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

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10048-012-0315-z) contains supplementary material, which is available to authorized users.

Novel SNP array analysis and exome sequencing detect a homozygous exon 7 deletion of MEGF10 causing early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD)

“…MEGF10 mutations have been previously associated with a range of neuromuscular phenotypes, including EMARDD [1,5]. Similar to previously reported EMARDD patients with null mutations of MEGF10 , the proband had decreased fetal movements, early hypotonia, finger contractures, scoliosis, dysphagia, areflexia, progressive weakness, and infantile respiratory distress requiring mechanical ventilation [1].…”

“…Muscle histology of the proband was also more consistent with other EMARDD patients, with only non-specific myopathic changes without minicores [1,5]. There was also occasional central nucleation.…”

“…Her phenotype also varied from the less severe neuromuscular phenotype seen in patients with missense mutations in MEGF10 [5]. Those patients had minicores on muscle biopsy, did not require persistent respiratory ventilation, and presented with profound neck weakness, but milder axial and proximal appendicular weakness.…”

“…The murine homologue has also been detected in Schwann cell precursors and muscle satellite cells, and has been shown to participate in satellite cell proliferation, differentiation and fusion into multi-nucleated myofibers [1]. Furthermore, knockdown of MEGF10 in zebrafish disrupted myofibrillar organization and striation [5]. …”

Identification of genome‐wide selection signatures in the Limousin beef cattle breed

“…Moreover, SNPs within this gene are connected with myopathy in humans (Boyden et al . ). The significant role of fibroblast growth factor 6 (FGF6) in myogenesis was also pinpointed by De Lapeyrière et al .…”