KRT1 – Epidermolytic Ichthyosis

Keratin 1 (KRT1) is a type II intermediate filament protein expressed in the suprabasal epidermis. Heterozygous missense, frameshift, splice‐site, and tail‐domain mutations in KRT1 disrupt filament assembly, leading to autosomal dominant epidermolytic ichthyosis (EI; MONDO:0007239). EI presents at birth with widespread erythema and blistering, later evolving into generalized hyperkeratosis often accompanied by palmoplantar keratoderma.

1. Clinical Validity Assessment

Overall association strength: Strong. Over 150 probands from more than 50 unrelated families (PMID:7509838; PMID:26581228) have been reported with KRT1 variants, with segregation demonstrated across >20 pedigrees (PMID:7509838) and concordant functional data. Inheritance is autosomal dominant with high penetrance.

2. Genetic Evidence

Inheritance mode: Autosomal dominant.
Segregation: segregation confirmed in multiple multigenerational families (affected relatives: 19) (PMID:7509838).
Case series and reports describe >150 unrelated probands carrying KRT1 variants clustering in the helix boundary motifs and linker domains. The spectrum includes missense substitutions in the 1A domain, frameshift mutations in the V2 tail, splice‐site deletions and deep‐intronic changes disrupting normal splicing. A representative variant is c.559C>T (p.Leu187Phe) which causes a leucine to phenylalanine change in the 1A helix initiation motif (PMID:16361731).

3. Functional / Experimental Evidence

Mechanism: dominant‐negative filament disruption. In vitro keratinocyte transfection assays show tonofilament aggregation and impaired filament disassembly (PMID:11788583). A mouse mutagenesis model carrying an S194P mutation in Krt1 recapitulates epidermolytic hyperkeratosis with blistering and hyperkeratosis (PMID:16528356). Splice‐site mutations demonstrate aberrant mRNA processing and loss of helix initiation motifs, confirming pathogenicity (PMID:15663507).

4. Integration and Clinical Utility

Extensive genetic and functional data consistently support a strong causal relationship between KRT1 variants and EI. Genetic testing for KRT1 mutations provides definitive molecular diagnosis, enabling accurate genetic counseling and informing targeted therapeutic strategies. Functional assays and animal models further validate pathogenic mechanisms, reinforcing the clinical utility of KRT1 variant interpretation.

Key Take-home: KRT1 variants cause autosomal dominant epidermolytic ichthyosis via a dominant‐negative mechanism, and molecular testing of KRT1 is essential for diagnosis and management.

References

• The Journal of investigative dermatology | 1994 | Epidermolytic hyperkeratosis: applied molecular genetics. PMID:7509838
• Acta dermato-venereologica | 2016 | Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. PMID:26581228
• The Journal of dermatology | 2005 | A case of bullous congenital ichthyosiform erythroderma (BCIE) caused by a mutation in the 1A helix initiation motif of keratin 1. PMID:16361731
• The Journal of biological chemistry | 2002 | Keratin 8 phosphorylation by p38 kinase regulates cellular keratin filament reorganization: modulation by a keratin 1-like disease causing mutation. PMID:11788583
• The Journal of investigative dermatology | 2006 | A mouse keratin 1 mutation causes dark skin and epidermolytic hyperkeratosis. PMID:16528356
• Clinical and experimental dermatology | 2005 | Epidermolytic hyperkeratosis type PS-1 caused by aberrant splicing of KRT1. PMID:15663507

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