Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy

The Bethlem myopathy is a rare autosomal dominant proximal myopathycharacterized by early childhood onset and joint contractures. Evidence forlinkage and genetic heterogeneity has been established, with the majorityof families linked to 21q22.3 and one large family linked to 2q37,implicating the three type VI collagen subunit genes, COL6A1 (chromosome21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes.Mutations of the invariant glycine residues in the triple-helicaldomain-coding region of COL6A1 and COL6A2 have been reported previously inthe chromosome 21-linked families. We report here the identification of aG-->A mutation in the N-terminal globular domain-coding region of COL6A3in a large American pedigree (19 affected, 12 unaffected), leading to thesubstitution of glycine by glutamic acid in the N2 motif, which ishomologous to the type A domains of the von Willebrand factor. Thismutation segregated to all affected family members, to no unaffected familymembers, and was not identified in 338 unrelated Caucasian controlchromosomes. Thus mutations in either the triple-helical domain or theglobular domain of type VI collagen appear to cause Bethlem myopathy.