The p.Glu477Lys Mutation in Keratin 5 Is Strongly Associated with Mortality in Generalized Severe Epidermolysis Bullosa Simplex

Sathishkumar, Dharshini; Orrin, Elizabeth; Terron-Kwiatkowski, Ana; Browne, Fiona; Martinéz, Anna E.; Mellerio, Jemima E.; Ogboli, Malobi; Hoey, Susannah; Ozoemena, Linda; Liu, Lu; Baty, D.; McGrath, John A.; Moss, Celia

doi:10.1016/j.jid.2015.11.024

Cited by 20 publications

(21 citation statements)

References 8 publications

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“…Interestingly, most patients had multiple developmental delays. In contrast to the report of Sathishkumar et al, in which five of eight patients with the p.Glu477Lys mutation died, there was only one fatality of these six cases. Awareness of the potential severity of this particular EBS‐GS mutation should alert providers to anticipate and treat the potential respiratory and nutritional complications they may develop.…”

Section: Discussioncontrasting

confidence: 96%

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

Lalor¹,

Titeux

Palisson

et al. 2018

Pediatric Dermatology

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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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Section: Discussioncontrasting

confidence: 96%

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

Lalor¹,

Titeux

Palisson

et al. 2018

Pediatric Dermatology

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show abstract

“…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 …”

mentioning

confidence: 62%

“…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 .…”

mentioning

confidence: 84%

“…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 .…”

mentioning

confidence: 99%

“…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 . 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 .…”

mentioning

confidence: 99%

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