A homeotic maxillary to mandibular transformation in humans resulting from loss of selective ligand affinity of the endothelin receptor type A. C. Gordon1, M. Oufadem1, Y. Kurihara2, A. Picard3, S. Breton4, S. Pierrot3, M.-A. Delrue5, M. Biosse-Duplan1, M. Guion-Almeida6, P. Moura6, D. Garib7, D. Weaver8, A. Munnich1,9, P. Corvol10, H. Kurihara2, R. Zechi-Ceide6, S. Lyonnet1,9, J. Amiel1,9 1) Université Paris Descartes, INSERM U-781, Paris, France; 2) Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 3) Service dORL Pediatrique, Hôpital Necker-Enfants Malades, Paris, France; 4) Service dImagerie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France; 5) Unité de génétique médicale, CHU Bordeaux, Bordeaux, France; 6) Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo (HRCA-USP), Bauru, SP, Brazil; 7) Department of Orthodontics, Bauru Dental School, University of São Paulo, Bauru, São Paulo, Brazil; 8) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; 9) Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France; 10) INSERM U833, Collège de France, Paris, France.

   A homeotic transformation is a fascinating genetic error of development first described in Drosophila. In humans, Auriculocondylar syndrome (OMIM 602483 and 614669) is thought to result from the homeotic transformation of the mandible into a maxilla. We present two unrelated and sporadic cases with a severe and syndromic form of mandibulofacial dysostosis (MFD) featuring malformation of the eyelids and alopecia. Craniofacial 3D CT scans of both patients showed a striking symmetry between the abnormal mandible and maxilla, suggestive of a mirror image version of mandibular structures in the upper jaw. The endothelin core system (i.e. ligands plus receptors) is a vertebrate-specific innovation implicated in the development of several neural crest cell (NCC)-derived tissues, and in mammals is comprised of three ligands and two receptors belonging to the G protein-coupled seven transmembrane domain receptor family. Endothelin receptor type A (Ednra) displays selective affinity for endothelin 1 (Edn1) relative to Edn2 and Edn3, and Edn1/Ednra signalling plays a critical role in specification of mandibular identity in post-migratory NCCs. Edn1 expression is restricted to the mandibular prominence and Ednra is expressed throughout the first pharyngeal arch. The phenotype of the two patients we report was considered similar to a mutant mouse in which the Edn1 cDNA is knocked-in to the Ednra locus, leading to their coexpression and resulting in a maxillary to mandibular transformation. EDNRA was thus considered as a candidate disease-causing gene for the syndromic MFD of the two patients. Sanger sequencing identified the same de novo, heterozygous missense mutation in EDNRA in both patients. In in vitro assays, the mutation increases affinity for EDN3 approximately 100 fold, while not affecting the affinity for EDN1. Expression analysis of Edn3 during mouse craniofacial development revealed strong expression in the epithelium of the caudal surface of the maxillary prominence, but not in the mandibular prominence, at E11.5. Whether the increase in affinity for EDN3 leads to increased levels of EDNRA signalling is unclear at present, but is consistent with a model in which the normal expression of EDN3 in the maxillary prominence would lead to a maxillary-to-mandibular transformation via overactivation of mutant EDNRA. These findings confirm the importance of selective EDN1-EDNRA affinity in human jaw development and gnathostome evolution.

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