KRT10 – Epidermolytic Ichthyosis

Epidermolytic ichthyosis (EI) is a congenital keratinization disorder characterized by widespread erythroderma, skin blistering in the neonatal period and progressive hyperkeratosis. The condition is most often inherited in an autosomal dominant manner due to dominant-negative mutations in suprabasal keratin genes, principally KRT1 and KRT10. Mutations in KRT10 disrupt keratin intermediate filament assembly in differentiating keratinocytes, leading to cytolysis and epidermal fragility.

Genetic evidence for KRT10 involvement in EI includes identification of pathogenic variants in at least 23 unrelated probands across 15 families, all demonstrating autosomal dominant segregation of missense mutations in conserved rod-domain motifs (PMID:8053700). A recurrent hotspot at codon 156 (c.467G>A (p.Arg156His)) accounts for numerous cases, and no such variants are found in unaffected controls or general population databases, supporting a highly penetrant dominant-negative effect (PMID:7508181).

Segregation analyses confirm clear co-segregation of KRT10 variants with disease in multiple pedigrees, with more than 52 affected individuals reported across 21 kindreds (PMID:8053700). Functional assays in vitro, including peptide disaggregation studies, demonstrate severely impaired keratin filament dynamics for canonical 1A rod–domain mutations (PMID:7508181).

Variant spectrum is dominated by missense changes clustering within helix 1A (e.g., p.Arg156His, p.Arg156Cys) and 2B domains (e.g., p.Leu436Pro, p.Gln434Ter), as well as small in-frame deletions (p.Gln434del). These alter coiled-coil interactions and lead to keratin aggregate formation in patient keratinocytes, with severity correlating to degree of filament collapse (PMID:26176760).

An animal model in Norfolk terrier dogs carrying a recessive donor splice-site mutation in KRT10 recapitulates nonpalmoplantar EI with diminished K10 expression and epidermal fragility, providing cross-species functional concordance (PMID:16029326). A human KRT10 knockout case further underscores that complete loss of K10 can produce a severe EI phenotype in a recessive manner, albeit with distinct ultrastructural findings.

Therapeutic proof-of-concept has been demonstrated by TALEN-mediated disruption of mutant KRT10 alleles in patient-derived keratinocytes, which restored a normal filament network ex vivo and in murine xenografts (PMID:30998984). These data establish KRT10 haploinsufficiency or allele-specific inactivation as potential precision approaches.

Overall, the KRT10–EI association is Definitive, with strong genetic segregation across dozens of families, a consistent autosomal dominant inheritance pattern, a well-characterized mutational hotspot, and concordant functional and therapeutic studies. Clinically, identification of a KRT10 pathogenic variant enables definitive molecular diagnosis, informs genetic counseling regarding recurrence risks, and opens avenues for targeted gene-editing therapies.

References

• American Journal of Human Genetics • 1994 • Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis. PMID:7508181
• Archives of Dermatology • 1994 • Clinical heterogeneity in epidermolytic hyperkeratosis. PMID:8053700
• The British Journal of Dermatology • 2005 • Mild recessive epidermolytic hyperkeratosis associated with a novel keratin 10 donor splice-site mutation in a family of Norfolk terrier dogs. PMID:16029326
• The Journal of Investigative Dermatology • 2015 • Mutations Affecting Keratin 10 Surface-Exposed Residues Highlight the Structural Basis of Phenotypic Variation in Epidermolytic Ichthyosis. PMID:26176760
• Human Molecular Genetics • 2006 • A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis. PMID:16505000
• The Journal of Investigative Dermatology • 2019 • Gene Editing-Mediated Disruption of Epidermolytic Ichthyosis-Associated KRT10 Alleles Restores Filament Stability in Keratinocytes. PMID:30998984

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