A recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebral spectrum
- 21 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Human Genetics
- Vol. 140 (6), 933-944
- https://doi.org/10.1007/s00439-021-02255-6
Abstract
Goldenhar 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.Funding Information
- ANR (ANR-12-JVS1-0002)
- Académie de Médecine
This publication has 50 references indexed in Scilit:
- Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1Proceedings of the National Academy of Sciences of the United States of America, 2012
- Array‐CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrumAmerican Journal of Medical Genetics Part A, 2010
- Dephosphorylation of the C-terminal Tyrosyl Residue of the DNA Damage-related Histone H2A.X Is Mediated by the Protein Phosphatase Eyes AbsentOnline Journal of Public Health Informatics, 2009
- Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisionsNature, 2009
- Pleiotropic effects in Eya3knockout miceBMC Developmental Biology, 2008
- A child with features of Goldenhar syndrome and a novel 1.12 Mb deletion in 22q11.2 by cytogenetics and oligonucleotide array CGH: Is this a candidate region for the syndrome?American Journal of Medical Genetics Part A, 2008
- Interstitial deletion of 10p and atrial septal defect in DiGeorge 2 syndromeClinical Genetics, 2004
- Retinoic Acid Embryopathy: Case Report and Review of LiteraturePediatric Pathology & Laboratory Medicine, 1996
- Retinoic Acid EmbryopathyThe New England Journal of Medicine, 1985
- Oculoauriculovertebral dysplasiaThe Journal of Pediatrics, 1963