{"gene":"KRT9","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1994,"finding":"KRT9 was mapped to chromosome 17q21 and three missense mutations (N160K, R162Q, R162W) in the highly conserved coil 1A of the rod domain were identified as causative for epidermolytic palmoplantar keratoderma (EPPK). The coil 1A region is critical for keratin heterodimerization, and mutation of the equivalent arginine in KRT14 and KRT10 likewise causes epidermolysis bullosa simplex and generalized epidermolytic hyperkeratosis, respectively.","method":"Gene isolation, chromosomal localization, direct sequencing of PCR products from EPPK patients, restriction enzyme analysis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — original disease-gene discovery with sequencing in multiple unrelated families, replicated across populations in subsequent studies","pmids":["7512862"],"is_preprint":false},{"year":1994,"finding":"A single base mutation in the rod domain of keratin 9 cosegregates with EPPK in all affected individuals of a large French pedigree, confirming KRT9 as the causative gene for EPPK; the EPPK locus maps near the type I keratin gene cluster on chromosome 17q.","method":"Linkage analysis, partial sequencing of KRT9 rod domain in affected individuals","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — independent replication of KRT9 rod domain mutations causing EPPK in a separate large pedigree","pmids":["7511021"],"is_preprint":false},{"year":1998,"finding":"KRT9 mutations in EPPK are exclusively located in the helix initiation motif (coil 1A) of the central rod domain, with novel mutations M156T and M156V identified; expression is restricted to suprabasal keratinocytes of palmoplantar epidermis.","method":"Direct sequencing of PCR products, restriction enzyme analysis, epidemiological survey","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — multiple independent EPPK kindreds, consistent localization of mutations to helix initiation motif, replicated across labs","pmids":["9856842"],"is_preprint":false},{"year":1998,"finding":"The canine KRT9 ortholog spans ~7 kb over eight exons and encodes a protein with 75% identity and 95% similarity to human KRT9 in the rod domain. The C-terminal V2 variable subdomain contains a markedly expanded glycine-loop motif (43 repeats in dog vs. 19 in human), generating a 12 kDa size difference; no KRT9 mutation was found in canine palmoplantar hyperkeratosis in Dogue de Bordeaux.","method":"Inverse-PCR cloning, sequence comparison, structural analysis, pedigree screening","journal":"Animal genetics","confidence":"Medium","confidence_rationale":"Tier 2 — comparative genomic characterization of ortholog structure and expression, single lab","pmids":["9720175"],"is_preprint":false},{"year":2006,"finding":"New consensus nomenclature established KRT9 as the official symbol for the type I keratin expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis, clarifying its place within the broader keratin gene family.","method":"Systematic genomic annotation and nomenclature review","journal":"The Journal of cell biology","confidence":"Low","confidence_rationale":"Tier 4 — nomenclature/annotation paper, no direct functional experiment on KRT9 mechanism","pmids":["16831889"],"is_preprint":false},{"year":2013,"finding":"A novel KRT9 missense mutation at a poorly conserved position (L11V) causes EPPK not through direct protein dysfunction but by activating a cryptic donor splice site, resulting in deletion of 162 amino acids from the mature protein. This demonstrates that mutations outside the conserved rod domain can cause EPPK via a transcriptional/splicing mechanism.","method":"Patient sequencing, splice site analysis, RT-PCR to confirm aberrant splicing product","journal":"Clinical and experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic demonstration of cryptic splice site activation by direct RT-PCR, single lab","pmids":["23397986"],"is_preprint":false},{"year":2016,"finding":"siRNA specifically targeting the KRT9 R163W mutant allele suppresses mutant KRT9 mRNA and protein expression in HaCaT cells, demonstrating allele-specific silencing as a potential therapeutic strategy for EPPK.","method":"Transfection of wild-type and R163W mutant KRT9 constructs into HaCaT cells, allele-specific siRNA knockdown, qPCR and western blotting","journal":"Cancer genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct loss-of-function experiment in human keratinocyte cell line with quantitative readout, single lab","pmids":["27864007"],"is_preprint":false},{"year":2023,"finding":"KRT6C was identified as the probable heterodimer partner of KRT9 in palmoplantar epidermis. Co-immunoprecipitation coupled with mass spectrometry identified KRT6C as co-precipitating with KRT9 in a native endogenous environment. In silico modeling shows a typical coiled-coil structure in their 2B domains, and proteomics reveals the KRT6C/KRT9 pair participates in a protein-protein interaction network regulating cytoskeleton organization and keratinization.","method":"Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), proteomics