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.

Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

“…1, 5 The involvement of this pathway in ACS was recently confirmed by the finding of EDN1 variants in ACS and in isolated QMEs (OMIM 612798). 6 Thus far only two GNAI3 variants, c.118G4C and c.141C4A (predicted consequence p.(Gly40Arg) and p.(Ser47Arg), respectively) in three unrelated familial cases have been reported. 5,7 No de novo variants have been described.…”

A Mouse Splice-Site Mutant and Individuals with Atypical Chromosome 22q11.2 Deletions Demonstrate the Crucial Role for Crkl in Craniofacial and Pharyngeal Development

“…Consistent with this hypothesis, mutations in EDN1 , the gene encoding endothelin-1 itself, have also been identified in ACS and isolated the 'question mark ear' malformation [Gordon et al, 2013a]. Crkl has not been associated with the endothelin pathway previously, but given the significant phenotypic overlap between the snoopy mouse and ACS and the alteration to endothelin signalling in snoopy embryos, it is plausible that this is the case.…”

Identificação de novas variantes causativas e investigação da heterogeneidade clínica da Síndrome aurículo-condilar

“… endothelin 1 (EDN1, MIM 131240), localizado em 6p24.1 (Gordon et al, 2013b). O número total de casos da ACS molecularmente investigados ainda é pequenoapenas 21 casos, dentre os aproximadamente 50 descritos (incluindo IQME) (revisto em Gordon et al, 2013a).…”

“…O número total de casos da ACS molecularmente investigados ainda é pequenoapenas 21 casos, dentre os aproximadamente 50 descritos (incluindo IQME) (revisto em Gordon et al, 2013a). Dentre estes, 95,2% (20/21) dos pacientes estudados tiveram variantes identificadas em um dos três genes descritos: 80% segregam com padrão autossômico dominante, tendo mostrado alterações em qualquer um dos três genes identificados; e 20% segregam de maneira autossômica recessiva, onde somente variantes patogênicas em PLCB4 e EDN1 foram encontradas (Figura 5) (Gordon et al, 2013b;Gordon et al, 2013a;Kido et al, 2013;Rieder et al, 2012). O único caso publicado, investigado e ainda não solucionado refere-se ao paciente A001 descrito em Rieder et al (2012), para o qual não foram encontradas variantes patogênicas em GNAI3 e PLCB4.…”

“…A EDN1 é uma proteína primeiro traduzida como pre-proendotelina com 212 aminoácidos, posteriormente quebrada pela furina em 2 sítios específicos de reconhecimento (na região C-terminal da sequencia consenso Arg-Ser-Lys-Arg) para gerar a big-endothelin, então com 38 aminoácidos; e a seguir, a endothelin converting enzyme (ECE) faz a quebra da big-endothelin em EDN1 madura e ativa, com 21 aminoácidos (revisto em Clouthier et al, 2013;Gordon et al, 2013b). …”