KRT1 – congenital reticular ichthyosiform erythroderma

Congenital reticular ichthyosiform erythroderma (CRIE) is a rare autosomal-dominant keratinopathic ichthyosis characterized by widespread erythroderma with confetti-like pale spots and frequent revertant mosaicism. Frameshift mutations in KRT1 or KRT10 underlie CRIE, leading to abnormal keratin intermediate filament assembly and clonal reversion of mutant alleles (PMID:26581228). In one large cohort of 26 families with keratinopathic ichthyoses, CRIE patients harboring KRT1 frameshift alleles presented with intellectual disability, spasticity, symblepharon and fourth-toe malposition, expanding the phenotypic spectrum of KRT1-related disease.

At the molecular level, KRT1 mutations disrupt the rod domain resulting in filament aggregation in suprabasal keratinocytes, which correlates with barrier defects and activation of stress pathways in skin. Revertant mosaicism in patient epidermis supports a gain-of-function pathomechanism, whereby somatic correction of the frameshift restores wild-type KRT1 function in localized clones. These insights inform diagnostic genetic testing and underscore the potential for targeted therapies to modulate keratin filament dynamics in CRIE.

Key take-home: Autosomal-dominant KRT1 frameshift mutations cause CRIE via aberrant filament assembly and revertant mosaicism, guiding molecular diagnosis and future therapeutic strategies.

References

• Acta dermato-venereologica | 2016 | Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. PMID:26581228

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