network analysis, in silico structural modeling","journal":"Journal of proteomics","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/MS identification of heterodimer partner in native tissue, single lab, supported by structural modeling","pmids":["37467889"],"is_preprint":false},{"year":2025,"finding":"KRT9 is required for GBP5-mediated suppression of respiratory syncytial virus (RSV). Affinity mass spectrometry identified KRT9 as a GBP5-interacting protein. Silencing KRT9 reduced the antiviral effects of GBP5 and interferon-γ. A direct interaction between KRT9 and GBP5 was detected (but not between KRT9 and RSV-SH protein directly). A GBP5-binding domain was mapped on KRT9. The data suggest GBP5 acts as a bridge between KRT9 and RSV-SH to trigger RSV-SH transport into microvesicles, inhibiting viral replication.","method":"Affinity mass spectrometry, siRNA knockdown, co-immunoprecipitation, domain mapping","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (affinity MS, Co-IP, KD with functional readout), single lab, novel innate immunity role","pmids":["39835811"],"is_preprint":false},{"year":2025,"finding":"KRT9 expression in palmoplantar epidermis rises dramatically post-birth following a transient induction of stress-related keratin K16, and onset of Krt9 expression is dependent on K16. Krt9-null mice exhibit elevated K16 and aberrant nuclear-localized YAP1 by postnatal day 3. K9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm, suppressing YAP1 nuclear activity. EPPK-causing pathogenic variants of K9 impair 14-3-3σ binding and YAP1 cytoplasmic sequestration. Pharmacological or genetic inhibition of YAP1 in vivo rescues palmoplantar keratoderma in Krt9-null mice.","method":"Krt9 knockout mouse model, immunofluorescence for YAP1 localization, co-immunoprecipitation (K9 with 14-3-3σ), in vivo YAP1 inhibitor treatment, postnatal expression profiling","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with defined cellular phenotype, direct protein interaction (Co-IP), in vivo rescue, multiple orthogonal methods in single rigorous study","pmids":[],"is_preprint":true},{"year":2004,"finding":"The R162W mutation in KRT9 represents a mutational hotspot; confirmed in five unrelated families from multiple geographic backgrounds, and the corresponding arginine is conserved across keratin family members KRT14 and KRT10 where equivalent mutations cause other blistering/keratinizing disorders.","method":"RT-PCR, direct sequencing, restriction enzyme analysis across multiple unrelated EPPK families","journal":"European journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — convergent genetic evidence from multiple independent families establishing hotspot mutation in conserved rod domain residue","pmids":["15564199"],"is_preprint":false}],"current_model":"KRT9 encodes a type I keratin expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis, where it heterodimerizes with KRT6C via coiled-coil interactions in the rod domain to form intermediate filaments; pathogenic mutations cluster in the helix initiation motif (coil 1A) of the rod domain and disrupt filament integrity, causing EPPK. Beyond structural roles, K9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm of differentiating keratinocytes—loss of K9 causes aberrant nuclear YAP1 accumulation and hyperkeratosis that is rescued by YAP1 inhibition in vivo—and K9 also participates in innate antiviral immunity by binding GBP5 to facilitate RSV-SH protein transport into microvesicles."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of KRT9 as the causative gene for EPPK established that coil 1A rod domain integrity is essential for palmoplantar keratin function, answering which gene underlies this site-restricted genodermatosis.","evidence":"Sequencing of EPPK patients in multiple unrelated families identified missense mutations (N160K, R162Q, R162W) in the coil 1A helix initiation motif; confirmed by linkage in an independent French pedigree","pmids":["7512862","7511021"],"confidence":"High","gaps":["Heterodimer partner of KRT9 in vivo was unknown","No animal model to assess phenotype of total KRT9 loss","Mechanism by which rod domain mutations disrupt filament assembly not resolved at atomic level"]},{"year":1998,"claim":"Systematic survey of EPPK kindreds confirmed that all pathogenic KRT9 mutations map exclusively to the helix initiation motif and that KRT9 expression is restricted to suprabasal palmoplantar keratinocytes, defining the genotype-phenotype constraint.","evidence":"Direct sequencing across multiple EPPK families identifying novel mutations M156T/M156V; epidemiological survey of expression pattern","pmids":["9856842"],"confidence":"High","gaps":["Mutations outside the rod domain had not been evaluated for pathogenicity","No functional assay to test mutant filament assembly in vitro"]},{"year":2004,"claim":"Confirmation of R162W as a recurrent mutational hotspot across geographically diverse families reinforced the functional criticality of this conserved arginine in the coil 1A domain.","evidence":"RT-PCR and