{"gene":"KRT6C","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2009,"finding":"KRT6C is expressed in plantar epidermis and heterozygous in-frame deletion mutations (p.Asn172del; p.Ile462-Glu470del) in KRT6C cause focal palmoplantar keratoderma (FPPK) in three unrelated families, establishing KRT6C as a distinct disease gene with a dominant-negative mechanism analogous to other pachyonychia congenita keratins.","method":"RT-PCR of plantar epidermis; mutational analysis (PCR/direct sequencing) of KRT6C in affected families; co-segregation analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — RT-PCR expression plus genetic co-segregation in three independent kindreds; no in vitro filament assembly assay in this paper","pmids":["19609311"],"is_preprint":false},{"year":2013,"finding":"Expression of the disease-associated KRT6C missense mutation p.Glu472Lys (c.1414G>A, located in the helix termination motif of the 2B domain) in human HaCaT keratinocytes causes dose-dependent collapse of the keratin intermediate filament network, demonstrating a dominant-negative effect on keratin filament assembly. The mutated glutamate residue is conserved across type II, III, and IV intermediate filament proteins.","method":"Exogenous expression of mutant KRT6C in HaCaT cells; immunofluorescence microscopy of keratin filament network; dose-response analysis","journal":"The Journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — direct cell-based functional assay with dose-dependent readout; single lab, single method","pmids":["23662636"],"is_preprint":false},{"year":2018,"finding":"A common polymorphism in KRT6C (rs151117600, p.Ser143Asn) alters the assembly of keratin 6 filaments in ameloblast-like cells, and KRT6C protein is incorporated into human dental enamel by ameloblasts, identifying a role for KRT6C in tooth enamel formation.","method":"Filament assembly assay in ameloblast-like cells (transfection + immunofluorescence); RNA-seq of mouse enamel organ; immunohistochemistry of human enamel; structural analysis of PC patient teeth","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — filament assembly functional assay combined with structural analysis; single study but multiple orthogonal methods","pmids":["29357356"],"is_preprint":false},{"year":2023,"finding":"KRT6C is the heterodimer partner of keratin 9 (KRT9) in palmoplantar epidermis. Co-immunoprecipitation coupled with mass spectrometry from palmoplantar tissue identified KRT6C as co-purifying with KRT9; in silico modeling predicts a coiled-coil interface at their 2B domains. Proteomics shows the KRT6C/KRT9 complex participates in a densely connected network regulating cytoskeleton organization and keratinization.","method":"Co-immunoprecipitation from palmoplantar epidermis coupled with mass spectrometry (Co-IP/MS); in silico structural modeling of coiled-coil heterodimer; proteomics network analysis","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP/MS from native tissue is moderately strong; in silico model not experimentally validated by mutagenesis; single lab","pmids":["37467889"],"is_preprint":false},{"year":2015,"finding":"KRT6C mRNA is downregulated in MCF-7 breast cancer cells by the active tamoxifen metabolite endoxifen (4OHNDtam) and also by estrogen deprivation and knockdown of the steroid receptor coactivator SRC-3/AIB1, indicating that KRT6C expression is regulated in an estrogen receptor-dependent manner through SRC-3/AIB1.","method":"Global gene expression profiling (microarray) in MCF-7 cells treated with tamoxifen metabolites; E2 deprivation; siRNA knockdown of SRC-3/AIB1; qRT-PCR validation","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 — transcriptomic/knockdown with expression readout, no direct promoter or protein-level mechanistic follow-up for KRT6C specifically","pmids":["25867603"],"is_preprint":false},{"year":2026,"finding":"KRT6C is upregulated upon CRISPR/Cas9-mediated knockout of the transcription factor PA2G4 (proliferation-associated protein 2G4) in primary human keratinocytes, placing KRT6C downstream of PA2G4 in a pathway where PA2G4 suppresses keratinocyte differentiation; KRT6C induction accompanies activation of differentiation pathways and suppression of proliferation.","method":"CRISPR/Cas9 knockout of PA2G4 in primary human keratinocytes; RNA-seq; western blot; pharmacological inhibition with WS6","journal":"The British journal of dermatology","confidence":"Low","confidence_rationale":"Tier 3 — KRT6C is one of many upregulated differentiation genes; no direct mechanistic follow-up specifically for KRT6C","pmids":["42008715"],"is_preprint":false}],"current_model":"KRT6C encodes a type II keratin expressed in palmoplantar epidermis and dental ameloblasts, where it forms a coiled-coil heterodimer with keratin 9 (KRT9) to maintain cytoskeletal integrity; disease-associated dominant-negative mutations (e.g., p.Glu472Lys, p.Asn172del) cause dose-dependent collapse of the keratin intermediate filament network in keratinocytes, disrupting the structural scaffold of palmoplantar skin and leading to focal palmoplantar keratoderma, while KRT6C expression is regulated in an estrogen receptor/SRC-3-dependent manner in epithelial cells."},"narrative":{"teleology":[{"year":2009,"claim":"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","pmids":["19609311"],"confidence":"Medium","gaps":["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"]},{"year":2013,"claim":"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","pmids":["23662636"],"confidence":"Medium","gaps":["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"]},{"year":2018,"claim":"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","pmids":["29357356"],"confidence":"Medium","gaps":["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"]},{"year":2023,"claim":"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","pmids":["37467889"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"High","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2]}],"complexes":[],"partners":["KRT9"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P48668","full_name":"Keratin, type II cytoskeletal 6C","aliases":["Cytokeratin-6C","CK-6C","Cytokeratin-6E","CK-6E","Keratin K6h","Keratin-6C","K6C","Type-II keratin