PUBLICATION

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

Authors
Gordon, C.T., Weaver, K.N., Zechi-Ceide, R.M., Madsen, E.C., Tavares, A.L., Oufadem, M., Kurihara, Y., Adameyko, I., Picard, A., Breton, S., Pierrot, S., Biosse-Duplan, M., Voisin, N., Masson, C., Bole-Feysot, C., Nitschké, P., Delrue, M.A., Lacombe, D., Guion-Almeida, M.L., Moura, P.P., Garib, D.G., Munnich, A., Ernfors, P., Hufnagel, R.B., Hopkin, R.J., Kurihara, H., Saal, H.M., Weaver, D.D., Katsanis, N., Lyonnet, S., Golzio, C., Clouthier, D.E., Amiel, J.
ID
ZDB-PUB-150530-6
Date
2015
Source
American journal of human genetics   96: 519-31 (Journal)
Registered Authors
Clouthier, David, Gordon, Chris, Katsanis, Nicholas, Lyonnet, Stanislas
Keywords
none
MeSH Terms
  • Alopecia/genetics*
  • Alopecia/pathology
  • Animals
  • Base Sequence
  • Endothelin-1/metabolism
  • Exome/genetics
  • Humans
  • In Situ Hybridization
  • Mandibulofacial Dysostosis/genetics*
  • Mandibulofacial Dysostosis/pathology
  • Molecular Sequence Data
  • Morpholinos/genetics
  • Mutation, Missense/genetics
  • Pedigree
  • RNA, Messenger/administration & dosage
  • Real-Time Polymerase Chain Reaction
  • Receptor, Endothelin A/genetics*
  • Receptor, Endothelin A/metabolism
  • Sequence Analysis, DNA
  • Syndrome
  • Tomography, X-Ray Computed
  • Zebrafish
  • Zygoma/pathology
PubMed
25772936 Full text @ Am. J. Hum. Genet.
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.
Genes / Markers
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping