Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation: Genotype‐phenotype correlation and in silico modeling analysis

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.

Generalized, severe epidermolysis bullosa simplex caused by a Keratin 5 p.E477K mutation

“…Interestingly, developmental delay was seen in five patients in the literature as well, but there is no sign of this for either of the patients reported here . The p.E477K mutation is thought to be so severe given it affects the most evolutionarily conserved motif present in intermediate filament proteins …”

“…EBS due to KRT5 p.E477K is characterized by severe blistering in childhood with improvement over time and evolution to palmoplantar keratoderma and nail dysplasia, similar to the mother's course . Interestingly, developmental delay was seen in five patients in the literature as well, but there is no sign of this for either of the patients reported here . The p.E477K mutation is thought to be so severe given it affects the most evolutionarily conserved motif present in intermediate filament proteins …”

“…The current case represents the second reported living mother‐child pair with KRT5 p.E477K mutation . The KRT5 p.E477K mutation causes a very severe, often lethal form of EBS . In the four studies of patients with EBS due to the p.E477K mutation, seven out of 17 died within the first six months of life, while the living patients were reported to be ages ranging from 40 days old to reproductive age .…”

“…The KRT5 p.E477K mutation causes a very severe, often lethal form of EBS . In the four studies of patients with EBS due to the p.E477K mutation, seven out of 17 died within the first six months of life, while the living patients were reported to be ages ranging from 40 days old to reproductive age . EBS due to KRT5 p.E477K is characterized by severe blistering in childhood with improvement over time and evolution to palmoplantar keratoderma and nail dysplasia, similar to the mother's course .…”

Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 “knock-out”

“…EBS is inherited in most cases in an autosomal dominant pattern, and a large number of dominant-negative mutations in the genes, KRT5 and KRT14, which encode basal keratins 5 and 14, respectively, have been disclosed [8][9][10]. In addition, autosomal dominant inheritance of EBS has been associated with mutations in the KLHL24 gene [11][12][13] and with a distinct PLEC missense variant [14].…”