Kb12"],"length_aa":564,"mass_kda":60.0,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P48668/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT6C","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1047,"dependency_fraction":0.0019102196752626551},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT6C","total_profiled":1310},"omim":[{"mim_id":"615735","title":"PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL OR DIFFUSE; PPKNEFD","url":"https://www.omim.org/entry/615735"},{"mim_id":"612315","title":"KERATIN 6C, TYPE II; KRT6C","url":"https://www.omim.org/entry/612315"},{"mim_id":"600962","title":"PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC; NEPPK","url":"https://www.omim.org/entry/600962"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":482.5},{"tissue":"esophagus","ntpm":792.4},{"tissue":"vagina","ntpm":322.2}],"url":"https://www.proteinatlas.org/search/KRT6C"},"hgnc":{"alias_symbol":[],"prev_symbol":["KRT6E"]},"alphafold":{"accession":"P48668","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P48668","model_url":"https://alphafold.ebi.ac.uk/files/AF-P48668-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P48668-F1-predicted_aligned_error_v6.png","plddt_mean":66.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT6C","jax_strain_url":"https://www.jax.org/strain/search?query=KRT6C"},"sequence":{"accession":"P48668","fasta_url":"https://rest.uniprot.org/uniprotkb/P48668.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P48668/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P48668"}},"corpus_meta":[{"pmid":"28619761","id":"PMC_28619761","title":"Exhaled breath condensate biomarkers for the early diagnosis of lung cancer using proteomics.","date":"2017","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28619761","citation_count":56,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28147318","id":"PMC_28147318","title":"Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28147318","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24611874","id":"PMC_24611874","title":"The molecular genetic analysis of the expanding pachyonychia congenita case collection.","date":"2014","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/24611874","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31995775","id":"PMC_31995775","title":"Assessing potential mechanisms of arsenic-induced skin lesions and cancers: Human and in vitro evidence.","date":"2020","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/31995775","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31021398","id":"PMC_31021398","title":"Pathophysiology of pachyonychia congenita-associated palmoplantar keratoderma: new insights into skin epithelial homeostasis and avenues for treatment.","date":"2019","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31021398","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19609311","id":"PMC_19609311","title":"Keratin K6c mutations cause focal palmoplantar keratoderma.","date":"2009","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/19609311","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32036224","id":"PMC_32036224","title":"Identification of gene modules and hub genes in colon adenocarcinoma associated with pathological stage based on WGCNA analysis.","date":"2020","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32036224","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31823354","id":"PMC_31823354","title":"Revisiting pachyonychia congenita: a case-cohort study of 815 patients.","date":"2020","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31823354","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20839314","id":"PMC_20839314","title":"A transcriptional network signature characterizes lung cancer subtypes.","date":"2010","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20839314","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33564003","id":"PMC_33564003","title":"Identification of potential salivary biomarker panels for oral squamous cell carcinoma.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33564003","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30307612","id":"PMC_30307612","title":"Pachyonychia congenita: a case report of a successful treatment with rosuvastatin in a patient with a KRT6A mutation.","date":"2018","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30307612","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33771844","id":"PMC_33771844","title":"circ-Keratin 6c Promotes Malignant Progression and Immune Evasion of Colorectal Cancer through microRNA-485-3p/Programmed Cell Death Receptor Ligand 1 Axis.","date":"2021","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/33771844","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29357356","id":"PMC_29357356","title":"Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29357356","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27552035","id":"PMC_27552035","title":"Proteomic profiling reveals candidate markers for arsenic-induced skin keratosis.","date":"2016","source":"Environmental pollution (Barking, Essex : 1987)","url":"https://pubmed.ncbi.nlm.nih.gov/27552035","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31047981","id":"PMC_31047981","title":"Enrichment of genes associated with squamous differentiation in cancer initiating cells isolated from urothelial cells transformed by the environmental toxicant arsenite.","date":"2019","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31047981","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28966516","id":"PMC_28966516","title":"Comprehensive Transcriptome Profiling of Balding and Non-Balding Scalps in Trichorhinophalangeal Syndrome Type I Patient.","date":"2017","source":"Annals of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28966516","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27041546","id":"PMC_27041546","title":"Pachyonychia Congenita: A Spectrum of KRT6a Mutations in Australian Patients.","date":"2016","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27041546","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24314272","id":"PMC_24314272","title":"Comprehensive transcriptome profiling of squamous cell carcinoma of horn in Bos indicus.","date":"2013","source":"Veterinary and comparative oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24314272","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28648685","id":"PMC_28648685","title":"Proteomic profiling of Pachyonychia congenita plantar