Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II)

Ehlers-Danlos syndrome (EDS) types I. and II, which comprise the classical variety, are well characterized from the clinical perspective, but it has b een difficult to identify the molecular basis of the disorder in the majori ty of affected individuals. Several explanations for this failure to detect mutations have been proposed, including genetic heterogeneity, failure of allele expression, and technical difficulties. Genetic heterogeneity has be en confirmed as an explanation for such failure, since causative mutations have been identified in the COL5A1, COL5A2, and tenascin X genes and since they have been inferred in the COL1A2 gene. Nonetheless, in the majority of families with autosomal dominant inheritance of EDS, there appears to be l inkage to loci that contain the COL5A1 or COL5A2 genes. To determine whethe r allele-product instability could explain failure to identify some mutatio ns, we analyzed polymorphic variants in the COL5A1 gene in 16 individuals, and we examined mRNA for the expression of both alleles and for alterations in splicing. We found a splice-site mutation in a single individual, and w e determined that, in six individuals, the mRNA from one COL5A1 allele eith er was not expressed or was very unstable. We identified small insertions o r deletions in five of these cell strains, but we could not identify the mu tation in the sixth individual. Thus, although as many as one-half of the m utations that give rise to EDS types I and II are likely to lie in the COL5 A1 gene, a significant portion of them result in very low levels of mRNA fr om the mutant allele, as a consequence of nonsense-mediated mRNA decay.