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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

Authors :
Anne W. Lucky
Anita N. Haggstrom
Laura Huilaja
Francis Palisson
Cristina Has
Alain Hovnanian
Gianluca Tadini
Leah Lalor
Ignacia Fuentes
María Joao Yubero
Kaisa Tasanen
Matthias Titeux
Source :
Pediatric Dermatology. 36:132-138
Publication Year :
2018
Publisher :
Wiley, 2018.

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.

Details

ISSN :
15251470 and 07368046
Volume :
36
Database :
OpenAIRE
Journal :
Pediatric Dermatology
Accession number :
edsair.doi.dedup.....679c5316235f70345da9a21526383957
Full Text :
https://doi.org/10.1111/pde.13722