Epidermolysis bullosa simplex-generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype-phenotype correlation and in silico modeling analysis. Pediatr Dermatol 2019 Jan;36(1):132-138
Date
12/06/2018Pubmed ID
30515866DOI
10.1111/pde.13722Scopus ID
2-s2.0-85057735622 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
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.
Author List
Lalor L, Titeux M, Palisson F, Fuentes I, Yubero MJ, Tasanen K, Huilaja L, Has C, Tadini G, Haggstrom AN, Hovnanian A, Lucky AWAuthor
Leah Lalor MD Associate Professor in the Dermatology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ChildChild, Preschool
Computer Simulation
Databases, Factual
Epidermolysis Bullosa Simplex
Female
Genetic Association Studies
Genotype
Humans
Infant, Newborn
Keratin-5
Male
Mutation
Phenotype
Skin
