Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation

Genotype-phenotype correlation and in silico modeling analysis

Leah Lalor, Matthias Titeux, Francis Palisson, Ignacia Fuentes, María J. Yubero, Kaisa Tasanen, Laura Huilaja, Cristina Has, Gianluca Tadini, Anita Haggstrom, Alain Hovnanian, Anne W. Lucky

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalPediatric Dermatology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Keratin-5
Epidermolysis Bullosa
Genetic Association Studies
Computer Simulation
Mutation
Keratins
Palmoplantar Keratoderma
Keratin-14
Ectodermal Dysplasia
Skin
Lysine
Glutamic Acid
Proteins
Genotype
Databases
Phenotype

Keywords

  • epidermolysis bullosa
  • genetic diseases/mechanisms
  • genodermatoses

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Dermatology

Cite this

Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation : Genotype-phenotype correlation and in silico modeling analysis. / Lalor, Leah; Titeux, Matthias; Palisson, Francis; Fuentes, Ignacia; Yubero, María J.; Tasanen, Kaisa; Huilaja, Laura; Has, Cristina; Tadini, Gianluca; Haggstrom, Anita; Hovnanian, Alain; Lucky, Anne W.

In: Pediatric Dermatology, 01.01.2018.

Research output: Contribution to journalArticle

Lalor, Leah ; Titeux, Matthias ; Palisson, Francis ; Fuentes, Ignacia ; Yubero, María J. ; Tasanen, Kaisa ; Huilaja, Laura ; Has, Cristina ; Tadini, Gianluca ; Haggstrom, Anita ; Hovnanian, Alain ; Lucky, Anne W. / Epidermolysis bullosa simplex–generalized severe type due to keratin 5 p.Glu477Lys mutation : Genotype-phenotype correlation and in silico modeling analysis. In: Pediatric Dermatology. 2018.
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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.",
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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

AU - Hovnanian, Alain

AU - Lucky, Anne W.

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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.

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