304 Type VII collagen NC2 domain expression differentiates severe from milder recessive dystrophic epidermolysis bullosa subtypes

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) results from type VII collagen (C7) deficiency due to COL7A1 gene mutations. C7 contains collagenous domains (COL) flanked by amino (NC1) and carboxyl (NC2) non-collagenous domains. The genotype spectrum of RDEB is well studied but does not entirely explain the highly variable clinical phenotype. In this retrospective study, we aimed to identify a disease severity and prognostic indicator, from an extensively characterized RDEB cohort. 41 RDEB patients were studied with mild, intermediate and severe clinical phenotypes in 7, 11 and 23 patients respectively. 22 of 23 severe RDEB patients showed negative NC2 expression, with variable NC1 staining and variable AF morphology. 7 of 7 mild RDEB patients showed at least one allele with missense mutations in COL domains and positive NC2 and NC1 expression. 5 of 11 intermediate patients showed positive NC2 expression with missense and/or splice site COL domain mutations. 6 intermediate patients with negative NC2 expression showed bi-allelic PTC mutations and very low NC1 staining. Given their paucity of C7 NC2 expression, its possible these latter 6 patients may evolve into a more severe clinical phenotype over time or other factors outside of C7 expression may be playing a role in dictating disease severity. This remains to be further studied. We conclude that genotype or anchoring fibril morphology do not entirely explain the phenotypic variability and C7 NC1 expression did not prove to be a good indicator of disease severity. However, of all the tests utilized, C7 NC2 expression proved the most useful in distinguishing mild from severe RDEB clinical phenotypes.