KRT14 – generalized severe epidermolysis bullosa simplex 1A

Keratin 14, encoded by KRT14, forms intermediate filaments in basal keratinocytes. Heterozygous pathogenic variants in KRT14 cause autosomal dominant generalized severe epidermolysis bullosa simplex 1A (MONDO:0007550). Affected individuals present with widespread skin blistering at birth and persistent severity, reflecting a dominant-negative mechanism.

Multiple independent studies have identified 5 unrelated probands with heterozygous KRT14 variants underlying the Dowling-Meara subtype of generalized severe EBS: three patients carrying the recurrent c.356T>C (p.Met119Thr) mutation and one each with c.1246del (p.Arg416AlafsTer26) and c.374G>T (p.Arg125Leu) ([PMID:16439965]; [PMID:1717157]). No familial segregation beyond the proband generation has been documented, consistent with de novo or simplex presentations.

Segregation analysis is limited, with zero additional affected relatives reported. Nonetheless, the reproducible occurrence of identical missense and frameshift alleles in independent cases supports pathogenicity.

Functional assays across multiple models demonstrate that K14 missense and truncating mutations disrupt keratin filament assembly and network integrity in vitro and in vivo. Transfection of mutant cDNAs into epithelial cells yields keratin clumping and 10-nm filament aggregation defects ([PMID:1702787]; [PMID:12930305]). These studies concordantly show a dominant-negative effect on filament elongation and resilience.

No studies have refuted the KRT14–EBS link or suggested an alternative molecular etiology for generalized severe EBS. Reports uniformly support a core mechanism of keratin network perturbation leading to basal cell cytolysis and blistering.

Together, genetic and experimental evidence robustly establish a strong gene-disease association. Genetic data include 5 probands with recurrent heterozygous mutations, while functional data confirm a dominant-negative mechanism disrupting filament assembly. This consolidated evidence affirms KRT14 testing for diagnostic decision-making, underpins potential allele-specific therapies, and guides genetic counseling. Key take-home: Heterozygous KRT14 mutations acting via a dominant-negative mechanism underlie autosomal dominant generalized severe EBS, with clear clinical and therapeutic implications.

References

• The Journal of investigative dermatology • 2006 • Three severe cases of EBS Dowling-Meara caused by missense and frameshift mutations in the keratin 14 gene. PMID:16439965
• Cell • 1991 • Point mutations in human keratin 14 genes of epidermolysis bullosa simplex patients: genetic and functional analyses. PMID:1717157
• The Journal of cell biology • 1990 • Deletions in epidermal keratins leading to alterations in filament organization in vivo and in intermediate filament assembly in vitro. PMID:1702787
• Experimental dermatology • 2003 • Functional testing of keratin 14 mutant proteins associated with the three major subtypes of epidermolysis bullosa simplex. PMID:12930305

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