Mutations in the endothelin receptor type a cause mandibulofacial dysostosis with alopecia

Christopher T. Gordon*, K. Nicole Weaver, Roseli Maria Zechi-Ceide, Erik C. Madsen, Andre L.P. Tavares, Myriam Oufadem, Yukiko Kurihara, Igor Adameyko, Arnaud Picard, Sylvain Breton, Sébastien Pierrot, Martin Biosse-Duplan, Norine Voisin, Cécile Masson, Christine Bole-Feysot, Patrick Nitschké, Marie Ange Delrue, Didier Lacombe, Maria Leine Guion-Almeida, Priscila Padilha MouraDaniela Gamba Garib, Arnold Munnich, Patrik Ernfors, Robert B. Hufnagel, Robert J. Hopkin, Hiroki Kurihara, Howard M. Saal, David D. Weaver, Elias Nicholas Katsanis, Stanislas Lyonnet, Christelle Golzio, David E. Clouthier, Jeanne Amiel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)519-531
Number of pages13
JournalAmerican journal of human genetics
Issue number4
StatePublished - Apr 2 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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