Identification of a new molecular modulator of severity in recessive dystrophic epidermolysis bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare disorder characterized by cutaneous fragility of the skin and mucous, due to COL7A1 mutations. Patients with RDEB have a poor quality of life as result of chronic wounds that trigger fibrotic processes and facilitate the development of highly aggressive squamous cell carcinomas. To find new disease-severity modulators, we previously reported a transcriptomic study (RNA-Seq) in two RDEB siblings with marked phenotypic differences despite being genotypically identical for COL7A1 (c.6527insC/c.6527insC). Enrichment analysis of the differentially expressed genes suggested differences regarding the extracellular matrix (ECM), cell contraction, and response to TGF-β, among others. Here, we explored in detail the biological relevance of some of these differentially altered processes. In particular, fibroblasts from the less affected sibling (M-RDEB) showed reduced response to TGF-β stimulus and lower contractile capacity of collagen lattices, contrary to what was observed in other RDEB patients (including the sister with severe phenotype) and similar to the behavior of fibroblasts from healthy donors. Interestingly, M-RDEB fibroblasts upregulate a previously undisclosed ECM protein capable of inhibiting the TGF-β pathway, and presumably responsible -at least in part- for the mild phenotype observed in M-RDEB. Overexpression of the gene encoding this factor in fibroblasts from the sister with severe phenotype (S-RDEB) counteracted TGF-β response and cell contraction capacity in in vitro functional assays. A similar result was obtained when treating S-RDEB fibroblasts with the molecule as a recombinant protein. Thus, our study identified new modulators and druggable targets in RDEB pathophysiology, which would enable novel symptom relief therapies to tackle disease progression.