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

Neurogenetics (2012) 13:115124 DOI 10.1007/s10048-012-0315-z

ORIGINAL ARTICLE

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

Steven E. Boyden & Lane J. Mahoney &

Genri Kawahara & Jennifer A. Myers &

Satomi Mitsuhashi & Elicia A. Estrella &

Anna R. Duncan & Friederike Dey &

Elizabeth T. DeChene & Jessica M. Blasko-Goehringer &

Carsten G. Bnnemann & Basil T. Darras &

Jerry R. Mendell & Hart G. W. Lidov & Ichizo Nishino &

Alan H. Beggs & Louis M. Kunkel & Peter B. Kang

Received: 25 October 2011 /Accepted: 25 January 2012 /Published online: 28 February 2012 # The Author(s) 2012. This article is published with open access at Springerlink.com

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

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S. E. Boyden : L. J. Mahoney : G. Kawahara : J. A. Myers :

S. Mitsuhashi : E. A. Estrella : A. R. Duncan : F. Dey :

E. T. DeChene : J. M. Blasko-Goehringer : H. G. W. Lidov :

A. H. Beggs : L. M. Kunkel : P. B. KangDivision of Genetics, Program in Genomics, and The Manton Center for Orphan Disease Research, Childrens Hospital Boston, Boston, MA, USA

S. E. Boyden : L. M. KunkelDepartment of...