Compound heterozygosity for COL7A1 mutations in twins with dystrophic epidermolysis bullosa: a recessive paternal deletion/insertion mutation and a dominant negative maternal glycine substitution result in a severe phenotype.

We have previously demonstrated genetic linkage between the type VII collagen gene (COL7A1) and the dominant (DDEB) and recessive (RDEB) forms of dystrophic epidermolysis bullosa (DEB) and have subsequently identified pathogenetic mutations in several families. Mutations in DDEB identified thus far are glycine substitutions in the collagenous domain of COL7A1, while the most severe forms of RDEB result from premature termination codon (PTC) mutations on both alleles. In this study, we performed mutation analysis in the COL7A1 gene in twins who displayed a severe DEB phenotype. Mutational analysis revealed a paternal 2-bp deletion/1-bp insertion in exon 56, designated 5103CC-->G, which results in a frameshift and downstream PTC. Analysis of the maternal COL7A1 allele revealed a glycine-to-arginine substitution in exon 91 (G2351R). Careful questioning of the mother revealed that she and her father had a history of shedding of toenails and occasional poorly healing erosions, consistent with a mild form of DDEB. Immunoprecipitation of type VII collagen from fibroblasts of the twins revealed a marked reduction in intracellular protein production, consistent with the drastic reduction in mRNA transcript from the paternal mutant allele, while the majority of polypeptides bearing the glycine substitution appeared to be degraded intracellularly. Thus, the severe RDEB phenotype in the probands results from compound heterozygosity for one glycine substitution and one PTC mutation in COL7A1.