Monozygotic twins discordant for recessive dystrophic epidermolysis bullosa phenotype highlight the role of TGF-Î² signalling in modifying disease severity.

[dystrophic epidermolysis bullosa]

Recessive dystrophic epidermolysis bullosa (RDEB ) is a genodermatosis characterized by fragile skin forming blisters that heal invariably with scars . It is due to mutations in the COL 7 A 1 gene encoding type VII collagen , the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis . Identical COL 7 A 1 mutations often result in inter- and intra-familial disease variability , suggesting that additional modifiers contribute to RDEB course . Here , we studied a monozygotic twin pair with RDEB presenting markedly different phenotypic manifestations , while expressing similar amounts of collagen VII . Genome-wide expression analysis in twins ' fibroblasts showed differential expression of genes associated with TGF-Î² pathway inhibition . In particular , decorin , a skin matrix component with anti-fibrotic properties , was found to be more expressed in the less affected twin . Accordingly , fibroblasts from the more affected sibling manifested a profibrotic and contractile phenotype characterized by enhanced Î±-smooth muscle actin and plasminogen activator inhibitor 1 expression , collagen I release and collagen lattice contraction . These cells also produced increased amounts of proinflammatory cytokines interleukin 6 and monocyte chemoattractant protein-1 . Both TGF-Î² canonical (Smads ) and non-canonical (MAPKs ) pathways were basally more activated in the fibroblasts of the more affected twin . The profibrotic behaviour of these fibroblasts was suppressed by decorin delivery to cells . Our data show that the amount of type VII collagen is not the only determinant of RDEB clinical severity , and indicate an involvement of TGF-Î² pathways in modulating disease variability . Moreover , our findings identify decorin as a possible anti-fibrotic /inflammatory agent for RDEB therapeutic intervention .

Diseases
Validation

Diseases presenting "fragile skin" symptom

dystrophic epidermolysis bullosa

junctional epidermolysis bullosa

kindler syndrome

This symptom has already been validated