Clinicopathological correlations of compound heterozygous COL7A1 mutations recessive dystrophic epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa is an inherited mechano-bullous disorder of skin and mucous membranes. Ultrastructurally, the disease is characterized by abnormalities of anchoring fibrils, attachment structures below the epidermal basement membrane, composed of type VII collagen. Mutations in the type VII collagen gene (COL7A1) have been shown conclusively to underlie dystrophic epidermolysis bullosa. Since there is variation of the phenotype, accompanied by heterogeneous anchoring 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 mutation in exon 13 of one allele, yet they were all compound heterozygotes, each having a different mutation in the second allele. The first patient had a premature termination codon within the collagenous region of COL7A1 associated with severe disease, absent anchoring fibrils and undetectable type VII collagen immunostaining. The second had a premature 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 identifiable anchoring fibrils, but near normal type VII collagen immunostaining. We conclude that the nature and position of mutations within COL7A1 correlate with specific disease features and may provide an insight into the molecular mechanisms of anchoring fibril formation and epidermal-dermal adhesion.