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Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.

dc.rights.licenseopenen_US
dc.contributor.authorPALMER, Elizabeth E
dc.contributor.authorPUSCH, Michael
dc.contributor.authorPICOLLO, Alessandra
dc.contributor.authorFORWOOD, Caitlin
dc.contributor.authorNGUYEN, Matthew H
dc.contributor.authorSUCKOW, Vanessa
dc.contributor.authorGIBBONS, Jessica
dc.contributor.authorHOFF, Alva
dc.contributor.authorSIGFRID, Lisa
dc.contributor.authorMEGARBANE, Andre
dc.contributor.authorNIZON, Mathilde
dc.contributor.authorCOGNÉ, Benjamin
dc.contributor.authorBENETEAU, Claire
dc.contributor.authorALKURAYA, Fowzan S.
dc.contributor.authorCHEDRAWI, Aziza
dc.contributor.authorHASHEM, Mais O.
dc.contributor.authorSTAMBERGER, Hannah
dc.contributor.authorWECKHUYSEN, Sarah
dc.contributor.authorVANLANDER, Arnaud
dc.contributor.authorCEULEMANS, Berten
dc.contributor.authorRAJAGOPALAN, Sulekha
dc.contributor.authorNUNN, Kenneth
dc.contributor.authorARPIN, Stéphanie
dc.contributor.authorRAYNAUD, Martine
dc.contributor.authorMOTTER, Constance S
dc.contributor.authorWARD-MELVER, Catherine
dc.contributor.authorJANSSENS, Katrien
dc.contributor.authorMEUWISSEN, Marije
dc.contributor.authorBEYSEN, Diane
dc.contributor.authorDIKOW, Nicola
dc.contributor.authorGRIMMEL, Mona
dc.contributor.authorHAACK, Tobias B.
dc.contributor.authorCLEMENT, Emma
dc.contributor.authorMCTAGUE, Amy
dc.contributor.authorHUNT, David
dc.contributor.authorTOWNSHEND, Sharron
dc.contributor.authorWARD, Michelle
dc.contributor.authorRICHARDS, Linda J
dc.contributor.authorSIMONS, Cas
dc.contributor.authorCOSTAIN, Gregory
dc.contributor.authorDUPUIS, Lucie
dc.contributor.authorMENDOZA-LONDONO, Roberto
dc.contributor.authorDUDDING-BYTH, Tracy
dc.contributor.authorBOYLE, Jackie
dc.contributor.authorSAUNDERS, Carol
dc.contributor.authorFLEMING, Emily
dc.contributor.authorEL CHEHADEH, Salima
dc.contributor.authorSPITZ, Marie-Aude
dc.contributor.authorPITON, Amelie
dc.contributor.authorGERARD, Bénédicte
dc.contributor.authorABI WARDE, Marie-Thérèse
dc.contributor.authorREA, Gillian
dc.contributor.authorMCKENNA, Caoimhe
dc.contributor.authorDOUZGOU, Sofia
dc.contributor.authorBANKA, Siddharth
dc.contributor.authorAKMAN, Cigdem
dc.contributor.authorBAIN, Jennifer M
dc.contributor.authorSANDS, Tristan T
dc.contributor.authorWILSON, Golder N
dc.contributor.authorSILVERTOOTH, Erin J
dc.contributor.authorMILLER, Lauren
dc.contributor.authorLEDERER, Damien
dc.contributor.authorSACHDEV, Rani
dc.contributor.authorMACINTOSH, Rebecca
dc.contributor.authorMONESTIER, Olivier
dc.contributor.authorKARADURMUS, Deniz
dc.contributor.authorCOLLINS, Felicity
dc.contributor.authorCARTER, Melissa
dc.contributor.authorROHENA, Luis
dc.contributor.authorWILLEMSEN, Marjolein H
dc.contributor.authorOCKELOEN, Charlotte W.
