. 2019 May;21(5):1199-1208.

doi: 10.1038/s41436-018-0300-5. Epub 2018 Oct 5.

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

Isabelle Schrauwen^#^{1

2

3}, Hanne Valgaeren^#¹, Laura Tomas-Roca^#^{4

5}, Manou Sommen^#¹, Umut Altunoglu^#⁶, Mieke Wesdorp^{5

7

8}, Matthias Beyens¹, Erik Fransen¹, Abdul Nasir⁹, Geert Vandeweyer¹, Anne Schepers¹, Malika Rahmoun^{4

5}, Ellen van Beusekom⁴, Matt J Huentelman², Erwin Offeciers¹⁰, Ingeborg Dhooghe¹¹, Alex Huber¹², Paul Van de Heyning¹³, Diego Zanetti¹⁴, Els M R De Leenheer^{7

11}, Christian Gilissen⁴, Alexander Hoischen^{4

7

15}, Cor W Cremers⁷, Berit Verbist^{16

17}, Arjan P M de Brouwer^{4

5}, George W Padberg^{5

18}, Ronald Pennings^{5

7}, Hülya Kayserili¹⁹, Hannie Kremer^#^{4

5

7}, Guy Van Camp^#²⁰, Hans van Bokhoven^#^{21

22}

Affiliations

¹ Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
² Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
³ Center for Statistical Genetics, Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶ Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, İstanbul, Turkey.
⁷ Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands.
⁸ Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
⁹ Synthetic Protein Engineering Lab (SPEL), Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
¹⁰ European Institute for ORL, St-Augustinus Hospital Antwerp, Antwerp, Belgium.
¹¹ Department of Otolaryngology, Ghent University Hospital, Ghent, Belgium.
¹² Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, Zurich, Switzerland.
¹³ Department of ORL and Head and Neck Surgery, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
¹⁴ Dept. of Clinical Sciences and Community Health, Audiology Unit, University of Milan, I.R.C.C.S. Fondazione "Cà Granda", Osp.le Maggiore Policlinico, Milano, Italy.
¹⁵ Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁶ Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁷ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁸ Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹ Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.
²⁰ Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium. guy.vancamp@uantwerpen.be.
²¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.vanBokhoven@radboudumc.nl.
²² Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.vanBokhoven@radboudumc.nl.

^# Contributed equally.

PMID: 30287925
DOI: 10.1038/s41436-018-0300-5

Free article

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

Isabelle Schrauwen et al. Genet Med. 2019 May.

Free article

. 2019 May;21(5):1199-1208.

doi: 10.1038/s41436-018-0300-5. Epub 2018 Oct 5.

Authors

Affiliations

¹ Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium.
² Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA.
³ Center for Statistical Genetics, Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵ Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶ Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, İstanbul, Turkey.
⁷ Department of Otorhinolaryngology, Hearing & Genes, Radboud University Medical Center, Nijmegen, The Netherlands.
⁸ Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
⁹ Synthetic Protein Engineering Lab (SPEL), Department of Molecular Science and Technology, Ajou University, Suwon, South Korea.
¹⁰ European Institute for ORL, St-Augustinus Hospital Antwerp, Antwerp, Belgium.
¹¹ Department of Otolaryngology, Ghent University Hospital, Ghent, Belgium.
¹² Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, Zurich, Switzerland.
¹³ Department of ORL and Head and Neck Surgery, Antwerp University Hospital, University of Antwerp, Edegem, Belgium.
¹⁴ Dept. of Clinical Sciences and Community Health, Audiology Unit, University of Milan, I.R.C.C.S. Fondazione "Cà Granda", Osp.le Maggiore Policlinico, Milano, Italy.
¹⁵ Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁶ Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁷ Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁸ Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁹ Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.
²⁰ Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Antwerp, Belgium. guy.vancamp@uantwerpen.be.
²¹ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.vanBokhoven@radboudumc.nl.
²² Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Hans.vanBokhoven@radboudumc.nl.

^# Contributed equally.

PMID: 30287925
DOI: 10.1038/s41436-018-0300-5

Abstract

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.

Keywords: MEPE; craniofacial bone disorder; hearing loss; hereditary congenital facial paresis; otosclerosis.

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References

1. Menger DJ, Tange RA. The aetiology of otosclerosis: a review of the literature. Clin Otolaryngol Allied Sci. 2003;28:112–120. - DOI
1. Kremer H, Kuyt LP, van den Helm B, et al. Localization of a gene for Mobius syndrome to chromosome 3q by linkage analysis in a Dutch family. Hum Mol Genet. 1996;5:1367–1371. - DOI
1. Michielse CB, Bhat M, Brady A, et al. Refinement of the locus for hereditary congenital facial palsy on chromosome 3q21 in two unrelated families and screening of positional candidate genes. Eur J Hum Genet. 2006;14:1306–1312. - DOI
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Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis

Affiliations

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

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Research Materials