enKCNQ2 Potassium Channel
dc.subject.enLanguage Development Disorders
dc.subject.enSeizures
dc.title.enKCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.
dc.title.alternativeEBioMedicineen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1016/j.ebiom.2022.104130en_US
dc.subject.halSciences du Vivant [q-bio]/Génétiqueen_US
dc.identifier.pubmed35780567en_US
bordeaux.journalEBioMedicineen_US
bordeaux.page104130en_US
bordeaux.volume81en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcepubmed
hal.identifierhal-04151914
hal.version1
hal.date.transferred2023-07-05T08:38:52Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=EBioMedicine&rft.date=2022-07-01&rft.volume=81&rft.spage=104130&rft.epage=104130&rft.eissn=2352-3964&rft.issn=2352-3964&rft.au=MICELI,%20Francesco&MILLEVERT,%20Charissa&SOLDOVIERI,%20Maria%20Virginia&MOSCA,%20Ilaria&AMBROSINO,%20Paolo&rft.genre=article


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