dc.contributor.authorPFUNDT, Rolph
dc.contributor.authorKROFT, Sanne D
dc.contributor.authorFIELD, Michael
dc.contributor.authorLARANJEIRA, Francisco E R
dc.contributor.authorFORTUNA, Ana M
dc.contributor.authorSOARES, Ana R
hal.structure.identifierCHU Bordeaux
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorMICHAUD, Vincent
dc.contributor.authorNAUDION, Sophie
dc.contributor.authorGOLLA, Sailaja
dc.contributor.authorWEAVER, David D
dc.contributor.authorBIRD, Lynne M
dc.contributor.authorFRIEDMAN, Jennifer
dc.contributor.authorCLOWES, Virginia
dc.contributor.authorJOSS, Shelagh
dc.contributor.authorPÖLSLER, Laura
dc.contributor.authorCAMPEAU, Philippe M
dc.contributor.authorBLAZO, Maria
dc.contributor.authorBIJLSMA, Emilia K
dc.contributor.authorROSENFELD, Jill A
dc.contributor.authorBEETZ, Christian
dc.contributor.authorPOWIS, Zöe
dc.contributor.authorMCWALTER, Kirsty
dc.contributor.authorBRANDT, Tracy
dc.contributor.authorTORTI, Erin
dc.contributor.authorMATHOT, Mikaël
dc.contributor.authorMOHAMMAD, Shekeeb S
dc.contributor.authorARMSTRONG, Ruth
dc.contributor.authorKALSCHEUER, Vera M
dc.date.accessioned2023-11-14T13:29:29Z
dc.date.available2023-11-14T13:29:29Z
dc.date.issued2023-02-01
dc.identifier.issn1476-5578en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/184755
dc.description.abstractEnMissense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subject.enMale
dc.subject.enFemale
dc.subject.enHumans
dc.subject.enNeurodevelopmental Disorders
dc.subject.enMutation
dc.subject.enMissense
dc.subject.enGenes
dc.subject.enX-Linked
dc.subject.enPhenotype
dc.subject.enChloride Channels
dc.title.enFunctional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition.
dc.title.alternativeMol Psychiatryen_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1038/s41380-022-01852-9en_US
dc.subject.halSciences du Vivant [q-bio]/Génétiqueen_US
dc.identifier.pubmed36385166en_US
bordeaux.journalMolecular Psychiatryen_US
bordeaux.page668-697en_US
bordeaux.volume28en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue2en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDFondazione AIRC per la ricerca sul cancro ETSen_US
bordeaux.identifier.funderIDWellcome Trusten_US
bordeaux.identifier.funderIDMedical Research Councilen_US
bordeaux.identifier.funderIDRosetrees Trusten_US
bordeaux.identifier.funderIDDeutsche Forschungsgemeinschaften_US
bordeaux.identifier.funderIDFonds Wetenschappelijk Onderzoeken_US
bordeaux.identifier.funderIDMinistero dell’Istruzione, dell’Università e della Ricercaen_US
bordeaux.identifier.funderIDKing Salman Center for Disability Researchen_US
bordeaux.identifier.funderIDCerebral Palsy Allianceen_US
bordeaux.identifier.funderIDTasmanian Department of Healthen_US
bordeaux.identifier.funderIDFondation Médicale Reine Elisabethen_US
bordeaux.import.sourcepubmed
hal.identifierhal-04284872
hal.version1
hal.date.transferred2023-11-14T13:29:41Z
hal.popularnonen_US
hal.audienceInternationaleen_US
hal.exporttrue
workflow.import.sourcepubmed
dc.rights.ccCC BYen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Molecular%20Psychiatry&rft.date=2023-02-01&rft.volume=28&rft.issue=2&rft.spage=668-697&rft.epage=668-697&rft.eissn=1476-5578&rft.issn=1476-5578&rft.au=PALMER,%20Elizabeth%20E&PUSCH,%20Michael&PICOLLO,%20Alessandra&FORWOOD,%20Caitlin&NGUYEN,%20Matthew%20H&rft.genre=article


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