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



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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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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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.

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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).

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