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Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

Nature Genetics volume 43, pages 1189–1192 (2011)Cite this article

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Abstract

Infantile myopathies with diaphragmatic paralysis are genetically heterogeneous, and clinical symptoms do not assist in differentiating between them. We used phased haplotype analysis with subsequent targeted exome sequencing to identify MEGF10 mutations in a previously unidentified type of infantile myopathy with diaphragmatic weakness, areflexia, respiratory distress and dysphagia. MEGF10 is highly expressed in activated satellite cells and regulates their proliferation as well as their differentiation and fusion into multinucleated myofibers, which are greatly reduced in muscle from individuals with early onset myopathy, areflexia, respiratory distress and dysphagia.

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Figure 1: Mutations in MEGF10 cause EMARDD, a recessive congenital myopathy.

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GenBank/EMBL/DDBJ

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Acknowledgements

The authors thank the families who participated in this study. F.M. is supported by the Great Ormond Street Hospital Children's Charity. Z.A.A. receives an Egyptian Government Scholarship. This work was supported by grants from Newlife Foundation for Disabled Children (to I.M.C. and C.A.J.) and the Sir Jules Thorn Award for Biomedical Research (to C.A.J., E.S., G.R.T. and D.T.B.), the Deutsche Forschungsgemeinschaft (SFB 665 TP C4 and KFO 192) and the NeuroCure Cluster of Excellence, Exc 257 (to M. Schuelke) and the parents' support group 'Helft dem muskelkranken Kind' Hamburg, Germany (to C.H.). We acknowledge the contribution of clinical data by U. Schara and T. Polster.

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Author notes

  1. Clare V Logan, Barbara Lucke and Caroline Pottinger: These authors contributed equally to this work.

  2. Markus Schuelke and Colin A Johnson: These authors jointly directed this work.

Authors and Affiliations

  1. Leeds Institute of Molecular Medicine, The University of Leeds, Leeds, UK

    Clare V Logan, Zakia A Abdelhamed, David A Parry, Katarzyna Szymanska, Christine P Diggle, Joanne E Morgan, Grace Markham, Alexander F Markham, Mike Shires, David T Bonthron, Graham R Taylor, Eamonn Sheridan, Ian M Carr & Colin A Johnson

  2. Department of Neuropediatrics and NeuroCure Clinical Research Center, Charité Universitätsmedizin Berlin, Berlin, Germany

    Barbara Lucke, Anne van Riesen, Christoph Hübner & Markus Schuelke

  3. Clinical Genetics Unit, West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, UK

    Caroline Pottinger

  4. Department of Anatomy and Embryology, Faculty of Medicine (Girls' Section), Al-Azhar University, Cairo, Egypt

    Zakia A Abdelhamed

  5. Department of Clinical Genetics, Alder Hey Children's Hospital, Liverpool, UK

    Ian Ellis

  6. Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital for Children, London, UK

    Adnan Y Manzur, Mariacristina Scoto & Francesco Muntoni

  7. Royal Liverpool University Hospital, Liverpool, UK

    Tim Helliwell

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  1. Clare V Logan
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Contributions

K.S., M. Schuelke and I.M.C. performed genetic mapping. C.V.L., B.L., D.A.P., C.P.D., G.M., M. Schuelke and C.A.J. performed mutation analyses in the cohorts of affected individuals. C.V.L., J.E.M., D.A.P. and G.R.T. generated the next-generation sequencing data. C.V.L. and D.A.P. performed the control genotyping. D.A.P., I.M.C., M. Schuelke and G.R.T. analyzed the SNP genotyping and next-generation sequencing data. C.V.L. examined the complementary DNA and protein expression in cell lines from affected individuals. Z.A.A. and M. Shires performed the immunohistochemistry staining experiments. C.P., A.v.R., I.E., A.F.M., T.H., E.S., C.H., F.M., A.Y.M., M. Scoto and M. Schuelke recruited subjects, gathered clinical information and contributed clinical samples. A.F.M., D.T.B., E.S., F.M., I.M.C., C.H., M. Schuelke and C.A.J. wrote the manuscript.

Corresponding authors

Correspondence to Markus Schuelke or Colin A Johnson.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5, Supplementary Tables 1 and 2, Supplementary Methods and Supplementary Note. (PDF 2074 kb)

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Logan, C., Lucke, B., Pottinger, C. et al. Mutations in MEGF10, a regulator of satellite cell myogenesis, cause early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). Nat Genet 43, 1189–1192 (2011). https://doi.org/10.1038/ng.995

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