Browsing by Author "Titeux, Matthias"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Epidermolysis bullosa simplex-generalized severe due to p.Glu477Lys mutation in keratin 5: a genotype-phenotype correlation with in silico modeling analysis(2019) Lalor, Leah; Titeux, Matthias; Palisson, Francis; Fuentes, Ignacia; Yubero, María; Tasanen, Kaisa; Huilaja, Laura; Has, Cristina; Tadini, Gianluca; Haggstrom, Anita N.; Hovnanian, Alain; Lucky, Anne W.Background/Objectives: Epidermolysis bullosa is a group of diseases caused by mutations in skin structural proteins. Availability of genetic sequencing makes identification of causative mutations easier, and genotype‐phenotype description and correlation are important. We describe six patients with a keratin 5 mutation resulting in a glutamic acid to lysine substitution at position 477 (p.Glu477Lys) who have a distinctive, severe and sometimes fatal phenotype. We also perform in silico modeling to show protein structural changes resulting in instability. Methods: In this case series, we collected clinical data from six patients with this mutation identified from their national or local epidermolysis bullosa databases. We performed in silico modeling of the keratin 5‐keratin 14 coil 2B complex using CCBuilder and rendered with Pymol (Schrodinger, LLC, New York, NY). Results: Features include aplasia cutis congenita, generalized blistering, palmoplantar keratoderma, onychodystrophy, airway and developmental abnormalities, and a distinctive reticulated skin pattern. Our in silico model of the keratin 5 p.Glu477Lys mutation predicts conformational change and modification of the surface charge of the keratin heterodimer, severely impairing filament stability. Conclusions: Early recognition of the features of this genotype will improve care. In silico analysis of mutated keratin structures provides useful insights into structural instability.Publication Novel variants impairing Sp1 transcription factor binding in the COL7A1 promoter cause mild cases of recessive dystrophic epidermolysis bullosa(2025) Pironon, Nathalie; Gasparyan, Artyom; Yubero, María; Duchatelet, Sabine; Hovhannesyan, Kristina; Leclerc-Mercier, Stephanie; Kostandyan, Natella; Palisson, Francis; Sarkisian, Tamara; Titeux, Matthias; Fuentes, Ignacia; Hovnanian, AlainRecessive 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 COL7A1 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 COL7A1 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 COL7A1 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 COL7A1 transcript and almost undetectable C7 protein levels. Our results reveal that mutations in the COL7A1 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 COL7A1 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.