sequencing in five unrelated EPPK families from multiple ethnic backgrounds","pmids":["15564199"],"confidence":"Medium","gaps":["No in vitro assembly assay comparing wild-type vs R162W filaments","No structural explanation for why arginine at this position is indispensable"]},{"year":2013,"claim":"Discovery that a mutation outside the rod domain (L11V) causes EPPK by activating a cryptic splice site revealed a splicing-mediated pathogenic mechanism, expanding the mutational landscape beyond missense changes in coil 1A.","evidence":"RT-PCR demonstrating aberrant splicing product with 162-amino-acid deletion in patient keratinocytes","pmids":["23397986"],"confidence":"Medium","gaps":["Single family; frequency of splice-site-mediated EPPK unknown","Effect of truncated protein on filament network not directly visualized"]},{"year":2016,"claim":"Allele-specific siRNA silencing of the R163W mutant demonstrated that selective knockdown of the dominant-negative allele is feasible, establishing proof-of-concept for a therapeutic strategy targeting EPPK at the mRNA level.","evidence":"Transfection of wild-type and R163W KRT9 into HaCaT cells with allele-specific siRNA, qPCR and western blot readout","pmids":["27864007"],"confidence":"Medium","gaps":["Performed in an immortalized cell line, not primary palmoplantar keratinocytes","No in vivo delivery or phenotype rescue demonstrated"]},{"year":2023,"claim":"Identification of KRT6C as the endogenous heterodimer partner of KRT9 resolved a long-standing question about which type II keratin pairs with KRT9 in palmoplantar epidermis.","evidence":"Co-immunoprecipitation coupled with mass spectrometry from native palmoplantar tissue; coiled-coil modeling of KRT6C/KRT9 2B domains","pmids":["37467889"],"confidence":"Medium","gaps":["No reciprocal IP or in vitro reconstitution of heterodimer","Functional consequence of disrupting the KRT6C–KRT9 pair specifically is untested","Single lab; awaits independent validation"]},{"year":2025,"claim":"KRT9 was shown to function in innate antiviral immunity by interacting with GBP5 to facilitate transport of RSV-SH protein into microvesicles, establishing a non-structural role for this keratin.","evidence":"Affinity mass spectrometry, co-IP, domain mapping, and siRNA knockdown with functional readout of RSV replication","pmids":["39835811"],"confidence":"Medium","gaps":["KRT9 is palmoplantar-restricted, so physiological relevance of antiviral function in vivo needs clarification","Mechanism of microvesicle cargo loading by KRT9–GBP5 not defined","Single lab finding; not independently replicated"]},{"year":2025,"claim":"KRT9 was found to regulate YAP1 cytoplasmic sequestration via 14-3-3σ interaction, directly linking intermediate filament identity to Hippo pathway control and explaining the hyperproliferative pathology in EPPK.","evidence":"Krt9 knockout mice, co-IP of K9 with 14-3-3σ, YAP1 immunofluorescence, in vivo rescue by YAP1 inhibition (preprint)","pmids":[],"confidence":"High","gaps":["Preprint; not yet peer-reviewed","Whether EPPK patient mutations uniformly disrupt 14-3-3σ binding quantitatively is not fully characterized","Downstream transcriptional targets of nuclear YAP1 in palmoplantar keratinocytes not defined"]},{"year":null,"claim":"Key open questions include the atomic-resolution structure of the KRT9–KRT6C heterodimer, the full spectrum of signaling functions mediated by the KRT9–14-3-3σ complex, and whether the antiviral role of KRT9 via GBP5 operates in tissues beyond its canonical palmoplantar expression domain.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of KRT9-containing intermediate filaments","In vivo relevance of KRT9–GBP5 antiviral axis unresolved","Whether YAP1 sequestration is the sole signaling function of KRT9 is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7,9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1,2,5,10]}],"complexes":["KRT9–KRT6C intermediate filament heterodimer"],"partners":["KRT6C","GBP5","SFN"],"other_free_text":[]},"mechanistic_narrative":"KRT9 is a type I intermediate filament keratin expressed exclusively in the suprabasal keratinocytes of palmoplantar epidermis, where it heterodimerizes with KRT6C via coiled-coil rod domain interactions to form cytoskeletal filaments essential for mechanical resilience [PMID:37467889]. Pathogenic missense mutations clustering in the helix initiation motif (coil 1A) of the rod domain cause epidermolytic palmoplantar keratoderma (EPPK), with R162W representing a recurrent mutational hotspot conserved across type I keratins [PMID:7512862, PMID:15564199]. Beyond its structural role, KRT9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm of differentiating keratinocytes; loss of KRT9 leads to aberrant nuclear YAP1 accumulation and hyperkeratosis that is rescued by YAP1 inhibition in vivo. KRT9 also participates in innate antiviral defense by binding GBP5, facilitating GBP5-mediated transport of RSV-SH protein into microvesicles and thereby suppressing respiratory syncytial virus replication [PMID:39835811]."