Universidad del Desarrollo

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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
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Artyom Gasparyan
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YUBERO GONCALVEZ, MARIA JOAO
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Sabine Duchatelet
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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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Multidisciplinary care of epidermolysis bullosa during the COVID-19 pandemic—Consensus: Recommendations by an international panel of experts
(2020)
Dedee F. Murrell
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Anne W. Lucky
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Julio C. Salas-Alanis
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David T. Woodley
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FRANCIS PALISSON ETCHARREN
Scopus© Citations 8 4
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Epidermolysis Bullosa Simplex with KLHL24 Mutations Is Associated with Dilated Cardiomyopathy
(2019)
Agnes Schwieger-Briel
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FUENTES BUSTOS, MARIA IGNACIA
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Daniele Castiglia
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Antonio Barbato
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Matthias Greutmann
Scopus© Citations 32 1
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APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa
(2018)
Raymond J. Cho
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Ludmil B. Alexandrov
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Nicoline Y. den Breems
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Velina S. Atanasova
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Mehdi Farshchian
<jats:p>Early-onset squamous cell carcinoma in recessive dystrophic epidermolysis bullosa patients is characterized by APOBEC mutagenesis.</jats:p>
5Scopus© Citations 100
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Epidermolysis bullosa simplex-generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype-phenotype correlation and in silico modeling analysis
(2019)
Leah Lalor
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Matthias Titeux
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FRANCIS PALISSON ETCHARREn
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Ignacia Fuentes
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María J. Yubero
Scopus© Citations 13 1
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Identification of Rigosertib for the Treatment of Recessive Dystrophic Epidermolysis Bullosa-Associated Squamous Cell Carcinoma
(2019)
Velina S. Atanasova
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Celine Pourreyron
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Mehdi Farshchian
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Michael Lawler
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Christian A. Brown
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Purpose:</jats:title> <jats:p>Squamous cell carcinoma (SCC) of the skin is the leading cause of death in patients with the severe generalized form of the genetic disease recessive dystrophic epidermolysis bullosa (RDEB). Although emerging data are identifying why patients suffer this fatal complication, therapies for treatment of RDEB SCC are in urgent need.</jats:p> <jats:p>Experimental Design: We previously identified polo-like kinase 1 (PLK1) as a therapeutic target in skin SCC, including RDEB SCC. Here, we undertake a screen of 6 compounds originally designated as PLK1 inhibitors, and detail the efficacy of the lead compound, the multipathway allosteric inhibitor ON-01910, for targeting RDEB SCC in vitro and in vivo.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>ON-01910 (or rigosertib) exhibited significant specificity for RDEB SCC: in culture rigosertib induced apoptosis in 10 of 10 RDEB SCC keratinocyte populations while only slowing the growth of normal primary skin cells at doses 2 orders of magnitude higher. Furthermore, rigosertib significantly inhibited the growth of two RDEB SCC in murine xenograft studies with no apparent toxicity. Mechanistically, rigosertib has been shown to inhibit multiple signaling pathways. Comparison of PLK1 siRNA with MEK inhibition, AKT inhibition, and the microtubule-disrupting agent vinblastine in RDEB SCC shows that only PLK1 reduction exhibits a similar sensitivity profile to rigosertib.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>These data support a "first in RDEB" phase II clinical trial of rigosertib to assess tumor targeting in patients with late stage, metastatic, and/or unresectable SCC.</jats:p> </jats:sec>
24Scopus© Citations 32

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