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
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Diseases presenting "prenatal diagnosis" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

alpha-thalassemia

aromatase deficiency

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

classical phenylketonuria

cohen syndrome

congenital adrenal hyperplasia

congenital diaphragmatic hernia

congenital toxoplasmosis

cystinuria

dentinogenesis imperfecta

epidermolysis bullosa simplex

harlequin ichthyosis

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kindler syndrome

krabbe disease

lamellar ichthyosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neonatal adrenoleukodystrophy

oculocutaneous albinism

omenn syndrome

phenylketonuria

primary hyperoxaluria type 1

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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