Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and 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 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.
De Paepe
A
A
Department of Medical Genetics, University Hospital Gent, Belgium. anne.depaepe@rug.ac.be
Nuytinck
L
L
Hausser
I
I
Anton-Lamprecht
I
I
Naeyaert
J M
JM
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics* / Q000648:ultrastructure; D017124:Conserved Sequence; D003545:Cysteine / Q000235:genetics; D004535:Ehlers-Danlos Syndrome / Q000235:genetics* / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011347:Procollagen / Q000737:chemistry / Q000235:genetics; D012694:Serine / Q000235:genetics; D012867:Skin / Q000648:ultrastructure
D011347:Procollagen; D012694:Serine; D003094:Collagen; D003545:Cysteine