Viable Ednra Y129F mice feature human mandibulofacial dysostosis with alopecia (MFDA) syndrome due to the homologue mutation

Abstract

Animal models resembling human mutations are valuable tools to research the features of complex human craniofacial syndromes. This is the first report on a viable dominant mouse model carrying a non-synonymous sequence variation within the endothelin receptor type A gene (Ednra c.386A>T, p.Tyr129Phe) derived by an ENU mutagenesis program. The identical amino acid substitution was reported recently as disease causing in three individuals with the mandibulofacial dysostosis with alopecia (MFDA, OMIM 616367) syndrome. We performed standardized phenotyping of wild-type, heterozygous, and homozygous Ednra Y129F 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 as described for MFDA-affected individuals. As observed in MFDA-affected individuals, mutant Ednra Y129F mice 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 as observed in MFDA patients but without showing any cleft palates, eyelid defects, or alopecia. Mutant Ednra Y129F mice represent a valuable viable model for complex human syndromes of the first and second pharyngeal arches and for further studies and analysis of impaired endothelin 1 (EDN1)–endothelin receptor type A (EDNRA) signaling. Above all, Ednra Y129F mice model the recently published human MFDA syndrome and may be helpful for further disease understanding and development of therapeutic interventions.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-016-9664-5) contains supplementary material, which is available to authorized users.

The role of teratogens in neural crest development

“…On the other hand, the Endothelin receptor B is found in the brain, endothelium, and smooth muscle cells and mediates endothelium‐dependent vasodilation through the release of nitric oxide, prostacyclin, and adrenomedullin (a circulating vasodilatory and natriuretic peptide of vascular endothelial and smooth muscle cell origin) (Issa et al, ; Kawasaki‐Nishihara, Nishihara, Nakamura, & Yamamoto, ). Regarding the role of the Endothelin Receptors in development, it has been shown that the Edn1/Ednra cell signaling plays a critical role in the specification, migration and patterning of mandibular identity in post‐migratory NCCs in different animal models such as Xenopus , zebrafish, chick, rat, rabbit and mouse (Bonano et al, ; Clouthier et al, ; Gordon et al, ; Kempf, Linares, Corvol, & Gasc, ; Miller, Schilling, Lee, Parker, & Kimmel, ; Sabrautzki et al, ; Spence, Anderson, Cukierski, & Patrick, ; Treinen, Louden, Dennis, & Wier, ).…”