KRT6C

KRT6C is a type II intermediate filament keratin that heterodimerizes with keratin 9 (KRT9) via a coiled-coil interaction to maintain the cytoskeletal scaffold of palmoplantar epidermis (PMID:37467889). Dominant-negative mutations in conserved rod domain residues (e.g., p.Asn172del, p.Glu472Lys) cause dose-dependent collapse of the keratin intermediate filament network in keratinocytes, leading to focal palmoplantar keratoderma (PMID:19609311, PMID:23662636). KRT6C is also expressed in ameloblasts and incorporated into human dental enamel, where a common polymorphism (p.Ser143Asn) alters filament assembly and influences enamel structure (PMID:29357356).

1. 2009 Medium

   Identification of KRT6C as a palmoplantar epidermis keratin whose loss-of-function-type mutations cause focal palmoplantar keratoderma established that KRT6C is non-redundant with KRT6A/KRT6B at this anatomical site.

   Evidence RT-PCR of plantar epidermis plus mutational and co-segregation analysis in three unrelated FPPK families

   PMID:19609311

   Open questions at the time

   • No in vitro filament assembly assay was performed to directly demonstrate the dominant-negative mechanism
   • The heterodimer partner of KRT6C in palmoplantar skin was not identified
   • Expression pattern across other stratified epithelia was not systematically mapped
2. 2013 Medium

   Cell-based reconstitution of the p.Glu472Lys mutation demonstrated that the dominant-negative mechanism acts through dose-dependent collapse of the keratin filament network, confirming the pathogenic model inferred from genetics.

   Evidence Exogenous expression of mutant KRT6C in HaCaT keratinocytes with immunofluorescence and dose-response analysis

   PMID:23662636

   Open questions at the time

   • Only one mutation was tested; other FPPK-causing variants were not functionally validated
   • Effect on specific binding partners (e.g., type I keratin heterodimer partner) was not assessed
   • No in vivo mouse model was generated
3. 2018 Medium

   Discovery that KRT6C is expressed in ameloblasts and incorporated into dental enamel broadened its biological role beyond epidermis, and showed that a common coding polymorphism (p.Ser143Asn) alters filament assembly.

   Evidence Filament assembly assay in ameloblast-like cells, RNA-seq of mouse enamel organ, immunohistochemistry of human enamel

   PMID:29357356

   Open questions at the time

   • Quantitative impact of p.Ser143Asn on enamel mechanical properties was not measured
   • Whether the ameloblast KRT6C partner is also KRT9 or a different type I keratin was not determined
4. 2023 Medium

   Identification of KRT9 as the physiological heterodimer partner of KRT6C in palmoplantar tissue resolved the specific pairing that builds the structural intermediate filament network at this site.

   Evidence Co-immunoprecipitation coupled with mass spectrometry from native palmoplantar epidermis; in silico coiled-coil modeling

   PMID:37467889

   Open questions at the time

   • The coiled-coil interface model was not experimentally validated by mutagenesis or cross-linking
   • Stoichiometry and higher-order filament organization of the KRT6C/KRT9 heterodimer remain uncharacterized
   • No reciprocal validation (e.g., reverse Co-IP with anti-KRT6C pull-down) was reported

• No high-resolution structural model of the KRT6C/KRT9 heterodimer exists, and the mechanistic basis by which specific rod-domain mutations selectively destabilize palmoplantar but not other epithelial filament networks remains unresolved.
• Crystal or cryo-EM structure of the KRT6C/KRT9 coiled-coil is unavailable
• In vivo mouse models recapitulating human FPPK mutations in Krt6c have not been reported
• Tissue-specific transcriptional regulation of KRT6C (beyond ER/SRC-3 in breast cancer cells) is poorly defined