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Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS
  1. Estelle Lopez1,
  2. Marie Berenguer1,
  3. Angèle Tingaud-Sequeira1,
  4. Sandrine Marlin2,
  5. Annick Toutain3,
  6. Françoise Denoyelle4,
  7. Arnaud Picard5,
  8. Sabine Charron1,
  9. Guilaine Mathieu1,
  10. Harmony de Belvalet1,
  11. Benoit Arveiler1,6,
  12. Patrick J Babin1,
  13. Didier Lacombe1,6,
  14. Caroline Rooryck1,6
  1. 1University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France
  2. 2Département de Génétique, Hôpital Universitaire Necker-Enfants-Malades, Centre de Référence des Surdités Génétiques, Paris, France
  3. 3Service de Génétique, Hôpital Bretonneau, Centre Hospitalier Universitaire, Tours, France
  4. 4Service d'ORL pédiatrique et de chirurgie cervicofaciale, Hôpital Universitaire Necker-Enfants-Malades, Centre de Référence des malformations ORL rares, Paris, France
  5. 5Service de chirurgie maxillo-faciale, Hôpital Universitaire Necker-Enfants Malades, Paris, France
  6. 6Service de Génétique Médicale, CHU de Bordeaux, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Bordeaux, France
  1. Correspondence to Dr Caroline Rooryck, Laboratoire Maladies Rares: Génétique et Métabolisme, U1211 INSERM CHU Pellegrin—Ecole des Sages-femmes, Place Amélie Raba-Léon, Bordeaux 33076, Cedex France; caroline.rooryck-thambo{at}


Background Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder involving first and second branchial arches derivatives, mainly characterised by asymmetric ear anomalies, hemifacial microsomia, ocular defects and vertebral malformations. Although numerous chromosomal abnormalities have been associated with OAVS, no causative gene has been identified so far.

Objectives We aimed to identify the first causative gene for OAVS.

Methods As sporadic cases are mostly described in Goldenhar syndrome, we have performed whole exome sequencing (WES) on selected affected individuals and their unaffected parents, looking for de novo mutations. Candidate gene was tested through transient knockdown experiment in zebrafish using a morpholino-based approach. A functional test was developed in cell culture in order to assess deleterious consequences of mutations.

Results By WES, we identified a heterozygous nonsense mutation in one patient in the myelin transcription factor 1 (MYT1) gene. Further, we detected one heterozygous missense mutation in another patient among a cohort of 169 patients with OAVS. This gene encodes the MYT1. Functional studies by transient knockdown of myt1a, homologue of MYT1 in zebrafish, led to specific craniofacial cartilage alterations. Treatment with all-trans retinoic acid (RA), a known teratogenic agent causing OAVS, led to an upregulation of cellular endogenous MYT1 expression. Additionally, cellular wild-type MYT1 overexpression induced a downregulation of RA receptor β (RARB), whereas mutated MYT1 did not.

Conclusion We report MYT1 as the first gene implicated in OAVS, within the RA signalling pathway.

  • MYT1
  • OAVS
  • Retinoic acid
  • Goldenhar syndrome
  • RARB

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  • EL, MB and AT-S have equally contributed to this work. These first three authors should be considered as joint first authors.

  • Contributors EL, MB and AT-S planned, performed experiments, analysed data and co-wrote the manuscript; SM and AT clinically ascertained patients and provided samples; SC performed experiments and analysed data; FD and AP clinically ascertained patients; GM and HdB performed experiments; BA, PJB and DL planned experiments and CR supervised, planned experiments, analysed data, co-wrote and edited the manuscript.

  • Funding This work was supported by the ANR (Agence Nationale pour la Recherche, ANR-12-JVS1-0002), the University Hospital of Bordeaux (Appel Offre Interne GOLDGEN 2012), the Fondation Maladies Rares and the Ministry of Research and Higher Education (PhD fellowship for MB).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval CPP: DC 2012/76.

  • Provenance and peer review Not commissioned; externally peer reviewed.