Keratin mutations in patients with epidermolysis bullosa simplex: correlations between phenotype severity and disturbance of intermediate filament molecular structure.

[epidermolysis bullosa simplex]

Epidermolysis bullosa simplex (EBS ) is an inherited skin disorder caused by mutations in the keratin 5 (KRT 5 ) and keratin 14 (KRT 14 ) genes , with fragility of basal keratinocytes leading to epidermal cytolysis and blistering .In this study , we characterized mutations in KRT 5 and KRT 14 genes in patients with EBS and investigated their possible structure-function correlations .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 2 B of KRT 5 and KRT 14 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 .We have identified mutations in the KRT 5 and KRT 14 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 ) [KRT 14 -p .Ser 128 P ro and KRT 14 -p .Gln 374 _Leu 387 dup (14 )] and in three patients with localized EBS (KRT 14 -p .Leu 136 Pro and KRT 5 -p .Val 143 Ala ). Molecular dynamics studies show that the mutations p .Glu 411 del and p .Ile 467 Thr perturb the secondary alpha-helical structure of the mutated polypeptide chain , the deletion p .Glu 411 del in KRT 14 has a strong but only local influence on the secondary structure of KRT 14 , and the structural impact of the mutation p .Ile 467 Thr in KRT 5 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 KRT 5 /KRT 14 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 .T he results of molecular modelling show relationships between patients ' phenotypes and the structural effects of individual mutations .

Diseases
Validation

Diseases presenting "skin disorder" symptom

aniridia

congenital adrenal hyperplasia

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

harlequin ichthyosis

junctional epidermolysis bullosa

kindler syndrome

lamellar ichthyosis

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