KRT9 – Epidermolytic Palmoplantar Keratoderma

Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant HP:0000962 skin disorder characterized by diffuse hyperkeratosis limited to the palms and soles with erythematous margins. Heterozygous missense mutations in KRT9 disrupt keratin filament assembly in suprabasal keratinocytes, leading to cytolysis and hyperkeratosis.

Extensive genetic evidence supports this association: over 100 unrelated families and more than 100 probands have been reported with KRT9 variants (PMID:30666268). Multi-generational segregation has been demonstrated in large pedigrees, including 38 affected individuals in a Uygur kindred (PMID:27864007).

The variant spectrum is dominated by dominant-negative missense substitutions clustering in the helix initiation motif of the 1A rod domain. A recurrent hotspot at codon 163 (c.488G>A (p.Arg163Gln)) accounts for a substantial fraction of cases and occurs in diverse populations (PMID:30666268).

Functional assays in HaCaT cells demonstrate that mutant K9 induces filament network collapse and cytoplasmic particle formation, confirming a dominant-negative mechanism (PMID:29719290). In a knock-in mouse model carrying a humanized indel mutation, shRNA-mediated knockdown of the mutant allele ameliorates the EPPK-like paw hyperkeratosis, validating gene-targeted therapy potential (PMID:27003758).

No significant conflicting reports have been identified; allelic heterogeneity in KRT1 underlies non-epidermolytic PPK subtypes. Overall, the genetic and experimental concordance over decades of study supports a definitive gene–disease relationship.

Integration of these data confirms KRT9 as a definitive cause of autosomal dominant EPPK. Molecular diagnosis via KRT9 sequencing enables accurate genetic counseling, differentiation from other PPK forms, and informs emerging gene-targeted therapies. Key take-home: KRT9 genetic testing is essential for precise diagnosis and guides potential therapeutic strategies in EPPK.

References

• Nature Genetics • 1994 • Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma PMID:7512862
• Frontiers in Genetics • 2018 • Genetic Analysis of KRT9 Gene Revealed Previously Known Mutations and Genotype-Phenotype Correlations in EPPK PMID:30666268
• Cancer Genetics • 2016 • Six generations of epidermolytic palmoplantar keratoderma, associated with a KRT9 R163W mutation PMID:27864007
• Cellular Physiology and Biochemistry • 2018 • Identification of a Novel Keratin 9 Missense Mutation in a Chinese Family with EPPK PMID:29719290
• Molecular Therapy. Nucleic Acids • 2016 • A Small Indel Mutant Mouse Model of Epidermolytic Palmoplantar Keratoderma and Its Application to Mutant-specific shRNA Therapy PMID:27003758

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