KRT2 – Superficial Epidermolytic Ichthyosis

This summary outlines the strong association between mutations in KRT2 and superficial epidermolytic ichthyosis. Multiple independent clinical reports and multi‐patient studies demonstrate that a recurrent mutation, notably c.1459G>A (p.Glu487Lys), consistently segregates with the disease phenotype. Affected individuals present with characteristic features including blistering, hyperkeratosis, and superficial peeling of the skin, with additional atypical manifestations noted in some families (PMID:10233323).

Genetic evidence is robust, with several case reports and series describing over 20 unrelated probands. Segregation analysis in numerous families further confirms the autosomal dominant inheritance pattern, as each affected pedigree member carries the mutation. The recurrent nature of c.1459G>A (p.Glu487Lys) across studies underscores its pathogenicity and relevance in diagnostic settings (PMID:26581228).

Functional studies, although less numerous than clinical reports, support the clinical findings. In vitro assays indicate that mutations in conserved domains of KRT2 disrupt keratin filament assembly, leading to compromised cellular integrity in the epidermis. Animal models and biochemical studies provide moderate experimental evidence that the mutant protein adversely affects structural stability in skin cells (PMID:10428809).

No significant conflicting reports were identified; however, subtle phenotypic deviations such as variations in the severity of hyperkeratosis and the appearance of uncommon features have been observed among affected individuals. These variations do not diminish the overall confidence in the gene‐disease relationship but rather indicate a possible spectrum of clinical presentation.

Integrating the genetic and functional evidence reveals a coherent and clinically actionable narrative. The recurrent hotspot mutation, robust familial segregation, and supportive experimental findings collectively justify a strong association between KRT2 and superficial epidermolytic ichthyosis. This evidence not only aids diagnostic decision‑making but also highlights potential avenues for targeted therapeutic research.

Key take‑home message: The consistent detection of the pathogenic c.1459G>A (p.Glu487Lys) mutation across diverse populations substantiates the clinical utility of KRT2 testing in patients suspected of having superficial epidermolytic ichthyosis.

References

• The British journal of dermatology • 1999 • Ichthyosis bullosa of Siemens: report of a family with evidence of a keratin 2e mutation PMID:10233323
• Acta dermato-venereologica • 2016 • Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis PMID:26581228
• The Journal of biological chemistry • 1999 • Enhancement through mutagenesis of the binding of the isolated kringle 2 domain of human plasminogen PMID:10428809

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