Project Title
Developing Discarded Dressings as a Diagnostic tool in Epidermolysis bullosa
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Internal ID
1220704
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    Novel variants impairing Sp1 transcription factor binding in the COL7A1 promoter cause mild cases of recessive dystrophic epidermolysis bullosa
    (Springer Science and Business Media LLC, 2024-12-05)
    Nathalie Pironon
    ;
    Artyom Gasparyan
    ;
    YUBERO GONCALVEZ, MARIA JOAO  
    ;
    Sabine Duchatelet
    ;
    Kristina Hovhannesyan
    <jats:title>Abstract</jats:title><jats:p>Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and most often severe genodermatosis characterized by recurrent blistering and erosions of the skin and mucous membranes after minor trauma, leading to major local and systemic complications. RDEB is caused by loss-of-function mutations in <jats:italic>COL7A1</jats:italic> encoding type VII collagen (C7), the main component of anchoring fibrils which form attachment structures stabilizing the cutaneous basement membrane zone. Most of the previously reported <jats:italic>COL7A1</jats:italic> mutations are located in the coding or intronic regions. We describe 6 patients with localized or intermediate RDEB for whom one recessive pathogenic variant in the coding region and a second variant in the <jats:italic>COL7A1</jats:italic> promoter were identified. These substitutions, three of which are novel, are localized in two Sp1 binding sites of the promoter region. DNA pull-down assay showed a drastic reduction of Sp1 binding consistent with a dramatic decrease in <jats:italic>COL7A1</jats:italic> transcript and almost undetectable C7 protein levels. Our results reveal that mutations in the <jats:italic>COL7A1</jats:italic> promoter on the background of a null allele can underlie localized or intermediate RDEB. They further emphasize the functional importance of Sp1 motifs in the proximal <jats:italic>COL7A1</jats:italic> promoter which should be carefully investigated for regulatory mutations in the case of RDEB with only one pathogenic variant identified in the coding or intronic regions.</jats:p>
    Scopus© Citations 2  5
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    Maintenance of chronicity signatures in fibroblasts isolated from recessive dystrophic epidermolysis bullosa chronic wound dressings under culture conditions
    (2023)
    DE GREGORIO CONCHA, CRISTIAN ALEJANDRO  
    ;
    Evelyng Catalán
    ;
    Gabriel Garrido
    ;
    Pilar Morandé
    ;
    CASTILLO BENNETT, JIMENA VICTORIA  
    <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a rare inherited skin disease caused by variants in the <jats:italic>COL7A1</jats:italic> gene, coding for type VII collagen (C7), an important component of anchoring fibrils in the basement membrane of the epidermis. RDEB patients suffer from skin fragility starting with blister formation and evolving into chronic wounds, inflammation and skin fibrosis, with a high risk of developing aggressive skin carcinomas. Restricted therapeutic options are limited by the lack of in vitro models of defective wound healing in RDEB patients.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>In order to explore a more efficient, non-invasive in vitro model for RDEB studies, we obtained patient fibroblasts derived from discarded dressings) and examined their phenotypic features compared with fibroblasts derived from non-injured skin of RDEB and healthy-donor skin biopsies. Our results demonstrate that fibroblasts derived from RDEB chronic wounds (RDEB-CW) displayed characteristics of senescent cells, increased myofibroblast differentiation, and augmented levels of TGF-β1 signaling components compared to fibroblasts derived from RDEB acute wounds and unaffected RDEB skin as well as skin from healthy-donors. Furthermore, RDEB-CW fibroblasts exhibited an increased pattern of inflammatory cytokine secretion (IL-1β and IL-6) when compared with RDEB and control fibroblasts. Interestingly, these aberrant patterns were found specifically in RDEB-CW fibroblasts independent of the culturing method, since fibroblasts obtained from dressing of acute wounds displayed a phenotype more similar to fibroblasts obtained from RDEB normal skin biopsies.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>Our results show that in vitro cultured RDEB-CW fibroblasts maintain distinctive cellular and molecular characteristics resembling the inflammatory and fibrotic microenvironment observed in RDEB patients’ chronic wounds. This work describes a novel, non-invasive and painless strategy to obtain human fibroblasts chronically subjected to an inflammatory and fibrotic environment, supporting their use as an accessible model for in vitro studies of RDEB wound healing pathogenesis. As such, this approach is well suited to testing new therapeutic strategies under controlled laboratory conditions.</jats:p> </jats:sec>
    Scopus© Citations 1  1