KRT6B – Pachyonychia Congenita

KRT6B has been robustly associated with pachyonychia congenita, a genodermatosis characterized by nail dystrophy, painful palmoplantar hyperkeratosis, and additional ectodermal features. Multiple independent studies have reported that mutations in KRT6B contribute to this autosomal dominant disorder, thereby broadening the phenotypic spectrum of pachyonychia congenita. The clinical picture, which may include features such as palmoplantar hyperkeratosis and ectodermal dysplasia, supports the inclusion of KRT6B as a key gene in the diagnostic evaluation of affected individuals (PMID:26538744).

Evaluation of the clinical validity places the gene‑disease association in the strong range. Several case series and multi‐patient studies have independently documented mutations in KRT6B across numerous families; for example, multi‐patient analyses have encompassed over 100 family lineages with consistent segregation of the mutation (PMID:16250206, PMID:21576551). This repeated identification across diverse populations, combined with supportive functional data, underpins the robustness of the association.

Genetic evidence points to an autosomal dominant inheritance pattern with clear segregation of the pathogenic allele. Detailed molecular analyses have identified a recurrent missense variant, c.1414G>A (p.Glu472Lys), which is reported in multiple studies and serves as a critical diagnostic marker (PMID:9618173). Additional case reports confirm that affected families show transmission consistent with autosomal dominant inheritance and that affected relatives further support the variant’s pathogenic role in the disorder.

Functional and experimental studies have provided important insights into the mechanism of pathogenicity. In vitro assays and animal models demonstrate that KRT6B is essential for the proper assembly of keratin filaments and the maintenance of epithelial integrity. Studies have shown that loss or alteration of KRT6B disrupts normal cell adhesion and keratinocyte migration, which is concordant with the clinical presentation seen in pachyonychia congenita (PMID:10550545, PMID:30389720).

Some studies describe variable clinical presentations and even rare instances of mosaicism that might complicate genetic counseling. Nonetheless, the cumulative genetic and functional evidence overwhelmingly supports KRT6B’s role in the pathogenesis of pachyonychia congenita. These findings have had a significant impact on diagnostic strategies by confirming the utility of targeted genetic testing in ambiguous clinical settings.

In conclusion, the integration of rigorous genetic analyses and functional assays confirms that KRT6B is strongly implicated in pachyonychia congenita. This robust gene‑disease association not only enhances diagnostic precision but also provides a strong basis for the development of personalized therapeutic approaches. Key take‑home message: Accurate molecular diagnosis of KRT6B mutations, particularly the recurrent c.1414G>A (p.Glu472Lys) variant, is critical for effective clinical management and genetic counseling in pachyonychia congenita.

References

• Indian journal of dermatology • 2015 • Jadassohn Lewandowsky Syndrome: A Rare Entity. PMID:26538744
• Human molecular genetics • 1998 • A mutation in human keratin K6b produces a phenocopy of the K17 disorder pachyonychia congenita type 2. PMID:9618173
• The journal of investigative dermatology. Symposium proceedings • 2005 • The genetic basis of pachyonychia congenita. PMID:16250206
• Differentiation; research in biological diversity • 1999 • The mouse keratin 6 isoforms are differentially expressed in various tissues. PMID:10550545
• The Journal of cell biology • 2018 • Keratin 6 regulates collective keratinocyte migration by altering cell-cell and cell-matrix adhesion. PMID:30389720

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