callus.","date":"2017","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/28648685","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37766547","id":"PMC_37766547","title":"Pachyonychia Congenita: Clinical Features and Future Treatments.","date":"2023","source":"The Keio journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37766547","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20081885","id":"PMC_20081885","title":"Mutations in a keratin 6 isomer (K6c) cause a type of focal palmoplantar keratoderma.","date":"2010","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20081885","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34085585","id":"PMC_34085585","title":"Assessing the potential value and mechanism of Ginkgo biloba L. On coal-fired arsenic-induced skin damage: In vitro and human evidence.","date":"2021","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/34085585","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21801157","id":"PMC_21801157","title":"Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation.","date":"2011","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/21801157","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38174414","id":"PMC_38174414","title":"Evaluation of Cd-induced cytotoxicity in primary human keratinocytes.","date":"2024","source":"Human & experimental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/38174414","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33486795","id":"PMC_33486795","title":"Identification of clinically useful predictive genetic variants in pachyonychia congenita.","date":"2021","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/33486795","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39000463","id":"PMC_39000463","title":"Assessment of Concentration KRT6 Proteins in Tumor and Matching Surgical Margin from Patients with Head and Neck Squamous Cell Carcinoma.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39000463","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31244373","id":"PMC_31244373","title":"Functional study of 14-3-3 protein epsilon (YWHAE) in keratinocytes: microarray integrating bioinformatics approaches.","date":"2019","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/31244373","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31777952","id":"PMC_31777952","title":"Symptomatic mucosal involvement in pachyonychia congenita: challenges in infants and young children.","date":"2019","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31777952","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26464567","id":"PMC_26464567","title":"Pachyonychia Congenita (K16) with Unusual Features and Good Response to Acitretin.","date":"2015","source":"Case reports in dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/26464567","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22668561","id":"PMC_22668561","title":"Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma.","date":"2012","source":"European journal of dermatology : EJD","url":"https://pubmed.ncbi.nlm.nih.gov/22668561","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36658016","id":"PMC_36658016","title":"Phenotype and genotype features of Vietnamese children with pachyonychia congenita.","date":"2023","source":"Pediatrics and neonatology","url":"https://pubmed.ncbi.nlm.nih.gov/36658016","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23662636","id":"PMC_23662636","title":"Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma.","date":"2013","source":"The Journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23662636","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29434467","id":"PMC_29434467","title":"Genomic Analysis Using Regularized Regression in High-Grade Serous Ovarian Cancer.","date":"2018","source":"Cancer informatics","url":"https://pubmed.ncbi.nlm.nih.gov/29434467","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29090033","id":"PMC_29090033","title":"First Report of Pachyonychia Congenita Type PC-K6a in the Romanian Population.","date":"2017","source":"Maedica","url":"https://pubmed.ncbi.nlm.nih.gov/29090033","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37467889","id":"PMC_37467889","title":"Proteomic profiling reveals KRT6C as a probable hereterodimer partner for KRT9: New insights into re-classifying epidermolytic palmoplantar keratoderma (EPPK) and a milder form of pachyonychia congenita (PC-K6c) as a group of genetic cutaneous disorders.","date":"2023","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/37467889","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34724947","id":"PMC_34724947","title":"A KRT6A mutation p.Ile462Asn in a Chinese family with pachyonychia congenita, and identification of maternal mosaicism: a case report.","date":"2021","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/34724947","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33762842","id":"PMC_33762842","title":"A KRT6A and a Novel KRT16 Gene Mutations in Chinese Patients with Pachyonychia Congenita.","date":"2021","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33762842","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33190296","id":"PMC_33190296","title":"Molecular epidemiology of pachyonychia congenita in the Israeli population.","date":"2020","source":"Clinical and experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/33190296","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28794556","id":"PMC_28794556","title":"Keratin 17 Mutations in Four Families from India with Pachyonychia Congenita.","date":"2017","source":"Indian journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/28794556","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30859684","id":"PMC_30859684","title":"A KRT16 mutation in the first Chinese pedigree with Pachyonychia congenita and review of the literatures.","date":"2019","source":"Journal of cosmetic dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30859684","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39391485","id":"PMC_39391485","title":"Landscape of epithelial cell subpopulations in the human esophageal squamous cell carcinoma microenvironment.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39391485","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25867603","id":"PMC_25867603","title":"The active tamoxifen metabolite endoxifen (4OHNDtam) strongly down-regulates cytokeratin 6 (CK6) in MCF-7 breast cancer cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25867603","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38612418","id":"PMC_38612418","title":"Six-Gene Signature for Differential Diagnosis and Therapeutic Decisions in Non-Small-Cell Lung Cancer-A Validation Study.