A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I).

Type V collagen is a constituent of type I collagen-rich fibrils in many connective tissues and is a regulator of fibril diameter. In tissues, type V collagen is a heterotrimer with the molecular structure: alpha 1(V)2 alpha 2(V) or alpha 1(V) alpha 2(V) alpha 3(V). We report that genomic polymorphisms at the pro alpha 1(V) gene (COL5A1) locus cosegregated with the gravis form of Ehlers-Danlos syndrome (EDS) (type I) in a three generation family. Affected family members, who had classical features including joint hyperextensibility, fragile skin, and widened, atrophic scars, were heterozygous for a 4 bp deletion at positions from +3 to +6 of intron 65, which resulted in removal of exon 65 sequences from processed mRNAs. Since exon 65 encodes 78 residues of the carboxyl propeptide, the expected result of this mutation is reduced efficiency in incorporating mutant pro alpha 1(V) chains into type V collagen molecules and reduced type V collagen synthesis. These studies indicate that heterozygous mutations in COL5A1 can result in EDS type I. However, linkage studies in other EDS I families indicate the disorder is heterogeneous; linkage to both COL5A1 and COL5A2 was excluded in two other families with EDS I while a fourth family was concordant for linkage to COL5A1 (Z = 2.11; theta = 0.00).