KRT16 – Pachyonychia Congenita

Pachyonychia congenita (PC) is a rare autosomal dominant genodermatosis characterized by painful palmoplantar keratoderma and hypertrophic nail dystrophy. Heterozygous missense mutations in the keratin 16 gene (KRT16) disrupt intermediate filament assembly in basal keratinocytes, leading to epidermal fragility and hyperkeratosis.

Genetic evidence for KRT16 involvement is robust: over 450 PC cases have been reported since 1906, including more than 30 unrelated probands with heterozygous KRT16 variants across multiple families ([PMID:23984242]). These variants segregate with disease in small kindreds and large pedigrees, and recurrent alleles such as p.Arg127His arise from founder effects in specific populations ([PMID:33190296]).

Segregation studies include a three-generation Chinese family with c.383T>C (p.Leu128Pro) cosegregating in all three affected individuals and absent in five unaffected relatives ([PMID:24357266]), and a Spanish kindred harboring c.1262T>C (p.Leu421Pro) in all affected members ([PMID:24118415]). Additional de novo and mosaic cases further support autosomal dominant transmission with complete penetrance.

Functional assays demonstrate that proline substitutions in the helix boundary motifs (e.g., p.Gln122Pro and p.Arg127Pro) induce keratin filament condensation and abnormal cell morphology in transfected epithelial cells ([PMID:10606845]). In silico modeling and in vitro overexpression of p.Leu128Pro confirm disruption of the α-helical rod domain and impaired filament network formation ([PMID:24357266]).

Genotype–phenotype correlations reveal that specific substitutions modulate disease severity: p.Leu132Pro associates with earlier onset and extensive keratoderma, whereas p.Asn125Ser and p.Arg127Cys cause milder phenotypes with later onset ([PMID:33486795]). Compared with PC-6a patients, those with KRT16 mutations exhibit fewer pilosebaceous cysts and oral leucokeratosis, underscoring gene-specific clinical spectra ([PMID:22098151]).

Integration of genetic and functional findings establishes a definitive gene–disease relationship. Genetic testing for KRT16 variants enables precise diagnosis, informs prognosis based on variant-specific data, and supports genetic counseling. Key Take-home: Pathogenic KRT16 missense mutations cause dominant pachyonychia congenita by disrupting keratin filament integrity, with variant-specific modifiers of clinical severity.

References

• Dermatology online journal • 2003 • Pachyonychia congenita, type II. PMID:14594585
• Indian dermatology online journal • 2013 • Pachyonychia congenita: A rare genodermatosis. PMID:23984242
• Experimental dermatology • 2013 • A new KRT16 mutation associated with a phenotype of pachyonychia congenita. PMID:24118415
• European journal of pediatrics • 2014 • Mutation p.Leu128Pro in the 1A domain of K16 causes pachyonychia congenita with focal palmoplantar keratoderma in a Chinese family. PMID:24357266
• Archives of dermatology • 2011 • Paternal germ cell mosaicism in autosomal dominant pachyonychia congenita. PMID:21576551
• The British journal of dermatology • 1999 • Novel proline substitution mutations in keratin 16 in two cases of pachyonychia congenita type 1. PMID:10606845
• Clinical and experimental dermatology • 2021 • Molecular epidemiology of pachyonychia congenita in the Israeli population. PMID:33190296
• Clinical and experimental dermatology • 2021 • Identification of clinically useful predictive genetic variants in pachyonychia congenita. PMID:33486795
• The British journal of dermatology • 2012 • Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. PMID:22098151

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