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Am J Hum Genet. 2015 Apr 2;96(4):519-31. doi: 10.1016/j.ajhg.2015.01.015. Epub 2015 Mar 12.

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia.

Author information

1
INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France. Electronic address: chris.gordon@inserm.fr.
2
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
3
Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru 17012-900, Brazil.
4
Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
5
Department of Craniofacial Biology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
6
INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
7
Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
8
Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden.
9
Service de Chirurgie Maxillo-Faciale et Plastique, Centre de Référence des Malformations de la Face et de la Cavité Buccale, Hôpital Necker-Enfants Malades et Université Pierre et Marie Curie, Paris 75015, France.
10
Service d'Imagerie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP et Laboratoire d'Anatomie, Université Paris Descartes, Paris 75015, France.
11
Service d'ORL Pediatrique, Hôpital Necker-Enfants Malades, AP-HP et Université Paris Descartes, Paris 75015, France.
12
INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service d'Odontologie, Hôpital Bretonneau, HUPNVS, AP-HP, Paris 75018, France.
13
Unité de génétique médicale, CHU Bordeaux, Bordeaux 33076, France.
14
Department of Orthodontics, Bauru Dental School, University of São Paulo, Bauru 17012-901, Brazil.
15
INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France.
16
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
17
INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France. Electronic address: jeanne.amiel@inserm.fr.

Abstract

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

PMID:
25772936
PMCID:
PMC4385188
DOI:
10.1016/j.ajhg.2015.01.015
[Indexed for MEDLINE]
Free PMC Article

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