title: Monozygotic twins discordant for recessive dystrophic epidermolysis bullosa phenotype highlight the role of TGF-β signalling in modifying disease severity.
abstract: 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 COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis. Identical COL7A1 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-β 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 α-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-β 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-β pathways in modulating disease variability. Moreover, our findings identify decorin as a possible anti-fibrotic/inflammatory agent for RDEB therapeutic intervention.
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Odorisio
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Di Salvio
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Orecchia
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Zenzo
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Piccinni
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cianfarani
authors.affiliation: CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Cagliari 09010, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Travaglione
authors.affiliation: CRS4 Bioinformatics Laboratory, Parco Scientifico e Tecnologico POLARIS, Pula, Cagliari 09010, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Uva
authors.affiliation: Laboratory of Cutaneous Physiopathology, San Gallicano Dermatologic Institute-IRCCS, Rome 00144, Italy and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bellei
authors.affiliation: Azienda Ospedaliera Universitaria Policlinico Modena, Modena 41100, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Conti
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata (IDI)-IRCCS, Rome 00167, Italy, d.castiglia@idi.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000328:Adult; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D024143:Collagen Type VII / Q000235:genetics / Q000378:metabolism; D016108:Epidermolysis Bullosa Dystrophica / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C111835:CCL2 protein, human; C569053:COL7A1 protein, human; D018932:Chemokine CCL2; D024143:Collagen Type VII; D015850:Interleukin-6; D017395:Plasminogen Activator Inhibitor 1; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases