Epidermolysis bullosa simplex-generalized severe type due to keratin 5 p.Glu477Lys mutation : genotype-phenotype correlation and <em>in silico</em> modeling analysis
Lalor, Leah; Titeux, Matthias; Palisson, Francis; Fuentes, Ignacia; Yubero, María J.; Tasanen, Kaisa; Huilaja, Laura; Has, Cristina; Tadini, Gianluca; Haggstrom, Anita N.; Hovnanian, Alain; Lucky, Anne W. (2018-12-04)
Lalor, L, Titeux, M, Palisson, F, et al. Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype‐phenotype correlation and in silico modeling analysis. Pediatr Dermatol. 2019; 36: 132– 138. https://doi.org/10.1111/pde.13722
© 2018 Wiley Periodicals, Inc. This is the peer reviewed version of the following article: Lalor, L, Titeux, M, Palisson, F, et al. Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype‐phenotype correlation and in silico modeling analysis. Pediatr Dermatol. 2019; 36: 132– 138. https://doi.org/10.1111/pde.13722, which has been published in final form at https://doi.org/10.1111/pde.13722. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
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https://urn.fi/URN:NBN:fi-fe2019103035825
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Abstract
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.
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