EDNRA – Mandibulofacial Dysostosis with Alopecia

Mandibulofacial dysostosis with alopecia (MFDA) is a rare craniofacial malformation syndrome characterized by hair loss, zygomatic arch hypoplasia and mandibular anomalies. Pathogenic heterozygous variants in the endothelin receptor type A gene EDNRA underlie this autosomal dominant condition. EDNRA signals via G proteins in neural crest cells to establish mandibular identity, and disruption of ligand–receptor specificity leads to maxillary-to-mandibular transformations in humans and mouse models.

Four unrelated probands, three with the recurrent de novo missense variant c.386A>T (p.Tyr129Phe) and one with a mosaic c.907G>A (p.Glu303Lys), presented with the full MFDA phenotype including alopecia and facial bone dysmorphism (PMID:25772936). All variants occurred de novo in the probands, and no additional familial segregation was observed. The variant spectrum comprises two recurrent gain-of-function missense changes targeting key ligand-binding or allosteric residues in EDNRA.

Functional assays demonstrate that p.Tyr129Phe increases EDNRA affinity for endothelin-3, while p.Glu303Lys enhances G protein coupling via altered helix dynamics, both resulting in ET3-dependent receptor hyperactivation (PMID:36637912). Mouse knock-in models recapitulate the maxillary-to-mandibular transformation, which is completely rescued by genetic deletion of EDN3, confirming a gain-of-function mechanism.

There are no reports disputing this gene–disease relationship. The concordance of multiple de novo variants, consistent gain-of-function biochemical data, and in vivo rescue constitutes strong clinical validity. EDNRA variant testing should be considered in patients with MFDA features, as it informs prognosis and potential future ligand-targeted therapies.

Key Take-home: De novo gain-of-function variants in EDNRA cause MFDA via ET3-dependent receptor hyperactivation, supported by robust genetic and functional evidence.

References

• American Journal of Human Genetics • 2015 • Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia PMID:25772936
• The Journal of Clinical Investigation • 2023 • Mandibulofacial dysostosis with alopecia results from ETAR gain-of-function mutations via allosteric effects on ligand binding PMID:36637912

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