Background: General genotype-phenotype correlations have been delineated in recessive dystrophic epidermolysis bullosa (RDEB), but these remain complicated and it is still difficult to assess the clinical consequences of individual COL7A1 mutations.
Objective: To characterize recurrent p.Glu2857X mutations and show how other COL7A1 mutations influence the phenotype in RDEB patients harboring p.Glu2857X.
Methods: Genotype-phenotype correlations were studied in six Japanese RDEB patients with the p.Glu2857X mutation.
Results: Besides the common p.Glu2857X mutation, premature termination codon (PTC) mutations were found in three patients, glycine substitution missense mutations in two patients, and a non-glycine substitution missense mutation in one patient. PTC mutations in both alleles generally cause the most severe, mutilating Hallopeau-Siemens (HS) variant of RDEB, whereas none of the PTC mutations resulted in severe phenotypes consistent with the HS subtype when coupled with p.Glu2857X. Missense glycine and non-glycine mutations caused phenotypes of differing severity, suggesting that the extent of destabilization of anchoring fibrils depends on the type of mutation.
Conclusion: A p.Glu2857X mutation exhibits mild pathogenic effects compared to other PTC mutations in COL7A1, and its uniqueness enables detailed analysis and comparison of the destabilizing effects of missense mutations in RDEB patients.