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38612418","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39835811","id":"PMC_39835811","title":"KRT9 is required for GBP5 suppression of human respiratory syncytial virus.","date":"2025","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/39835811","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38268915","id":"PMC_38268915","title":"Exploring KRAS-mutant pancreatic ductal adenocarcinoma: a model validation study.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38268915","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38072449","id":"PMC_38072449","title":"Pachyonychia Congenita Project: Advancing Research and Drug Development through Collaboration.","date":"2023","source":"The Keio journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38072449","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38770089","id":"PMC_38770089","title":"Mutation p.Arg127Pro in the 1A Domain of KRT16 Causes Pachyonychia Congenita in Chinese Patient: A Case Report of PC Associated with Acral Melanoma.","date":"2024","source":"Clinical, cosmetic and investigational dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/38770089","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32662074","id":"PMC_32662074","title":"Generalized bullae in a young girl with KRT6A-related pachyonychia congenita.","date":"2020","source":"Pediatric dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/32662074","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25174302","id":"PMC_25174302","title":"First case of pachyonychia congenita in the Czech Republic.","date":"2014","source":"Dermatologic therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25174302","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39980061","id":"PMC_39980061","title":"Whole exome sequencing identified mutations of forkhead box I 1 (FOXI1), keratin 6 C (KRT6C) and gap junction protein delta 2 (GJD2) in a low-grade oncocytic tumor of the kidney: a case report.","date":"2025","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39980061","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38468954","id":"PMC_38468954","title":"A novel heterozygous frameshift mutation in the KRT6A gene responsible for an uncommon phenotype of pachyonychia congenita: One case report and review of literature.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38468954","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30452289","id":"PMC_30452289","title":"Novel Splice-Site Mutation of KRT1 Underlies Diffuse Palmoplantar Keratoderma in a Large Chinese Pedigree.","date":"2018","source":"Genetic testing and molecular biomarkers","url":"https://pubmed.ncbi.nlm.nih.gov/30452289","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41042798","id":"PMC_41042798","title":"Towards a transcriptomic biomarker for the classification of melanocytic neoplasms.","date":"2025","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41042798","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"42008715","id":"PMC_42008715","title":"Proliferation-associated protein 2G4 promotes keratinocyte proliferation and survival in psoriasis.","date":"2026","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/42008715","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16189514","id":"PMC_16189514","title":"Towards a proteome-scale map of the human protein-protein interaction network.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16189514","citation_count":2090,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25416956","id":"PMC_25416956","title":"A proteome-scale map of the human interactome network.","date":"2014","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25416956","citation_count":977,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16831889","id":"PMC_16831889","title":"New consensus nomenclature for mammalian keratins.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16831889","citation_count":520,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21565611","id":"PMC_21565611","title":"Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways.","date":"2011","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21565611","citation_count":507,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25910212","id":"PMC_25910212","title":"Widespread macromolecular interaction perturbations in human genetic disorders.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25910212","citation_count":454,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22119785","id":"PMC_22119785","title":"Defining human ERAD networks through an integrative mapping strategy.","date":"2011","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22119785","citation_count":427,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26871637","id":"PMC_26871637","title":"Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26871637","citation_count":423,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22020285","id":"PMC_22020285","title":"Image-based genome-wide siRNA screen identifies selective autophagy factors.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/22020285","citation_count":405,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21145461","id":"PMC_21145461","title":"Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics.","date":"2010","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/21145461","citation_count":318,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"6191871","id":"PMC_6191871","title":"The cDNA sequence of a Type II cytoskeletal keratin reveals constant and variable structural domains among keratins.","date":"1983","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/6191871","citation_count":300,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17650314","id":"PMC_17650314","title":"Use of immunohistochemical markers can refine prognosis in triple negative breast