MUTATIONS IN THE COL5A1 GENE ARE CAUSAL IN THE EHLERS-DANLOS-SYNDROME-I AND EHLERS-DANLOS-SYNDROME-II

The Ehlers-Danlos syndrome (EDS) is a heterogeneous connective-tissue disorder of which at least nine subtypes are recognized. Considerable clinical overlap exists between the EDS I and II subtypes, suggesting that both are allelic disorders. Recent evidence based on linkage and transgenic mice studies suggest that collagen V is causally involved i n human EDS. Collagen V forms heterotypic fibrils with collagen I in m any tissues and plays an important role in collagen I fibrillogenesis. We have identified a mutation in COL5A1, the gene encoding the proal( V) collagen chain, segregating with EDS I in a four-generation family. The mutation causes the substitution of the most 5' cysteine residue by a serine within a highly conserved sequence of the proal(V) C-prope ptide domain and causes reduction of collagen V by preventing incorpor ation of the mutant proal(V) chains in the collagen V trimers. In addi tion, we have detected splicing defects in the COL5A1 gene in a patien t with EDS I and in a family with EDS II. These findings confirm the c ausal role of collagen V in at least a subgroup of EDS I, prove that E DS I and II are allelic conditions, and represent a, so far, unique ex ample of a human collagen disorder caused by substitution of a highly conserved cysteine residue in the C-propeptide domain of a fibrillar c ollagen.