TY - JOUR
T1 - Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation
T2 - Genotype-phenotype correlation and in silico modeling analysis
AU - Lalor, Leah
AU - Titeux, Matthias
AU - Palisson, Francis
AU - Fuentes, Ignacia
AU - Yubero, María J.
AU - Tasanen, Kaisa
AU - Huilaja, Laura
AU - Has, Cristina
AU - Tadini, Gianluca
AU - Haggstrom, Anita N.
AU - Hovnanian, Alain
AU - Lucky, Anne W.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - epidermolysis bullosa
KW - genetic diseases/mechanisms
KW - genodermatoses
UR - http://www.scopus.com/inward/record.url?scp=85057735622&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85057735622&partnerID=8YFLogxK
U2 - 10.1111/pde.13722
DO - 10.1111/pde.13722
M3 - Article
AN - SCOPUS:85057735622
VL - 36
SP - 132
EP - 138
JO - Pediatric Dermatology
JF - Pediatric Dermatology
SN - 0736-8046
IS - 1
ER -