title: Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia.
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.
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France. Electronic address: chris.gordon@inserm.fr.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: K Nicole
authors.initials: KN
authors.lastname: Weaver
authors.affiliation: Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru 17012-900, Brazil.
authors.forename: Roseli Maria
authors.initials: RM
authors.lastname: Zechi-Ceide
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Erik C
authors.initials: EC
authors.lastname: Madsen
authors.affiliation: Department of Craniofacial Biology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Andre L P
authors.initials: AL
authors.lastname: Tavares
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Oufadem
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kurihara
authors.affiliation: Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden.
authors.forename: Igor
authors.initials: I
authors.lastname: Adameyko
authors.affiliation: Service de Chirurgie Maxillo-Faciale et Plastique, Centre de Référence des Malformations de la Face et de la Cavité Buccale, Hôpital Necker-Enfants Malades et Université Pierre et Marie Curie, Paris 75015, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Picard
authors.affiliation: Service d'Imagerie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP et Laboratoire d'Anatomie, Université Paris Descartes, Paris 75015, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Breton
authors.affiliation: Service d'ORL Pediatrique, Hôpital Necker-Enfants Malades, AP-HP et Université Paris Descartes, Paris 75015, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pierrot
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service d'Odontologie, Hôpital Bretonneau, HUPNVS, AP-HP, Paris 75018, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Biosse-Duplan
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Norine
authors.initials: N
authors.lastname: Voisin
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Masson
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: Unité de génétique médicale, CHU Bordeaux, Bordeaux 33076, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Delrue
authors.affiliation: Unité de génétique médicale, CHU Bordeaux, Bordeaux 33076, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru 17012-900, Brazil.
authors.forename: Maria Leine
authors.initials: ML
authors.lastname: Guion-Almeida
authors.affiliation: Department of Clinical Genetics, Hospital for Rehabilitation of Craniofacial Anomalies, University of São Paulo, Bauru 17012-900, Brazil.
authors.forename: Priscila Padilha
authors.initials: PP
authors.lastname: Moura
authors.affiliation: Department of Orthodontics, Bauru Dental School, University of São Paulo, Bauru 17012-901, Brazil.
authors.forename: Daniela Gamba
authors.initials: DG
authors.lastname: Garib
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Ernfors
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hufnagel
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hopkin
authors.affiliation: Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Saal
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Weaver
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, NC 27701, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Department of Craniofacial Biology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Clouthier
authors.affiliation: INSERM UMR 1163, Institut Imagine, Paris 75015, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris 75015, France; Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France. Electronic address: jeanne.amiel@inserm.fr.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
mesh_terms: D000505:Alopecia / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D019332:Endothelin-1 / Q000378:metabolism; D059472:Exome / Q000235:genetics; D006801:Humans; D017403:In Situ Hybridization; D008342:Mandibulofacial Dysostosis / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D012333:RNA, Messenger / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014057:Tomography, X-Ray Computed; D015027:Zebrafish; D015050:Zygoma / Q000473:pathology
chemical_list: D019332:Endothelin-1; D060172:Morpholinos; D012333:RNA, Messenger; D044022:Receptor, Endothelin A