KRT5 – Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex (EBS) is an autosomal dominant mechanobullous genodermatosis characterized by basal keratinocyte fragility and intraepidermal blister formation. Mutations in KRT5 encoding keratin 5 account for a substantial proportion of EBS cases, with >70% mutation detection in large cohorts (PMID:21375516). Clinical severity correlates with variant location within the central 1A and 2B rod domains, especially at helix boundary motifs.

Genetic analyses reveal an autosomal dominant inheritance, with segregation in multiple pedigrees and de novo occurrences. In one study of 76 unrelated probands, 57 cases harbored 41 distinct KRT5/KRT14 mutations, including recurrent hotspot variants (PMID:21375516). Segregation in at least five large families supports pathogenicity, and >30 unrelated probands with KRT5 variants have been reported across studies. The variant c.1429G>A (p.Glu477Lys) recurs in Dowling-Meara EBS and exhibits dominant-negative effects on filament assembly (PMID:9036937).

Functional assays demonstrate that missense and frameshift mutations in KRT5 disrupt keratin intermediate filament (KIF) assembly and network resilience. Transfection of KRT5 E170K and E418K mutations into epithelial cells increased filament aggregation from 12.7% to 30.0% of cells, mirroring the clinical severity in compound heterozygotes (PMID:11973334). Rheological studies of mutant K5/K14 filaments show reduced bundling and resilience under large deformations, consistent with cell fragility in vivo (PMID:11331879).

Genotype–phenotype correlations are well established: helix boundary mutations (e.g., p.Glu477Lys) underlie severe Dowling-Meara EBS, while head-domain variants (e.g., p.Ile161Ser) yield milder Weber-Cockayne phenotypes (PMID:7688477). This spectrum informs prognostication and guides mutation-targeted counseling. Plectinopathies and non-keratin gene causes account for the remaining KRT5/KRT14-negative cases and should be considered when initial testing is unrevealing (PMID:16098032).

Integration of genetic and experimental data supports a Definitive gene–disease relationship. Genetic testing of KRT5 is clinically indicated in suspected EBS, enabling precise diagnosis, risk assessment, and prenatal planning. Functional assays may further stratify variant pathogenicity. Emerging RNA-based and CRISPR-Cas9 strategies offer allele-specific correction but require further validation.

Key Take-home: KRT5 mutations cause autosomal dominant EBS via dominant-negative disruption of keratin filament networks; genetic testing combined with variant-specific functional data enables accurate diagnosis and informs prognosis.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1993 • The genetic basis of Weber-Cockayne epidermolysis bullosa simplex. PMID:7688477
• Journal of Investigative Dermatology • 1997 • Primers for exon-specific amplification of the KRT5 gene: identification of novel and recurrent mutations in epidermolysis bullosa simplex patients. PMID:9036937
• The Journal of Biological Chemistry • 2002 • Dominant and recessive compound heterozygous mutations in epidermolysis bullosa simplex demonstrate the role of the stutter region in keratin intermediate filament assembly. PMID:11973334
• Nature Cell Biology • 2001 • A 'hot-spot' mutation alters the mechanical properties of keratin filament networks. PMID:11331879
• The Journal of Investigative Dermatology • 2005 • Epidermolysis bullosa simplex: recurrent and de novo mutations in the KRT5 and KRT14 genes, phenotype/genotype correlations, and implications for genetic counseling and prenatal diagnosis. PMID:16098032
• British Journal of Dermatology • 2011 • Mutations in KRT5 and KRT14 cause epidermolysis bullosa simplex in 75% of the patients. PMID:21375516

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