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


Journal

Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873

Informations de publication

Date de publication:
Jun 2021
Historique:
received: 15 10 2020
accepted: 06 01 2021
pubmed: 22 1 2021
medline: 13 5 2021
entrez: 21 1 2021
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 33475861
doi: 10.1007/s00439-021-02255-6
pii: 10.1007/s00439-021-02255-6
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
DNA-Binding Proteins 0
H2AX protein, human 0
Histones 0
MYC protein, human 0
NF-E2-Related Factor 2 0
NFE2L2 protein, human 0
PPARGC1B protein, human 0
Proto-Oncogene Proteins c-myc 0
RNA-Binding Proteins 0
Transcription Factors 0
YAP-Signaling Proteins 0
YAP1 protein, human 0
EYA3 protein, human EC 3.1.3.48
Protein Tyrosine Phosphatases EC 3.1.3.48

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

933-944

Subventions

Organisme : ANR
ID : ANR-12-JVS1-0002

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Auteurs

Angèle Tingaud-Sequeira (A)

Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Univ. Bordeaux, 33000, Bordeaux, France.

Aurélien Trimouille (A)

Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Univ. Bordeaux, 33000, Bordeaux, France.
CHU de Bordeaux, Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Pellegrin-Ecole des Sages-femmes, Place Amélie Raba-Léon, 33076, Bordeaux Cedex, France.

Manju Salaria (M)

Genetic Health Service, Monash Health, 246 Clayton Road, Clayton, VIC, 3168, Australia.
Wyndham Specialist Care Centre, 289 Princes Highway, Werribee, VIC, 3030, Australia.

Rachel Stapleton (R)

Genetic Health Service NZ-South Island Hub, Christchurch Hospital, Christchurch, 8140, New Zealand.

Stéphane Claverol (S)

Plateforme Protéome, Centre Génomique Fonctionnelle Bordeaux, Bordeaux, France.

Claudio Plaisant (C)

CHU de Bordeaux, Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Pellegrin-Ecole des Sages-femmes, Place Amélie Raba-Léon, 33076, Bordeaux Cedex, France.

Marc Bonneu (M)

Plateforme Protéome, Centre Génomique Fonctionnelle Bordeaux, Bordeaux, France.

Estelle Lopez (E)

Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Univ. Bordeaux, 33000, Bordeaux, France.

Benoit Arveiler (B)

Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Univ. Bordeaux, 33000, Bordeaux, France.
CHU de Bordeaux, Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Pellegrin-Ecole des Sages-femmes, Place Amélie Raba-Léon, 33076, Bordeaux Cedex, France.

Didier Lacombe (D)

Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Univ. Bordeaux, 33000, Bordeaux, France.
CHU de Bordeaux, Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Pellegrin-Ecole des Sages-femmes, Place Amélie Raba-Léon, 33076, Bordeaux Cedex, France.

Caroline Rooryck (C)

Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Univ. Bordeaux, 33000, Bordeaux, France. caroline.rooryck-thambo@chu-bordeaux.fr.
CHU de Bordeaux, Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHU Pellegrin-Ecole des Sages-femmes, Place Amélie Raba-Léon, 33076, Bordeaux Cedex, France. caroline.rooryck-thambo@chu-bordeaux.fr.

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