- MeSH
- epidermolysis bullosa dystrophica diagnóza genetika patofyziologie MeSH
- epidermolysis bullosa junkční diagnóza genetika patofyziologie MeSH
- epidermolysis bullosa simplex diagnóza genetika patofyziologie MeSH
- epidermolysis bullosa * diagnóza genetika patofyziologie MeSH
- lidé MeSH
- sekvenční analýza DNA MeSH
- Check Tag
- lidé MeSH
BACKGROUND: Epidermolysis bullosa simplex (EBS) is an inherited skin disorder caused by mutations in the keratin 5 (KRT5) and keratin 14 (KRT14) genes, with fragility of basal keratinocytes leading to epidermal cytolysis and blistering. OBJECTIVES: In this study, we characterized mutations in KRT5 and KRT14 genes in patients with EBS and investigated their possible structure-function correlations. MATERIALS AND METHODS: Mutations were characterized using polymerase chain reaction (PCR) and DNA sequencing. Further, to explore possible correlations with function, the structural effects of the mutations in segment 2B of KRT5 and KRT14 and associated with EBS in our patients, as well as those reported previously, were modelled by molecular dynamics with the aid of the known crystal structure of the analogous segment of human vimentin. RESULTS: We have identified mutations in the KRT5 and KRT14 genes in 16 of 23 families affected by EBS in the Czech Republic. Eleven different sequence variants were found, of which four have not been reported previously. Novel mutations were found in two patients with the EBS-Dowling-Meara variant (EBS-DM) [KRT14-p.Ser128Pro and KRT14-p.Gln374_Leu387dup(14)] and in three patients with localized EBS (KRT14-p.Leu136Pro and KRT5-p.Val143Ala). Molecular dynamics studies show that the mutations p.Glu411del and p.Ile467Thr perturb the secondary alpha-helical structure of the mutated polypeptide chain, the deletion p.Glu411del in KRT14 has a strong but only local influence on the secondary structure of KRT14, and the structural impact of the mutation p.Ile467Thr in KRT5 is spread along the helix to the C-terminus. In all the other point mutations studied, the direct structural impact was significantly weaker and did not destroy the alpha-helical pattern of the secondary protein structure. The changes of 3-D structure of the KRT5/KRT14 dimer induced by the steric structural impact of the single point mutations, and the resulting altered inter- and intramolecular contacts, are spread along the protein helices to the protein C-terminus, but the overall alpha-helical character of the secondary structure is not destroyed and the atomic displacements induced by mutations cause only limited-scale changes of the quaternary structure of the dimer. CONCLUSIONS: The results of molecular modelling show relationships between patients' phenotypes and the structural effects of individual mutations.
- MeSH
- dítě MeSH
- dospělí MeSH
- epidermolysis bullosa simplex genetika patologie MeSH
- fenotyp MeSH
- fluorescenční mikroskopie MeSH
- genetická predispozice k nemoci MeSH
- intermediární filamenta ultrastruktura MeSH
- keratin-14 genetika MeSH
- keratin-5 genetika MeSH
- kůže ultrastruktura MeSH
- lidé MeSH
- molekulární modely MeSH
- mutace MeSH
- předškolní dítě MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Epidermolysis bullosa simplex (EBS) patří do skupiny vrozených mechanobulózních chorob, které jsou převážně autosomálně dominantně dědičné. Vývoj klinického obrazu, správný odběr čerstvého puchýře a zkušenosti s histologickou diagnostikou včetně elektronové mikroskopie jsou základem pro správnou diagnózu. Pacienti zejména s lokalizovanou formou epidermolysis bullosa simplex často unikají pozornosti lékařů. Rozebrány jsou vlastní zkušenosti autorů s diagnostikou 18 pacientů s EBS.
- MeSH
- dítě MeSH
- epidermolysis bullosa simplex genetika MeSH
- genetické nemoci vrozené MeSH
- histologie MeSH
- kožní nemoci MeSH
- lidé MeSH
- prenatální diagnóza MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