cancer.","date":"2007","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17650314","citation_count":297,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7525601","id":"PMC_7525601","title":"Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins.","date":"1994","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/7525601","citation_count":255,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19720911","id":"PMC_19720911","title":"Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel.","date":"2009","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19720911","citation_count":248,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15174051","id":"PMC_15174051","title":"An investigation into the human serum \"interactome\".","date":"2004","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/15174051","citation_count":247,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19199708","id":"PMC_19199708","title":"Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).","date":"2009","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/19199708","citation_count":237,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7545493","id":"PMC_7545493","title":"Mutation of a type II keratin gene (K6a) in pachyonychia congenita.","date":"1995","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7545493","citation_count":196,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36147463","id":"PMC_36147463","title":"PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer.","date":"2022","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36147463","citation_count":143,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23533145","id":"PMC_23533145","title":"In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23533145","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19380743","id":"PMC_19380743","title":"Charting the molecular network of the drug target Bcr-Abl.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19380743","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27591049","id":"PMC_27591049","title":"SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling.","date":"2016","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/27591049","citation_count":134,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24457600","id":"PMC_24457600","title":"The central role of EED in the orchestration of polycomb group complexes.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24457600","citation_count":131,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21630459","id":"PMC_21630459","title":"Proteomic characterization of the human sperm nucleus.","date":"2011","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/21630459","citation_count":116,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":29173,"output_tokens":1770,"usd":0.057035},"stage2":{"model":"claude-opus-4-6","input_tokens":5023,"output_tokens":1940,"usd":0.110423},"total_usd":0.345194,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":41861,"output_tokens":3015,"usd":0.085404},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5201,"output_tokens":1422,"usd":0.092332}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"Heterozygous in-frame deletion mutations in KRT6C (p.Asn172del and p.Ile462-Glu470del) cause focal palmoplantar keratoderma, establishing KRT6C as a disease gene expressed in plantar epidermis; RT-PCR confirmed KRT6C expression in plantar skin consistent with the plantar-restricted phenotype.\",\n      \"method\": \"Sanger sequencing of KRT6C in affected families; RT-PCR expression analysis in plantar epidermis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-segregation in three independent kindreds plus expression confirmation, replicated across labs\",\n      \"pmids\": [\"19609311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Expression of the dominant-negative KRT6C p.Glu472Lys mutant protein in HaCaT keratinocytes causes collapse of the keratin filament network in a dose-dependent manner, demonstrating that the mutation acts via dominant-negative disruption of intermediate filament assembly; the mutated residue lies in the helix termination motif, a region conserved across type II, III and IV intermediate filament proteins.\",\n      \"method\": \"Exogenous expression of mutant KRT6C in HaCaT cells; immunofluorescence microscopy of keratin filament network\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct cellular loss-of-function readout with dose-dependence and structural rationale\",\n      \"pmids\": [\"23662636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT6C is a heterodimer partner for KRT9 in palmoplantar epidermis; co-immunoprecipitation coupled with mass spectrometry identified KRT6C as pulled down with KRT9, and in silico modeling shows a coiled-coil structure in their 2B domains. Proteomics placed the KRT6C/KRT9 pair in a protein interaction network regulating intermediate filament-based cytoskeleton organization and keratinization.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry (proteomics); in silico structural modeling of coiled-coil heterodimer\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/MS study from one lab; no reciprocal pull-down or in vitro reconstitution\",\n      \"pmids\": [\"37467889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Missense polymorphisms in KRT6C (including p.Ser143Asn encoded by rs151117600) alter assembly of K6 filaments in ameloblast-like cells, establishing a role for KRT6C in tooth enamel formation; KRT6C is expressed in human ameloblasts and incorporated into mature enamel.\",\n      \"method\": \"Genetic association in 573 adults and 449 children; keratin filament assembly assay in ameloblast-like cells; structural analysis of PC patient teeth; RNA-seq of mouse enamel organ\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional filament assembly assay plus genetic and structural validation across multiple methods in one study\",\n      \"pmids\": [\"29357356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KRT6C mRNA is strongly down-regulated by the active tamoxifen metabolite endoxifen (4OHNDtam) and by estrogen deprivation and SRC-3/AIB1 knockdown in MCF-7 breast cancer cells, indicating that KRT6C expression is regulated in an estrogen receptor-dependent manner.\",\n      \"method\": \"Global gene expression microarray; quantitative RT-PCR; E2 deprivation and SRC-3/AIB1 siRNA knockdown in MCF-7 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (array + qPCR + KD) in single lab establishing ER-dependent transcriptional regulation\",\n      \"pmids\": [\"25867603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"circ-KRT6C (a circular RNA derived from the KRT6C locus) acts as a miR-485-3p sponge to increase PDL1 expression, thereby promoting proliferation, migration, invasion, and immune evasion of colorectal cancer cells; inhibition of circ-KRT6C suppressed tumor growth in a xenograft model.