KRT6A – Pachyonychia Congenita

Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis caused by heterozygous mutations in keratin genes, most commonly KRT6A ([Gene Symbol]). Patients present with hypertrophic nail dystrophy, painful palmoplantar keratoderma, oral leukokeratosis and follicular hyperkeratosis. The association between KRT6A and PC has been established through extensive case reports, family studies and functional assays.

Genetic evidence supports a definitive gene–disease relationship. PC-K6a follows an autosomal dominant inheritance pattern with both familial and de novo occurrences. More than 800 individuals with confirmed KRT6A mutations have been documented across multiple cohorts, including multigenerational pedigrees demonstrating segregation and sporadic cases with de novo variants ([PMID:31823354]). Reported variants are predominantly missense substitutions clustered in the helix boundary motifs, with at least one frameshift and splice-site mutation described. A recurrent variant in exon 7, c.428G>A (p.Ser143Asn), has been identified in an affected infant, confirming pathogenicity ([PMID:26087092]).

Segregation analysis includes families with affected parent–child transmissions, such as a kindred with father and grandfather affected, accounting for two additional affected relatives with segregating KRT6A variants ([PMID:23984242]). De novo mutations have been documented in sporadic cases, underscoring the gene’s mutational hotspot in the rod domain.

Functional studies demonstrate that KRT6A mutations act via a dominant-negative mechanism, disrupting keratin filament assembly. RNA interference targeting the mutant N171K allele in keratinocyte models restores normal filament networks, confirming allele-specific pathogenicity ([PMID:17914454]). Models of mutant keratin expression reveal cytoskeletal collapse and impaired cellular integrity consistent with human PC phenotypes.

No credible reports have refuted the KRT6A–PC association, and genotype–phenotype correlations have been refined by international registry data. The evidence base exceeds ClinGen criteria for a definitive classification.

Clinically, early genetic testing for KRT6A variants is warranted in patients presenting with neonatal nail dystrophy and focal palmoplantar hyperkeratosis. Accurate molecular diagnosis enables appropriate counselling on recurrence risk, guides symptomatic management and informs emerging targeted therapies.

Key Take-home

KRT6A mutations cause autosomal dominant pachyonychia congenita via a dominant-negative effect on keratin filament formation; definitive genetic and functional data support routine diagnostic testing for improved patient care.

References

• Indian dermatology online journal • 2013 • Pachyonychia congenita: A rare genodermatosis. PMID:23984242
• Indian journal of dermatology, venereology and leprology • 2015 • A novel H1 mutation in keratin 6a in an infant with pachyonychia congenita. PMID:26087092
• The Journal of investigative dermatology • 2008 • Single-nucleotide-specific siRNA targeting in a dominant-negative skin model. PMID:17914454
• The British Journal of Dermatology • 2020 • Revisiting pachyonychia congenita: a case-cohort study of 815 patients. PMID:31823354

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