CLINICOPATHOLOGICAL CORRELATIONS OF COMPOUND HETEROZYGOUS COL7A1 MUTATIONS RECESSIVE DYSTROPHIC EPIDERMOLYSIS-BULLOSA

Recessive dystrophic epidermolysis bullosa is an inherited mechano-bul lous disorder of skin and mucous membranes. Ultrastructurally, the dis ease is characterized by abnormalities of anchoring fibrils, attachmen t structures below the epidermal basement membrane, composed of type V II collagen. Mutations in the type VII collagen gene (COL7A1) have bee n shown conclusively to underlie dystrophic epidermolysis bullosa. Sin ce there is variation of the phenotype, accompanied by heterogeneous a nchoring fibril morphology and type VII collagen immunostaining, it is conceivable that different types and combinations of COL7A1 mutations correlate with different phenotypes. We therefore screened recessive dystrophic epidermolysis bullosa patients for COL7A1 mutations. Three unrelated patients showed the same premature termination codon mutatio n in exon 13 of one allele, yet they were all compound heterozygotes, each having a different mutation in the second allele. The first patie nt had a premature termination codon within the collagenous region of COL7A1 associated with severe disease, absent anchoring fibrils and un detectable type VII collagen immunostaining. The second had a prematur e termination codon in the non-collagenous NC-2 region associated with severe disease, wispy anchoring fibrils, and patchy type VII collagen immunostaining. The third had a glycine-to-aspartic acid substitution within the collagenous region, associated with milder disease, no ide ntifiable anchoring fibrils, but near normal type VII collagen immunos taining. We conclude that the nature and position of mutations within COL7A1 correlate with specific disease features and may provide an ins ight into the molecular mechanisms of anchoring fibril formation and e pidermal-dermal adhesion.