MODULATION OF DISEASE SEVERITY OF DYSTROPHIC EPIDERMOLYSIS-BULLOSA BYA SPLICE-SITE MUTATION IN COMBINATION WITH A MISSENSE MUTATION IN THECOL7A1 GENE

Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous s kin disorder, characterized by abnormal anchoring fibrils (AF) and los s of dermal-epidermal adherence, EBD has been linked to the COL7A1 gen e at chromosome 3p21 which encodes collagen VII, the major component o f the AF, Here we investigated two unrelated EBD families with differe nt clinical phenotypes and novel combinations of recessive and dominan t COL7A1 mutations. Both families shared the same recessive heterozygo us 14 bp deletion at the exon-intron 115 boundary of the COL7A1 gene. The deletion caused in-frame skipping of exon 115 and the elimination of 29 amino acid residues from the pro-alpha 1(VII) polypeptide chain. As a result, procollagen VII was not converted to collagen VII and th e C-terminal NC-2 propeptide which is normally removed from the procol lagen VII prior to formation of the anchoring fibrils was retained in the skin. All affected individuals also carried missense mutations in exon 73 of COL7A1 which lead to different glycine-to-arginine substitu tions in the triple-helical domain of collagen VII. Combination of the deletion mutation with a G2009R substitution resulted in a mild pheno type. In contrast, combination of the deletion with a G2043R substitut ion led to a severe phenotype. The G2043R substitution was a de novo m utation which alone caused a mild phenotype, Thus, different combinati ons of dominant and recessive COL7A1 mutations can modulate disease ac tivity of EBD and alter the clinical presentation of the patients.