Abstract

Epidermolysis Bullosa Simplex (EBS) is a genodermatosis characterized by the production of superficial bullous lesions on the skin as a result of minor mechanical or frictional injury. It is caused by mutation in either the Keratin 5(KRT5) or Keratin 14(KRT14) gene. This paper used various computational approaches to understand the effect of select missense mutations in KRT5. The crystal structure of the 2B domain of the KRT5 protein has been determined. Missense mutations present in this domain were selected for further analysis. To predict the pathogenicity of the selected mutants, seven web-based algorithms were employed, resulting in the identification of nine mutants predicted to be pathogenic. Stability predictions for these mutants revealed that all of them destabilize the protein structure and function. Evolutionary conservation of these mutants was assessed using the ConSurf web server, which demonstrated that, except for two mutants, all the other pathogenic mutants were found to be highly conserved. The electrostatic potential of mutants E418K and E475K revealed that change led to the replacement of net negative to net positive and favoured domain interaction with negatively charged receptors. Molecular dynamics studies revealed that E475G shows high fluctuation compared with the wild type, and there is loss of interaction with other residues.

Keywords: Epidermolysis bullosa simplex (EBS), missense mutations, seven web-based algorithms and mutants.