Endothelin 1 (EDN1,2)–endothelin receptor type A (EDNRA) signaling seems to play an important role in normal craniofacial development in humans as well as in animal models. A viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A[T, p.Tyr129Phe) was derived by an ENU mutagenesis program. Recently the identical amino acid substitution was reported as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome.
The scientists around Sibylle Sabrautzki from the Institute of Experimental Genetics at the Helmholtz Zentrum München performed standardized phenotyping of wild-type, heterozygous, and homozygous EdnraY129F mice within the German Mouse Clinic.
Mutant mice mimic the craniofacial phenotypes of jaw dysplasia, micrognathia, dysplastic temporomandibular joints, auricular dysmorphism, and missing of the squamosal zygomatic process. Mutant EdnraY129F mice also exhibit hearing impairment in line with strong abnormalities of the ossicles and further, reduction of some lung volumetric parameters. In general, heterozygous and homozygous mice demonstrated inter-individual diversity of expression of the craniofacial phenotypes. Many of these phenotypes were also observed or described for MFDA patients. Thus the mutant EdnraY129F mice seem to be a valuable viable model for complex human syndromes of the first and second pharyngeal arches, the understanding of the human MFDA syndrome and for the development of therapeutic interventions.
Sibylle Sabrautzki, Michael A. Sandholzer, Bettina Lorenz-Depiereux, Robert Brommage, Gerhard Przemeck, Ingrid L. Vargas Panesso, Alexandra Vernaleken, Lillian Garrett, Katharina Baron, Ali O. Yildirim, Jan Rozman, Birgit Rathkolb, Christine Gau, Wolfgang Hans, Sabine M. Hoelter, Susan Marschall, Claudia Stoeger, Lore Becker, Helmut Fuchs, Valerie Gailus-Durner, Martin Klingenspor, Thomas Klopstock, Christoph Lengger, Leuchtenberger Stefanie, Eckhard Wolf, Tim M. Strom, Wolfgang Wurst, Martin Hrabeˇ de Angelis. Viable EdnraY129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation. Mamm Genome (2016) 27:587–598. DOI 10.1007/s00335-016-9664-5