Glycine substitution mutations in the type VII collagen gene (COL7A1) in dystrophic epidermolysis bullosa: implications for genetic counseling.

Dystrophic epidermolysis bullosa (DEB) is an inherited mechanobullous disorder characterized by fragility of the skin and mucous membranes. The anchoring fibril protein, type VII collagen, is encoded by COL7A1, which harbors mutations in this group of diseases. In this study, we report novel glycine substitution mutations in COL7A1 in two Japanese families with DEB. The mutation detection strategy consisted of PCR amplification of genomic DNA, followed by heteroduplex analysis and nucleotide sequencing of the PCR products demonstrating altered mobility. The first case is a patient with clinically severe recessive DEB. The proband was shown to have a homozygous glycine-to-valine substitution (G2671V) in exon 108. The clinically unaffected parents were heterozygous carriers of this mutation, indicating that this glycine substitution in one allele is "silent" when combined with a normal COL7A1 allele. Thus, this patient appeared to be affected with DEB inherited in an autosomal recessive pattern. The second case was a DEB patient with a heterozygous glycine-to-glutamic acid substitution (G2079E) in exon 75. The parents were clinically unaffected and neither had this mutation in their peripheral blood leukocyte DNA. Haplotype analyses suggested that this case arose as a de novo occurrence of autosomal dominant DEB. These cases illustrate the consequences of COL7A1 glycine substitution mutations underlying DEB in terms of the mode of inheritance and the phenotype, with profound implications for genetic counseling of individuals at risk for recurrence of DEB in subsequent offspring or future generations.