The Yin and the Yang of Keratin Amino Acid Substitutions and Epidermolysis Bullosa Simplex

Abstract

Mutations that change the same amino acid can result in different clinical phenotypes. Through in silico modeling and keratin filament assessment of genetically engineered HaCaT cells, Natsuga et al., as reported in this issue, have demonstrated how changes in charge and structure of a replacement amino acid in keratin 14 can cause disease (KRT14pA413P, EB simplex) or no clinical effect (KRT14pA413T, polymorphism).

Digenic Inheritance in Epidermolysis Bullosa Simplex

“…A patient with EBS and his affected mother were also found to carry mutations in two distinct EB-associated genes, KRT5 (p.E168D) and KRT14 (p.A413T) (Murrell et al, 2011). The fact that the p.E168D in KRT5 mutation reported in this study affects a highly conserved residue, involved in another EBS-causing mutation (p.E168K; Muller et al, 2006), supports a potential pathogenic role for this mutation in causing a disease phenotype.…”

“…In contrast, p.A413T is most likely a polymorphism of no consequence, as this sequence alteration was found in a substantial number of healthy controls in a heterozygous state (5% of a control population); a healthy individual was found to carry p.A413T in a homozygous state; bioinformatic analysis predicts lack of effect of the p.A413T change on K14 structure; and in contrast with p. A413P, p.A413T did not have any deleterious effect on keratin filament formation as assayed in vitro (Natsuga et al, 2011). In addition, looking more carefully at the data, Murrell et al (2011) even suggested that p.A413T may have a protective effect, which in turn may explain the fact that this polymorphism has been maintained through evolution. Thus, these data suggest that digenic inheritance was not directly involved in causing/modifying the clinical phenotype in the above case.…”

Digenic inheritance in epidermolysis bullosa simplex involving two novel mutations in KRT5 and KRT14

“…The p.Met294Thr mutation is located in the keratin 14 linker 2 region, which is less critical for normal keratin formation, hence not causing disease in the father who carried this mutation, despite the substitution from hydrophobic nonpolar methionine to hydrophilic and polar threonine (Fig. b) …”

A Novel Keratin 5 Mutation in an African Family with Epidermolysis Bullosa Simplex Indicates the Importance of the Amino Acid Located at the Boundary Site Between the H1 and Coil 1A Domains

“…Two substitution mutations at Glu 168 in KRT5 (p.Glu168Asp (c.504G > T) and p.Glu168Lys (c.502G > A), respectively, leading to EBS, gen-nonDM and EBS-DM) have been reported (9,12). Both Glu and Asp are highly polar, negatively charged acidic amino acids.…”