\",\n      \"method\": \"Dual-luciferase reporter assay; siRNA knockdown; cell proliferation, apoptosis, migration/invasion assays; co-culture with immune cells; xenograft mouse model\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo methods in single lab; functional mechanism established via reporter assay\",\n      \"pmids\": [\"33771844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A novel KRT6C missense mutation (c.1414G>A, p.Glu472Lys) causes both focal and diffuse palmoplantar keratoderma in a Japanese family with phenotypic heterogeneity, demonstrating that KRT6C mutations can produce diffuse in addition to focal hyperkeratosis.\",\n      \"method\": \"Sanger sequencing; heterozygosity confirmation; clinical phenotyping of three affected individuals\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic co-segregation in affected family members; same mutation as functionally validated in separate study\",\n      \"pmids\": [\"21801157\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT6C encodes a type II keratin that forms obligate coiled-coil heterodimers (with KRT9 as a palmoplantar partner) to maintain intermediate filament network integrity in stratified epithelia; dominant-negative mutations disrupt filament assembly in a dose-dependent manner, causing palmoplantar keratoderma and pachyonychia congenita, while KRT6C expression is regulated in an estrogen receptor-dependent manner and a circular RNA derived from its locus (circ-KRT6C) acts as a miR-485-3p sponge to modulate PDL1-driven immune evasion in colorectal cancer.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\n- Papers [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[46],[47],[48],[49],[50],[51],[52],[53],[54]: Mostly about KRT6C in disease context, biomarkers, or general PC genetics — many are expression/biomarker studies.\n\n- Paper [12] (circ-KRT6C): EXCLUDE — case (B) alt-locus product (circular RNA from the KRT6C locus, not the canonical protein).\n\n- Additional papers [1]-[5] (interactome maps), [6] (m6A), [7] (GO), [8] (New keratin nomenclature — KEEP, foundational), [9] (ciliopathy), [10] (disease mutations/interactions — mentions keratins broadly), [11] (MGC cDNA), [12] (ERAD), [13] (alternative splicing), [14] (alternative promoters), [15] (autophagy screen), [16] (CRL ubiquitin), [17] (Type II keratin cDNA — KEEP, foundational for keratin structure), [18] (breast cancer IHC), [19] (keratin-desmoplakin binding — KEEP, mechanistic), [20] (breast cancer prognosis), [21] (serum interactome), [22] (parotid exosomes), [23] (K6a mutation in PC — KEEP, mechanistic), [24] (mitochondrial proximity), [25] (bladder cancer), [26] (prostate exosomes), [27] (Bcr-Abl network), [28] (LUBAC/CYLD), [29] (EED/polycomb), [30] (sperm nucleus proteome).\n\nNow extracting mechanistic discoveries from KEPT papers about KRT6C specifically:\n\n**KEEP papers with mechanistic content about KRT6C:**\n\n1. **PMID:19609311** (Wilson 2009): KRT6C mutations (in-frame deletions) cause FPPK; KRT6C expressed in plantar epidermis by RT-PCR; dominant-negative mechanism implied.\n\n2. **PMID:23662636** (Kubo 2013): KRT6C p.Glu472Lys mutation expressed in HaCaT cells causes collapse of keratin filament network in dose-dependent manner → dominant-negative effect on filament assembly.\n\n3. **PMID:37467889** (Li 2023): Co-IP + MS shows KRT6C is a heterodimer partner for KRT9 in palmoplantar epidermis; in silico modeling shows coiled-coil in 2B domains; proteomics shows KRT6C/KRT9 in cytoskeleton organization network.\n\n4. **PMID:29357356** (Duverger 2018): KRT6C variants (rs151117600, p.Ser143Asn) alter K6 filament assembly in ameloblast-like cells; KRT6C expressed in human enamel organ/ameloblasts.\n\n5. **PMID:16831889** (Schweizer 2006): New nomenclature paper defining KRT6C as a type II keratin — not mechanistic enough about KRT6C specifically.\n\n6. **PMID:6191871** (Hanukoglu 1983): Type II keratin cDNA/structure — general, not KRT6C specific.\n\n7. **PMID:7525601** (Kouklis 1994): Desmoplakin tail binds type II epidermal keratin heads (K1, K2, K5, K6) — mentions K6 generically, not KRT6C specifically.\n\n8. **PMID:7545493** (Bowden 1995): K6a (KRT6A) mutation in PC — not KRT6C.\n\n9. **PMID:25867603** (Helland 2015): Endoxifen (4OHNDtam) down-regulates KRT6A, KRT6B, and KRT6C in MCF-7 cells after E2 deprivation and SRC-3/AIB1 knockdown — mechanistic (estrogen receptor-dependent regulation).\n\n10. **PMID:21801157** (Akasaka 2011): Novel KRT6C mutation p.Glu472Lys in Japanese family — clinical, confirms dominant-negative but no new cell biology.\n\n11. **PMID:28648685** (Rice 2017): Proteomic profiling of PC callus — KRT6C mutation subjects show few differences from normal protein profile (compared to KRT6A/KRT16 mutations); descriptive proteomics.\n\n12. **PMID:42008715** (Raunegger 2026): PA2G4 KO in keratinocytes upregulates KRT6C (among differentiation markers) — KRT6C upregulated upon PA2G4 knockout, suggesting PA2G4 suppresses KRT6C expression as part of differentiation regulation.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"KRT6C is expressed in plantar epidermis and heterozygous in-frame deletion mutations (p.Asn172del; p.Ile462-Glu470del) in KRT6C cause focal palmoplantar keratoderma (FPPK) in three unrelated families, establishing KRT6C as a distinct disease gene with a dominant-negative mechanism analogous to other pachyonychia congenita keratins.\",\n      \"method\": \"RT-PCR of plantar epidermis; mutational analysis (PCR/direct sequencing) of KRT6C in affected families; co-segregation analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RT-PCR expression plus genetic co-segregation in three independent kindreds; no in vitro filament assembly assay in this paper\",\n      \"pmids\": [\"19609311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Expression of the disease-associated KRT6C missense mutation p.Glu472Lys (c.1414G>A, located in the helix termination motif of the 2B domain) in human HaCaT keratinocytes causes dose-dependent collapse of the keratin intermediate filament network, demonstrating a dominant-negative effect on keratin filament assembly. The mutated glutamate residue is conserved across type II, III, and IV intermediate filament proteins.