Original Article

neurogenetics

, Volume 13, Issue 2, pp 115-124

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

Mutations in the satellite cell gene MEGF10 cause a recessive congenital myopathy with minicores

  • Steven E. BoydenAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital BostonDepartment of Genetics, Harvard Medical School
  • , Lane J. MahoneyAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
  • , Genri KawaharaAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
  • , Jennifer A. MyersAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
  • , Satomi MitsuhashiAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital BostonDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry
  • , Elicia A. EstrellaAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
  • , Anna R. DuncanAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
  • , Friederike DeyAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
  • , Elizabeth T. DeCheneAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
    • , Jessica M. Blasko-GoehringerAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital Boston
    • , Carsten G. BönnemannAffiliated withNational Institute of Neurological Disorders and Stroke, National Institutes of Health
    • , Basil T. DarrasAffiliated withDepartment of Neurology, Children’s Hospital Boston and Harvard Medical School
    • , Jerry R. MendellAffiliated withCenter for Gene Therapy Research Institute, Nationwide Children’s Hospital
    • , Hart G. W. LidovAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital BostonDepartment of Pathology, Children’s Hospital Boston and Harvard Medical School
    • , Ichizo NishinoAffiliated withDepartment of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry
    • , Alan H. BeggsAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital BostonDepartment of Pediatrics, Harvard Medical School
    • , Louis M. KunkelAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital BostonDepartment of Genetics, Harvard Medical SchoolDepartment of Pediatrics, Harvard Medical School
    • , Peter B. KangAffiliated withDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children’s Hospital BostonDepartment of Neurology, Children’s Hospital Boston and Harvard Medical School Email author 

Abstract

We ascertained a nuclear family in which three of four siblings were affected with an unclassified autosomal recessive myopathy characterized by severe weakness, respiratory impairment, scoliosis, joint contractures, and an unusual combination of dystrophic and myopathic features on muscle biopsy. Whole genome sequence from one affected subject was filtered using linkage data and variant databases. A single gene, MEGF10, contained nonsynonymous mutations that co-segregated with the phenotype. Affected subjects were compound heterozygous for missense mutations c.976T > C (p.C326R) and c.2320T > C (p.C774R). Screening the MEGF10 open reading frame in 190 patients with genetically unexplained myopathies revealed a heterozygous mutation, c.211C > T (p.R71W), in one additional subject with a similar clinical and histological presentation as the discovery family. All three mutations were absent from at least 645 genotyped unaffected control subjects. MEGF10 contains 17 atypical epidermal growth factor-like domains, each of which contains eight cysteine residues that likely form disulfide bonds. Both the p.C326R and p.C774R mutations alter one of these residues, which are completely conserved in vertebrates. Previous work showed that murine Megf10 is required for preserving the undifferentiated, proliferative potential of satellite cells, myogenic precursors that regenerate skeletal muscle in response to injury or disease. Here, knockdown of megf10 in zebrafish by four different morpholinos resulted in abnormal phenotypes including unhatched eggs, curved tails, impaired motility, and disorganized muscle tissue, corroborating the pathogenicity of the human mutations. Our data establish the importance of MEGF10 in human skeletal muscle and suggest satellite cell dysfunction as a novel myopathic mechanism.

Keywords

MEGF10 Whole genome sequencing Linkage analysis Congenital myopathy Satellite cells Cleft palate