A heterozygous splice site mutation in COL6A1 leading to an in-frame deletion of the alpha 1(VI) collagen chain in an Italian family affected by Bethlem myopathy

Bethlem myopathy is a mild neuromuscular disorder with proximal muscular we akness and early flexion contractures, It is an autosomal dominant disease due to mutations in type VI collagen genes. We found a T-->C substitution a t the +2 position of COL6A1 intron 14 in a family, leading to skipping of e xon 14 and an in-frame deletion of 18 amino acids in the triple-helical dom ain of the alpha 1(VI) collagen chain. The deletion included a cysteine res idue believed to be involved in the assembly of type VI collagen dimers int racellularly, prior to the protein secretion. Analysis of the affected fibr oblasts showed that the shortened alpha 1(VI) collagen chains were synthesi zed but not secreted by the cells and that the amount of type VI collagen m icrofibrils deposited by the cells was reduced. The results suggest that th e clinical phenotype is due to a reduction in the level of type VI collagen in the extracellular matrix. (C) 1999 Academic Press.