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A recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebral spectrum

dc.rights.licenseopenen_US
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorTINGAUD-SEQUEIRA, Angele
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorTRIMOUILLE, Aurelien
dc.contributor.authorSALARIA, Manju
dc.contributor.authorSTAPLETON, Rachel
hal.structure.identifierCentre Génomique Fonctionnelle Bordeaux [Bordeaux] [CGFB]
dc.contributor.authorCLAVEROL, Stephane
dc.contributor.authorPLAISANT, Claudio
hal.structure.identifierCentre Génomique Fonctionnelle Bordeaux [Bordeaux] [CGFB]
dc.contributor.authorBONNEU, Marc
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorLOPEZ, Estelle
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorARVEILER, Benoit
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorLACOMBE, Didier
hal.structure.identifierLaboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
dc.contributor.authorROORYCK-THAMBO, Caroline
dc.date.accessioned2021-10-26T13:16:21Z
dc.date.available2021-10-26T13:16:21Z
dc.date.issued2021
dc.identifier.issn0340-6717 (print) 1432-1203 (online)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/112979
dc.description.abstractEnGoldenhar syndrome or oculo-auriculo-vertebral spectrum (OAVS) is a complex developmental disorder characterized by asymmetric ear anomalies, hemifacial microsomia, ocular and vertebral defects. We aimed at identifying and characterizing a new gene associated with OAVS. Two affected brothers with OAVS were analyzed by exome sequencing that revealed a missense variant (p.(Asn358Ser)) in the EYA3 gene. EYA3 screening was then performed in 122 OAVS patients that identified the same variant in one individual from an unrelated family. Segregation assessment in both families showed incomplete penetrance and variable expressivity. We investigated this variant in cellular models to determine its pathogenicity and demonstrated an increased half-life of the mutated protein without impact on its ability to dephosphorylate H2AFX following DNA repair pathway induction. Proteomics performed on this cellular model revealed four significantly predicted upstream regulators which are PPARGC1B, YAP1, NFE2L2 and MYC. Moreover, eya3 knocked-down zebrafish embryos developed specific craniofacial abnormalities corroborating previous animal models and supporting its involvement in the OAVS. Additionally, EYA3 gene expression was deregulated in vitro by retinoic acid exposure. EYA3 is the second recurrent gene identified to be associated with OAVS. Moreover, based on protein interactions and related diseases, we suggest the DNA repair as a key molecular pathway involved in craniofacial development.
dc.language.isoENen_US
dc.title.enA recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebral spectrum
dc.typeArticle de revueen_US
dc.identifier.doi10.1007/s00439-021-02255-6en_US
dc.subject.halSciences du Vivant [q-bio]/Médecine humaine et pathologieen_US
dc.identifier.pubmed33475861en_US
bordeaux.journalHuman Geneticsen_US
bordeaux.page933-944en_US
bordeaux.volume140en_US
bordeaux.hal.laboratoriesMaladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211en_US
bordeaux.issue6en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03404245
hal.version1
hal.date.transferred2021-10-26T13:16:28Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Human%20Genetics&rft.date=2021&rft.volume=140&rft.issue=6&rft.spage=933-944&rft.epage=933-944&rft.eissn=0340-6717%20(print)%201432-1203%20(online)&rft.issn=0340-6717%20(print)%201432-1203%20(online)&rft.au=TINGAUD-SEQUEIRA,%20Angele&TRIMOUILLE,%20Aurelien&SALARIA,%20Manju&STAPLETON,%20Rachel&CLAVEROL,%20Stephane&rft.genre=article


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