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

dc.contributor.coauthorSchrauwen, Isabelle
dc.contributor.coauthorValgaeren, Hanne
dc.contributor.coauthorTomas-Roca, Laura
dc.contributor.coauthorSommen, Manou
dc.contributor.coauthorAltunoglu, Umut
dc.contributor.coauthorWesdorp, Mieke
dc.contributor.coauthorBeyens, Matthias
dc.contributor.coauthorFransen, Erik
dc.contributor.coauthorNasir, Abdul
dc.contributor.coauthorVandeweyer, Geert
dc.contributor.coauthorSchepers, Anne
dc.contributor.coauthorRahmoun, Malika
dc.contributor.coauthorvan Beusekom, Ellen
dc.contributor.coauthorHuentelman, Matt J.
dc.contributor.coauthorOffeciers, Erwin
dc.contributor.coauthorDhooghe, Ingeborg
dc.contributor.coauthorHuber, Alex
dc.contributor.coauthorVan de Heyning, Paul
dc.contributor.coauthorZanetti, Diego
dc.contributor.coauthorDe Leenheer, Els M. R.
dc.contributor.coauthorGilissen, Christian
dc.contributor.coauthorHoischen, Alexander
dc.contributor.coauthorCremers, Cor W.
dc.contributor.coauthorVerbist, Berit
dc.contributor.coauthorde Brouwer, Arjan P. M.
dc.contributor.coauthorPadberg, George W.
dc.contributor.coauthorPennings, Ronald
dc.contributor.coauthorKremer, Hannie
dc.contributor.coauthorVan Camp, Guy
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorKayserili, Hülya
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T22:45:29Z
dc.date.issued2019
dc.description.abstractPurpose: 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.
dc.description.indexedbyWOS
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.issue5
dc.description.openaccessYES
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.volume21
dc.identifier.doi10.1038/s41436-018-0300-5
dc.identifier.issn1098-3600
dc.identifier.scopus2-s2.0-85054472762
dc.identifier.urihttps://doi.org/10.1038/s41436-018-0300-5
dc.identifier.urihttps://hdl.handle.net/20.500.14288/6094
dc.keywordsOtosclerosis
dc.keywordsHereditary congenital facial paresis
dc.keywordsMEPE
dc.keywordsCraniofacial bone disorder
dc.keywordsHearing loss
dc.language.isoeng
dc.publisherNature Publishing Group (NPG)
dc.relation.ispartofGenetics in Medicine
dc.subjectGenetics
dc.subjectHeredity
dc.titleVariants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorKayserili, Hülya
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit2School of Medicine
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relation.isParentOrgUnitOfPublication.latestForDiscovery17f2dc8e-6e54-4fa8-b5e0-d6415123a93e

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