Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis

Isabelle Schrauwen, Hanne Valgaeren, Laura Tomas-Roca, Manou Sommen, Umut Altunoglu, Mieke Wesdorp, Matthias Beyens, Erik Fransen, Abdul Nasir, Geert Vandeweyer, Anne Schepers, Malika Rahmoun, Ellen van Beusekom, Matt J. Huentelman, Erwin Offeciers, Ingeborg Dhooghe, Alex Huber, Paul Van de Heyning, Diego Zanetti, Els M.R. De LeenheerChristian Gilissen, Alexander Hoischen, Cor W. Cremers, Berit Verbist, Arjan P.M. de Brouwer, George W. Padberg, Ronald Pennings, Hülya Kayserili, Hannie Kremer, Guy Van Camp, Hans van Bokhoven

Research output: Contribution to journalArticlepeer-review


Purpose: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. Methods: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. Results: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006–0.0060). Conclusion: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

Original languageEnglish
Pages (from-to)1199-1208
JournalGenetics in Medicine
Issue number5
Publication statusPublished - 2019


  • craniofacial bone disorder
  • hearing loss
  • hereditary congenital facial paresis
  • MEPE
  • otosclerosis

ASJC Scopus subject areas

  • Genetics(clinical)


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