\",\n      \"method\": \"Exogenous expression of mutant KRT6C in HaCaT cells; immunofluorescence microscopy of keratin filament network; dose-response analysis\",\n      \"journal\": \"The Journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cell-based functional assay with dose-dependent readout; single lab, single method\",\n      \"pmids\": [\"23662636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A common polymorphism in KRT6C (rs151117600, p.Ser143Asn) alters the assembly of keratin 6 filaments in ameloblast-like cells, and KRT6C protein is incorporated into human dental enamel by ameloblasts, identifying a role for KRT6C in tooth enamel formation.\",\n      \"method\": \"Filament assembly assay in ameloblast-like cells (transfection + immunofluorescence); RNA-seq of mouse enamel organ; immunohistochemistry of human enamel; structural analysis of PC patient teeth\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — filament assembly functional assay combined with structural analysis; single study but multiple orthogonal methods\",\n      \"pmids\": [\"29357356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT6C is the heterodimer partner of keratin 9 (KRT9) in palmoplantar epidermis. Co-immunoprecipitation coupled with mass spectrometry from palmoplantar tissue identified KRT6C as co-purifying with KRT9; in silico modeling predicts a coiled-coil interface at their 2B domains. Proteomics shows the KRT6C/KRT9 complex participates in a densely connected network regulating cytoskeleton organization and keratinization.\",\n      \"method\": \"Co-immunoprecipitation from palmoplantar epidermis coupled with mass spectrometry (Co-IP/MS); in silico structural modeling of coiled-coil heterodimer; proteomics network analysis\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP/MS from native tissue is moderately strong; in silico model not experimentally validated by mutagenesis; single lab\",\n      \"pmids\": [\"37467889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KRT6C mRNA is downregulated in MCF-7 breast cancer cells by the active tamoxifen metabolite endoxifen (4OHNDtam) and also by estrogen deprivation and knockdown of the steroid receptor coactivator SRC-3/AIB1, indicating that KRT6C expression is regulated in an estrogen receptor-dependent manner through SRC-3/AIB1.\",\n      \"method\": \"Global gene expression profiling (microarray) in MCF-7 cells treated with tamoxifen metabolites; E2 deprivation; siRNA knockdown of SRC-3/AIB1; qRT-PCR validation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — transcriptomic/knockdown with expression readout, no direct promoter or protein-level mechanistic follow-up for KRT6C specifically\",\n      \"pmids\": [\"25867603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"KRT6C is upregulated upon CRISPR/Cas9-mediated knockout of the transcription factor PA2G4 (proliferation-associated protein 2G4) in primary human keratinocytes, placing KRT6C downstream of PA2G4 in a pathway where PA2G4 suppresses keratinocyte differentiation; KRT6C induction accompanies activation of differentiation pathways and suppression of proliferation.\",\n      \"method\": \"CRISPR/Cas9 knockout of PA2G4 in primary human keratinocytes; RNA-seq; western blot; pharmacological inhibition with WS6\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KRT6C is one of many upregulated differentiation genes; no direct mechanistic follow-up specifically for KRT6C\",\n      \"pmids\": [\"42008715\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT6C encodes a type II keratin expressed in palmoplantar epidermis and dental ameloblasts, where it forms a coiled-coil heterodimer with keratin 9 (KRT9) to maintain cytoskeletal integrity; disease-associated dominant-negative mutations (e.g., p.Glu472Lys, p.Asn172del) cause dose-dependent collapse of the keratin intermediate filament network in keratinocytes, disrupting the structural scaffold of palmoplantar skin and leading to focal palmoplantar keratoderma, while KRT6C expression is regulated in an estrogen receptor/SRC-3-dependent manner in epithelial cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT6C encodes a type II keratin expressed in palmoplantar epidermis and ameloblasts that forms intermediate filament heterodimers with partners including KRT9, contributing to cytoskeletal integrity in stratified epithelia and enamel formation [PMID:37467889, PMID:29357356]. Heterozygous dominant-negative mutations in KRT6C—particularly in the conserved helix termination motif—cause dose-dependent collapse of the keratin filament network and underlie focal and diffuse palmoplantar keratoderma [PMID:19609311, PMID:23662636, PMID:21801157]. A circular RNA derived from the KRT6C locus (circ-KRT6C) functions as a miR-485-3p sponge to upregulate PDL1, promoting immune evasion in colorectal cancer cells [PMID:33771844].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of heterozygous in-frame deletions in KRT6C as the cause of focal palmoplantar keratoderma established KRT6C as a disease gene and demonstrated its expression in plantar epidermis, resolving the molecular basis of a previously unmapped keratoderma.\",\n      \"evidence\": \"Sanger sequencing in three independent kindreds plus RT-PCR of plantar skin\",\n      \"pmids\": [\"19609311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional assay was performed to demonstrate how the deletions disrupt filament assembly\",\n        \"Expression in non-plantar stratified epithelia was not systematically profiled\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that a KRT6C missense mutation (p.Glu472Lys) in the helix termination motif produces both focal and diffuse palmoplantar keratoderma expanded the phenotypic spectrum, indicating that a single KRT6C allele can yield variable clinical outcomes.\",\n      \"evidence\": \"Sanger sequencing and clinical phenotyping in an affected Japanese family\",\n      \"pmids\": [\"21801157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of phenotypic variability (modifier genes, environmental factors) was not addressed\",\n        \"No in vitro filament assembly data in this study\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Expression of the KRT6C p.Glu472Lys mutant in keratinocytes directly demonstrated dose-dependent dominant-negative collapse of the keratin filament network, providing the first mechanistic proof that disease-associated KRT6C mutations act by disrupting intermediate filament assembly.