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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
Author(s) -
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.
Publication year - 2018
Publication title -
pediatric dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.542
H-Index - 73
eISSN - 1525-1470
pISSN - 0736-8046
DOI - 10.1111/pde.13722
Subject(s) - epidermolysis bullosa simplex , epidermolysis bullosa , in silico , keratin 5 , mutation , keratin , genetics , keratin 14 , phenotype , biology , medicine , dermatology , gene , transgene , genetically modified mouse
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 CCB uilder 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.