A glycine substitution in the COL7A1 gene causes mild RDEB in a Pakistani family.

Pathogenic glycine substitutions can cause destabilization of the triple helix and a diverse range of heritable connective tissue disorders, dependent on the collagen gene in which the mutation occurs. Mutations in the type VII collagen gene (COL7A1) cause an inherited mechanobullous skin disease known as dystrophic epidermolysis bullosa (DEB). Typically, the dominant forms (DDEB) result from glycine substitutions within COL7A1, whereas other glycine mutations are 'silent' in the heterozygous state and produce disease only when they are homozygous. We studied three affected individuals from a large inbred Pakistani family with a history of skin fragility and scarring indicative of dystrophic EB. We identified a new glycine substitution within the collagenous region in exon 94 of the COL7A1 gene. This mutation, designated G2422V, resulted in a glycine (GGA) to valine (GTA) substitution presumably causing a destabilization of the protein by interrupting the Gly-X-Y repeats. This finding expands the allelic series of COL7A1 mutations underlying mild recessive dystrophic epidermolysis bullosa (RDEB) and sheds further light upon regions of the type VII collagen triple helix that are tolerant of heterozygous glycine substitutions.