Yasukawa et al. (2002) described a Japanese family with EBS and 2 mutations in the KRT5 gene, resulting in phenotypic variability. Individuals with blisters localized to the palms and soles, who had received a diagnosis of EBS Weber-Cockayne type (EBS2C; 619594), were heterozygous for a G-to-A transition in exon 1, resulting in a glu170-to-lys (E170K) substitution in the highly conserved helix initiation peptide sequence of the 1A rod domain. One individual, with a classic phenotype of generalized blistering who had received a diagnosis of EBS Koebner type (see EBS2B, 619588), was compound heterozygous for the E170K mutation and a G-to-A transition in exon 7 of KRT5, resulting in a glu418-to-lys (E418K; 148040.0021) substitution in the 2B domain, which is the so-called 'stutter' region, an interruption in the heptad repeat substructure. Two unaffected family members were heterozygous for the E418K substitution, implying that it is not pathogenic in isolation. Neither mutation was identified in 100 control alleles. In vitro functional expression studies showed that cells transfected with either mutation developed small ball-like filament aggregates, indicating a disruption of the keratin network, although the effect was more pronounced for the E170K mutation. Expression of both mutant proteins exacerbated the clumping and resulted in significantly more disruption than either alone. These findings were consistent with the marked phenotypic and genotypic variability observed in this family.
Homozygosity for E170K
Oldak et al. (2011) reported a clinically heterogeneous EBS family with the E170K mutation in the KRT5 gene. The proband was a 10-year-old girl who had received a diagnosis of EBS Koebner type and had widespread blistering and skin fragility that improved with age. She was found to be homozygous for the E170K mutation. Each of her parents carried the E170K mutation in heterozygosity and had blisters restricted to soles of the feet since their teenage years after extensive walking; they were diagnosed with localized EBS. Oldak et al. (2011) concluded that the KRT5 E170K mutation alone causes a mild phenotype, and exhibits a gene dosage effect consistent with the phenomenon of 'partial dominance.' Oldak et al. (2011) noted that partial dominance had also been reported with the KRT14 mutation M119I (148066.0010).
The proband of the family reported by Gonzalez-Cantero et al. (2017) was a 7-year-old girl who had blisters and erosions from birth on palms, soles, and other trauma-prone sites. She was homozygous for the E170K mutation. Her parents, who were heterozygotes for the mutation, had a 'nail only' phenotype, with no blisters or erosions but mildly dystrophic toenails, micronychia and thickening of the nail plate of the second toe, and horizontal ridging of the great toenail. Gonzalez-Cantero et al. (2017) noted that the E170K mutation exhibits 'partial dominance.'
Vahidnezhad et al. (2019) reported a 32-year-old woman from a consanguineous family (family 1) of Iranian origin with Kurdish ethnicity who had trauma-induced blistering and erosions noted a few days after birth. She was homozygous for the E170K mutation. Although her parents, who were heterozygous for the mutation, were described as 'clinically unaffected,' they were noted to have mild blistering of the feet after strenuous and prolonged walking, and showed evidence of perturbed intermediate filament assembly in basal keratinocytes on electron microscopy.
