title: 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.
authors.affiliation: Division of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Boyden
authors.forename: Lane J
authors.initials: LJ
authors.lastname: Mahoney
authors.forename: Genri
authors.initials: G
authors.lastname: Kawahara
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Myers
authors.forename: Satomi
authors.initials: S
authors.lastname: Mitsuhashi
authors.forename: Elicia A
authors.initials: EA
authors.lastname: Estrella
authors.forename: Anna R
authors.initials: AR
authors.lastname: Duncan
authors.forename: Friederike
authors.initials: F
authors.lastname: Dey
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: DeChene
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Blasko-Goehringer
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: Basil T
authors.initials: BT
authors.lastname: Darras
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Mendell
authors.forename: Hart G W
authors.initials: HG
authors.lastname: Lidov
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
authors.forename: Peter B
authors.initials: PB
authors.lastname: Kang
mesh_terms: D000818:Animals; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000151:congenital* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism*; D015027:Zebrafish
chemical_list: C522055:MEGF10, human; D008565:Membrane Proteins