Ehlers-Danlos syndrome (EDS) types I and II, which comprise the classical 
variety, are well characterized from the clinical perspective, but it has been 
difficult to identify the molecular basis of the disorder in the majority 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 been 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 linkage to loci that 
contain the COL5A1 or COL5A2 genes. To determine whether allele-product 
instability could explain failure to identify some mutations, 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 we determined that, in six 
individuals, the mRNA from one COL5A1 allele either was not expressed or was 
very unstable. We identified small insertions or deletions in five of these cell 
strains, but we could not identify the mutation in the sixth individual. Thus, 
although as many as one-half of the mutations that give rise to EDS types I and 
II are likely to lie in the COL5A1 gene, a significant portion of them result in 
very low levels of mRNA from the mutant allele, as a consequence of 
nonsense-mediated mRNA decay.