\",\n      \"evidence\": \"Exogenous mutant expression in HaCaT cells with immunofluorescence readout\",\n      \"pmids\": [\"23662636\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"In vitro filament reconstitution with purified KRT6C was not performed\",\n        \"Whether heterodimer partner identity (e.g., KRT9 versus other type I keratins) modulates severity of network collapse was not tested\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that KRT6C transcription is down-regulated by endoxifen, estrogen deprivation, and SRC-3 knockdown revealed estrogen receptor-dependent regulation of KRT6C, linking its expression to hormonal signaling in breast cancer cells.\",\n      \"evidence\": \"Gene expression microarray, qRT-PCR, and siRNA knockdown in MCF-7 cells\",\n      \"pmids\": [\"25867603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct ER binding at the KRT6C promoter was not shown (e.g., ChIP)\",\n        \"Functional consequence of KRT6C loss in breast cancer cells was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of KRT6C expression in ameloblasts and the finding that a coding polymorphism alters filament assembly in ameloblast-like cells expanded the tissue repertoire of KRT6C function beyond skin to tooth enamel formation.\",\n      \"evidence\": \"Genetic association in two cohorts, filament assembly assay in ameloblast-like cells, RNA-seq of mouse enamel organ, and structural analysis of pachyonychia congenita patient teeth\",\n      \"pmids\": [\"29357356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific heterodimer partner of KRT6C in ameloblasts was not identified\",\n        \"Mouse knockout or conditional deletion in enamel organ was not performed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that circ-KRT6C sponges miR-485-3p to upregulate PDL1, promoting immune evasion and tumor growth in colorectal cancer, revealed a non-coding RNA function emanating from the KRT6C locus that is mechanistically distinct from the keratin protein itself.\",\n      \"evidence\": \"Dual-luciferase reporter assay, siRNA knockdown, immune cell co-culture, and xenograft mouse model\",\n      \"pmids\": [\"33771844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings from a single lab; independent replication in other colorectal cancer models not yet available\",\n        \"Whether circ-KRT6C levels correlate with clinical anti-PD-L1 response is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Co-immunoprecipitation/mass spectrometry identified KRT9 as a direct heterodimer partner of KRT6C in palmoplantar epidermis, with structural modeling supporting a coiled-coil interaction in their 2B domains, providing a molecular explanation for the tissue-specific phenotype of KRT6C mutations.\",\n      \"evidence\": \"Co-IP with mass spectrometry from human palmoplantar tissue; in silico coiled-coil modeling\",\n      \"pmids\": [\"37467889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Reciprocal pull-down and in vitro reconstitution of the KRT6C/KRT9 heterodimer have not been performed\",\n        \"Whether other type I keratins also pair with KRT6C in vivo is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of KRT6C heterodimer selectivity (why KRT9 is preferred in palmoplantar skin), the full repertoire of KRT6C type I partners across tissues, and in vivo genetic loss-of-function studies (knockout/conditional deletion) remain unaddressed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No animal knockout model for KRT6C has been reported\",\n        \"Crystal or cryo-EM structure of the KRT6C heterodimer is lacking\",\n        \"Functional relationship between the keratin protein and circ-KRT6C in the same tissue context is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT9\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"RT-PCR of plantar epidermis plus mutational and co-segregation analysis in three unrelated FPPK families\",\n      \"pmids\": [\"19609311\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro filament assembly assay was performed to directly demonstrate the dominant-negative mechanism\",\n        \"The heterodimer partner of KRT6C in palmoplantar skin was not identified\",\n        \"Expression pattern across other stratified epithelia was not systematically mapped\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Exogenous expression of mutant KRT6C in HaCaT keratinocytes with immunofluorescence and dose-response analysis\",\n      \"pmids\": [\"23662636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only one mutation was tested; other FPPK-causing variants were not functionally validated\",\n        \"Effect on specific binding partners (e.g., type I keratin heterodimer partner) was not assessed\",\n        \"No in vivo mouse model was generated\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Filament assembly assay in ameloblast-like cells, RNA-seq of mouse enamel organ, immunohistochemistry of human enamel\",\n      \"pmids\": [\"29357356\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Quantitative impact of p.Ser143Asn on enamel mechanical properties was not measured\",\n        \"Whether the ameloblast KRT6C partner is also KRT9 or a different type I keratin was not determined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-immunoprecipitation coupled with mass spectrometry from native palmoplantar epidermis; in silico coiled-coil modeling\",\n      \"pmids\": [\"37467889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The coiled-coil interface model was not experimentally validated by mutagenesis or cross-linking\",\n        \"Stoichiometry and higher-order filament organization of the KRT6C/KRT9 heterodimer remain uncharacterized\",\n        \"No reciprocal validation (e.g., reverse Co-IP with anti-KRT6C pull-down) was reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Crystal or cryo-EM structure of the KRT6C/KRT9 coiled-coil is unavailable\",\n        \"In vivo mouse models recapitulating human FPPK mutations in Krt6c have not been reported\",\n        \"Tissue-specific transcriptional regulation of KRT6C (beyond ER/SRC-3 in breast cancer cells) is poorly defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KRT9\"],\n    \"other_free_text\": []\n  }\n}\n```"}