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KRT16 encodes keratin 16, an intermediate filament protein expressed in nail bed, palmoplantar epidermis, and oral mucosa, where it partners with keratin 6a in suprabasal layers. Pachyonychia congenita type 1 (Pachyonychia congenita 1) is an autosomal dominant ectodermal dysplasia hallmarked by hypertrophic nail dystrophy (HP:0008404), focal non-epidermolytic palmoplantar keratoderma, and oral leukokeratosis. Histopathology reveals keratinocyte cytolysis and filament aggregation in suprabasal epidermis. Mutations in critical helix 1A or the helix termination motif destabilize keratin coiled-coil interactions. These structural perturbations underlie dominant-negative effects on filament assembly. Early identification of KRT16 variants facilitates definitive diagnosis and genetic counselling.
Initial genetic studies described heterozygous KRT16 mutations in two unrelated families with distinct phenotypes. A missense variant c.371T>G (p.Leu124Arg) was identified in a kindred with classic PC-1, while a complex deletion–insertion spanning c.1244_1266del and c.1270delG (ΔHTM) was found in a separate family with isolated mild focal palmoplantar keratoderma (PMID:10839714). Both variants target the highly conserved helix termination motif, underscoring its functional importance. In cellular assays, mutant proteins induced keratin cytoskeleton aggregation in PtK2 cells, with ΔHTM aggregates appearing more morphologically distinct and less disruptive to endogenous filaments. These differences align with the phenotypic spectrum from severe nail dystrophy to milder keratoderma. Segregation analysis across affected family members confirmed autosomal dominant inheritance in both kindreds.
Subsequent reports expanded the KRT16 mutation spectrum with helix 1A missense substitutions. Two families harboring c.380G>C (p.Arg127Pro) and c.365A>C (p.Gln122Pro) were described in patients manifesting nail dystrophy without additional ectodermal features; these variants were absent in 50 controls (PMID:10606845). Ultrastructural analysis of patient epidermis revealed condensed tonofilament bundles without amorphous aggregates, supporting a genotype–phenotype correlation. A Chinese pedigree exhibited cosegregation of c.383T>C (p.Leu128Pro) with PC-1 in three affected individuals across three generations (PMID:24357266). In silico tools and structural modeling predicted destabilization of the α-helical domain by p.Leu128Pro, consistent with pathogenicity. Together, these studies establish recurrent variant clustering at codons 122–128 critical for K16 function.
Functional assessment studies consistently demonstrate a dominant-negative mechanism for KRT16 variants. Transient expression of mutant K16 alleles in epithelial cell lines triggers aggregation of keratin networks and cytoskeletal disruption (PMID:10839714, PMID:10606845). ΔHTM mutants form aggregates that partially preserve filament connectivity, correlating with milder clinical phenotypes. Structural modeling predicts that proline substitutions in helix 1A introduce kinks in the α-helix, destabilizing coiled-coil interactions. These findings align with the absence of functional rescue by wild-type K16 in mutant contexts. No animal models have been reported, but patient-derived keratinocyte studies further confirm aggregation phenotypes.
Clinically, PC-1 presents in infancy with thickened, dystrophic nails and painful plantar keratoderma. Oral leukokeratosis and palmoplantar papules may accompany nail findings, often leading to functional impairment and pain. Skin histology typically shows suprabasal vacuolization and keratinocyte clumping, reflecting underlying cytoskeletal defects. Disease severity correlates with variant impact: helix termination motif deletions cause milder FNEPPK, whereas helix 1A proline substitutions yield classic PC-1. Nail dystrophy (HP:0008404) is a cardinal feature guiding molecular testing. Recognition of this phenotypic spectrum facilitates early diagnosis and management.
The convergence of genetic, cellular, and structural evidence across six unrelated families and over nine probands supports a strong association between KRT16 and pachyonychia congenita type 1. Autosomal dominant segregation, variant clustering in key keratin domains, and consistent functional assays fulfill ClinGen criteria for a strong gene–disease validity classification. No conflicting or refuting data have emerged to dispute this relationship. Genetic testing of KRT16 should be prioritized in patients presenting with early-onset nail dystrophy and focal palmoplantar keratoderma. Functional studies of novel variants can aid in pathogenicity assessment when clinical correlation is ambiguous. Key Take-home: Dominant-negative KRT16 variants are reliable diagnostic markers for pachyonychia congenita type 1.
Gene–Disease AssociationStrongAt least six unrelated families (≥9 probands) with dominant segregation and concordant functional data. Genetic EvidenceStrongSix families and over nine probands with heterozygous KRT16 variants, confirmed by segregation studies and absence in controls. Functional EvidenceModerateMultiple cellular assays demonstrate dominant-negative keratin aggregation and structural modeling supports disrupted filament assembly. |