Epidermolysis bullosa simplex, severe type (EBS1A; 131760), formerly known as the Dowling-Meara type, is distinguished from other subtypes not only by its severity but also by the presence of large cytoplasmic clumps of tonofilaments that can be labeled with antibodies against the basal epidermal keratins. In 2 patients with the Dowling-Meara form, Coulombe et al. (1991) demonstrated critical mutations in the KRT14 gene. One patient had a C-to-T transition corresponding to nucleotide 433 of the gene, converting an arginine residue (CGC) to a cysteine residue (TGC) at amino acid 125 (R125C), located near the amino end of the KRT14 rod segment. To demonstrate the effect on function, Coulombe et al. (1991) engineered the arg125-to-cys mutation in a KRT14 cDNA and showed that this cDNA disrupted keratin network formation in transfected keratinocytes and disturbed filament assembly in vitro. Also see 148066.0003.
Sasaki et al. (1999) reported that the arg125-to-cys mutation had been identified in 4 of 6 Japanese families with the Dowling-Meara type of EBS. They stated that 8 of 19 families with mutations in the KRT14 gene carried the arg125-to-cys mutation.
Hut et al. (2000) identified a de novo heterozygous R125C mutation in 2 patients with EBS Dowling-Meara type.
Ma et al. (2001) used differential interference contrast microscopy to show that the arg125-to-cys mutation in the KRT14 gene greatly reduced the ability of reconstituted mutant filaments to bundle under crosslinking conditions, possibly causing the fragility of epithelial cells seen in some keratin-based disorders.
From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 2 patients who were heterozygous for the R125C mutation in the KRT14 gene.
In an Italian male infant with generalized severe EB simplex and a hoarse cry with mild inspiratory stridor, Diociaiuti et al. (2020) identified heterozygosity for the recurrent R125C mutation in the KRT14 gene. The mutation arose de novo in the proband.
