In silico analysis of all point mutations on the 2B domain of K5/K14 causing epidermolysis bullosa simplex: a genotype-phenotype correlation.

[epidermolysis bullosa simplex]

Epidermolysis bullosa simplex (EBS ) is a genodermatosis caused by mutations in keratins 5 and 14 (K 5 and K 14 ), which leads to fragility of basal keratinocytes and eventually epidermal cytolysis and blistering . Depending upon the severity of symptoms , EBS is classified into three major subtypes . In order of increasing severity these classes are EBS , localized (EBS-loc ), EBS , other generalized (EBS , gen-non DM ), and EBS , Dowling-Meara (EBS -DM ). We have searched and assembled 36 previously reported point mutations located on the 2 B domain of K 5 /K 14 in order to investigate the effects of point mutations . By performing a comprehensive in silico analysis we determine the underlying relationship between the mutation and its phenotypic effects . Our result showed that all pathogenic point mutations exert their dominant negative effect on the K 5 /K 14 coiled-coil heterodimer complex by altering interchain interaction , leading to the changes in stability and assembly competence of the heterodimer complex . The physico-chemical properties of substituted amino acid and location of the mutation are also deeply correlated with disease severity . In addition , we found a SNP previously reported as non-pathogenic (K 14 p .M 338 R ) that likely affects the stability of the dimer structure due to the loss of interchain interaction and steric clashes . Overall , our finding demonstrates the significance of in silico characterization of EBS severity and would allow for accurate genetic counseling and prenatal diagnosis .

Diseases
Validation

Diseases presenting "steric clashes" symptom

epidermolysis bullosa simplex

You can validate or delete this automatically detected symptom