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)

Abstract

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.

Genetic Covariation of Pelvic Organ and Elbow Mobility in Twins and their Sisters

“…The results indicate that multivariate molecular genetic studies, which aim to identify quantitative trait loci (QTLs -locations on the chromosomes at which specific genes contribute to a quantitative trait) may provide important insights into the etiology of pelvic organ mobility. Genes related to collagen, elastin and fibrillin structure or metabolism (i.e., genes implicated in clinical connective tissue disorders such as Marfan's and Ehlers Danlos syndrome, Hutchinson et al, 2003;Schwarze, et al, 2000) may be appropriate candidate genes for ensuing association studies, which will examine the relationship between allelic variation and degree of mobility in the measures of interest.…”

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

“…In approximately one third of individuals with classic EDS, nonsense or frameshift mutations are responsible for a nonfunctional COL5A1 allele. 49,[53][54][55] Nonsense, frameshift, or splice site mutations that introduce a premature termination codon are usually responsible for this nonfunctional COL5A1 allele. A variety of mechanisms lead to nonsense-mediated decay of the mutation-bearing mRNA.…”

ColVa1 and ColXIa1 are required for myocardial morphogenesis and heart valve development

“…This change has been characterized in several mouse models with mutations in fibrillar collagens that recapitulate human connective tissue disorders Li et al, 1995;Aszodi et al, 2000;Wenstrup et al, 2000). Mutations in ColVa1 have been identified in over 40% of EhlersDanlos syndrome (EDS) cases (Schwarze et al, 2000;Wenstrup et al, 2000). ColVa1Ϫ/Ϫ mice are embryonic lethal at embryonic day (E) 10.5; however, ColVa1ϩ/Ϫ mice are viable and exhibit features of EDS associated with structural weaknesses in connective tissues including skin, tendon, and cornea (Wenstrup et al, 2004Segev et al, 2006;Wenstrup, unpublished observations).…”