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 myopathy ch aracterized by early childhood onset and joint contractures. Evidence for linkage and genetic heterogeneity has been established, with the m ajority of families linked to 21q22.3 and one large family linked to 2 q37, implicating the three type VI collagen subunit genes, COL6A1 (chr omosome 21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candi date genes. Mutations of the invariant glycine residues in the triple- helical domain-coding region of COL6A1 and COL6A2 have been reported p reviously in the chromosome 21-linked families. We report here the ide ntification of a G-->A mutation in the N-terminal globular domain-codi ng region of COL6A3 in a large American pedigree (19 affected, 12 unaf fected), leading to the substitution of glycine by glutamic acid in th e N2 motif, which is homologous to the type A domains of the von Wille brand factor. This mutation segregated to all affected family members, to no unaffected family members, and was not identified in 338 unrela ted Caucasian control chromosomes. Thus mutations in either the triple -helical domain or the globular domain of type VI collagen appear to c ause Bethlem myopathy.