Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II.

A De Paepe, L Nuytinck, I Hausser… - American journal of …, 1997 - ncbi.nlm.nih.gov
A De Paepe, L Nuytinck, I Hausser, I Anton-Lamprecht, JM Naeyaert
American journal of human genetics, 1997ncbi.nlm.nih.gov
Abstract 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 in
human EDS. Collagen V forms heterotypic fibrils with collagen I in many tissues and plays
an important role in collagen I fibrillogenesis. We have identified a mutation in COL5A1, the …
Abstract
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 in human EDS. Collagen V forms heterotypic fibrils with collagen I in many tissues and plays an important role in collagen I fibrillogenesis. We have identified a mutation in COL5A1, the gene encoding the pro (alpha) 1 (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 pro (alpha) 1 (V) C-propeptide domain and causes reduction of collagen V by preventing incorporation of the mutant pro (alpha) 1 (V) chains in the collagen V trimers. In addition, we have detected splicing defects in the COL5A1 gene in a patient with EDS I and in a family with EDS II. These findings confirm the causal role of collagen V in at least a subgroup of EDS I, prove that EDS I and II are allelic conditions, and represent a, so far, unique example of a human collagen disorder caused by substitution of a highly conserved cysteine residue in the C-propeptide domain of a fibrillar collagen.
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