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 am plification of genomic DNA, followed by heteroduplex analysis and nucl eotide 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 heterozyg ous carriers of this mutation, indicating that this glycine substituti on in one allele is ''silent'' when combined with a normal COL7A1 alle le, Thus, this patient appeared to be affected with DEB inherited in a n autosomal recessive pattern, The second case was a DEB patient with a heterozygous glycine-to-glutamic acid substitution (G2079E) ill exon 75, The parents were clinically unaffected and neither had this mutat ion in their peripheral blood leukocyte DNA, Haplotype analyses sugges ted that this case arose as a ne novo occurrence of autosomal dominant DEB, These cases illustrate the consequences of COL7A1 glycine substi tution mutations underlying DEB in terms of the made of inheritance an d the phenotype, with profound implications for genetic counseling of individuals at risk for recurrence of DEB in subsequent offspring or f uture geuerations.