Compound heterozygosity for a disease-causing G1489E [corrected] and disease-modifying G530S substitution in COL5A1 of a patient with the classical type of Ehlers-Danlos syndrome: an explanation of intrafamilial variability?

The classical type of Ehlers-Danlos syndrome (EDS) is an autosomal dominant connective tissue disorder characterized by skin hyperelasticity, tissue fragility, and joint hypermobility. We investigated the molecular defect of EDS in a three-generation family. Cultured dermal fibroblasts from the propositus and his daughter produced abnormal alpha1(V) and alpha2(V) collagen molecules. Mutation analysis by means of RNase cleavage and direct sequencing of reverse transcription-polymerase chain reaction products showed in both the presence of a heterozygous G1489E [correction] mutation in the COL5A1 gene, which represents the first report of a glycine substitution in the main triple-helical region of alpha1(V) collagen. In the propositus, his unaffected daughter, and mother we identified a further newly recognized G530S substitution in the NH2-terminal domain, which did not cosegregate with the EDS phenotype and was found in only one of 51 unrelated control individuals. Because the NH2-terminal domain plays a crucial role in modulating fibril formation, the G530S substitution may alter the structure and function of this region and consequently the formation of collagen fibrils. Indeed, indirect evidence supports our hypothesis: (1) the EDS phenotype in the compound heterozygous propositus is more severe than that of his affected daughter with the G1489E [correction] mutation only; (2) his unaffected daughter and mother with the G530S substitution present with thin skin and delayed wound healing; (3) as does the only control individual with the same substitution. Thus, in the compound heterozygous propositus the EDS phenotype is caused by the G1489E [correction] mutation and possibly aggravated by the G530S substitution, which may explain intrafamilial variability.