Modulation of disease severity of dystrophic epidermolysis bullosa by a splice site mutation in combination with a missense mutation in the COL7A1 gene

Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous skindisorder, characterized by abnormal anchoring fibrils (AF) and loss ofdermal-epidermal adherence. EBD has been linked to the COL7A1 gene atchromosome 3p21 which encodes collagen VII, the major component of the AF.Here we investigated two unrelated EBD families with different clinicalphenotypes and novel combinations of recessive and dominant COL7A1mutations. Both families shared the same recessive heterozygous 14 bpdeletion at the exon-intron 115 boundary of the COL7A1 gene. The deletioncaused in-frame skipping of exon 115 and the elimination of 29 amino acidresidues from the pro-alpha1(VII) polypeptide chain. As a result,procollagen VII was not converted to collagen VII and the C-terminal NC-2propeptide which is normally removed from the procollagen VII prior toformation of the anchoring fibrils was retained in the skin. All affectedindividuals also carried missense mutations in exon 73 of COL7A1 which leadto different glycine- to-arginine substitutions in the triple-helicaldomain of collagen VII. Combination of the deletion mutation with a G2009Rsubstitution resulted in a mild phenotype. In contrast, combination of thedeletion with a G2043R substitution led to a severe phenotype. The G2043Rsubstitution was a de novo mutation which alone caused a mild phenotype.Thus, different combinations of dominant and recessive COL7A1 mutations canmodulate disease activity of EBD and alter the clinical presentation of thepatients.