title: Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears.
abstract: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder with mandibular hypoplasia and question-mark ears (QMEs) as major features. QMEs, consisting of a specific defect at the lobe-helix junction, can also occur as an isolated anomaly. Studies in animal models have indicated the essential role of endothelin 1 (EDN1) signaling through the endothelin receptor type A (EDNRA) in patterning the mandibular portion of the first pharyngeal arch. Mutations in the genes coding for phospholipase C, beta 4 (PLCB4) and guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 3 (GNAI3), predicted to function as signal transducers downstream of EDNRA, have recently been reported in ACS. By whole-exome sequencing (WES), we identified a homozygous substitution in a furin cleavage site of the EDN1 proprotein in ACS-affected siblings born to consanguineous parents. WES of two cases with vertical transmission of isolated QMEs revealed a stop mutation in EDN1 in one family and a missense substitution of a highly conserved residue in the mature EDN1 peptide in the other. Targeted sequencing of EDN1 in an ACS individual with related parents identified a fourth, homozygous mutation falling close to the site of cleavage by endothelin-converting enzyme. The different modes of inheritance suggest that the degree of residual EDN1 activity differs depending on the mutation. These findings provide further support for the hypothesis that ACS and QMEs are uniquely caused by disruption of the EDN1-EDNRA signaling pathway.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U781, Hôpital Necker - Enfants Malades, 75015 Paris, France; Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France. Electronic address: chris.gordon@inserm.fr.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Gordon
authors.forename: Florence
authors.initials: F
authors.lastname: Petit
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kroisel
authors.forename: Linda
authors.initials: L
authors.lastname: Jakobsen
authors.forename: Roseli Maria
authors.initials: RM
authors.lastname: Zechi-Ceide
authors.forename: Myriam
authors.initials: M
authors.lastname: Oufadem
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Solenn
authors.initials: S
authors.lastname: Pruvost
authors.forename: Cécile
authors.initials: C
authors.lastname: Masson
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tores
authors.forename: Thierry
authors.initials: T
authors.lastname: Hieu
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.forename: Pernille
authors.initials: P
authors.lastname: Lindholm
authors.forename: Philippe
authors.initials: P
authors.lastname: Pellerin
authors.forename: Maria Leine
authors.initials: ML
authors.lastname: Guion-Almeida
authors.forename: Nancy Mizue
authors.initials: NM
authors.lastname: Kokitsu-Nakata
authors.forename: Siulan
authors.initials: S
authors.lastname: Vendramini-Pittoli
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D004423:Ear / Q000002:abnormalities*; D004427:Ear Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D019332:Endothelin-1