},"prefetch_data":{"uniprot":{"accession":"P35527","full_name":"Keratin, type I cytoskeletal 9","aliases":["Cytokeratin-9","CK-9","Keratin-9","K9"],"length_aa":623,"mass_kda":62.1,"function":"May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues. Plays a role in keratin filament assembly","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P35527/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT9","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT9","total_profiled":1310},"omim":[{"mim_id":"613000","title":"PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC, FOCAL 1; FNEPPK1","url":"https://www.omim.org/entry/613000"},{"mim_id":"607606","title":"KERATIN 9, TYPE I; KRT9","url":"https://www.omim.org/entry/607606"},{"mim_id":"600962","title":"PALMOPLANTAR KERATODERMA, NONEPIDERMOLYTIC; NEPPK","url":"https://www.omim.org/entry/600962"},{"mim_id":"600194","title":"KERATIN 2, TYPE II; KRT2","url":"https://www.omim.org/entry/600194"},{"mim_id":"248300","title":"MAL DE MELEDA; MDM","url":"https://www.omim.org/entry/248300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":11.3}],"url":"https://www.proteinatlas.org/search/KRT9"},"hgnc":{"alias_symbol":["EPPK","K9","CK-9"],"prev_symbol":[]},"alphafold":{"accession":"P35527","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35527","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35527-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35527-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT9","jax_strain_url":"https://www.jax.org/strain/search?query=KRT9"},"sequence":{"accession":"P35527","fasta_url":"https://rest.uniprot.org/uniprotkb/P35527.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35527/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35527"}},"corpus_meta":[{"pmid":"15145825","id":"PMC_15145825","title":"A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin.","date":"2004","source":"Genes & 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/27545878","citation_count":115,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30737378","id":"PMC_30737378","title":"The p300/YY1/miR-500a-5p/HDAC2 signalling axis regulates cell proliferation in human colorectal cancer.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30737378","citation_count":115,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"7511021","id":"PMC_7511021","title":"Epidermolytic palmoplantar keratoderma cosegregates with a keratin 9 mutation in a pedigree with breast and ovarian cancer.","date":"1994","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7511021","citation_count":110,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43160,"output_tokens":1757,"usd":0.077918},"stage2":{"model":"claude-opus-4-6","input_tokens":5017,"output_tokens":2215,"usd":0.12069},"total_usd":0.447373,"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":55458,"output_tokens":3342,"usd":0.108252},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6390,"output_tokens":2469,"usd":0.140513}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"KRT9 mutations in the highly conserved coil 1A of the rod domain (N160K, R162Q, R162W) cause epidermolytic palmoplantar keratoderma (EPPK), establishing that this domain is critical for keratin heterodimerization and filament integrity in palmoplantar suprabasal keratinocytes.\",\n      \"method\": \"Direct sequencing of PCR products from EPPK patients; gene localization to chromosome 17q21\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — founding mutation study replicated across multiple unrelated families, confirmed by multiple subsequent independent studies\",\n      \"pmids\": [\"7512862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"All reported EPPK-causing mutations in KRT9 occur in the helix initiation motif at the start of the central coiled-coil rod domain (coil 1A), confirming this as the critical functional region; novel mutations M156T and M156V identified in addition to R162Q.\",\n      \"method\": \"Direct sequencing of PCR products; restriction enzyme analysis; epidemiological survey\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent replication of coil 1A as mutation hotspot across multiple unrelated kindreds\",\n      \"pmids\": [\"9856842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The canine KRT9 gene encodes an ortholog with high structural similarity to human KRT9 (75% identity, 95% similarity in rod domain), spanning 8 exons; the glycine-loop motif in the C-terminal V2 subdomain differs between species (43 in dog vs 19 in human), generating a 12 kDa size difference.\",\n      \"method\": \"Inverse-PCR cloning, sequence comparison, structural analysis\",\n      \"journal\": \"Animal genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — structural/comparative analysis by cloning and sequencing, single study\",\n      \"pmids\": [\"9720175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A missense mutation in KRT9 at a poorly conserved position (V11) can cause EPPK not by altering protein structure directly but by activating a cryptic donor splice site, resulting in deletion of 162 amino acids from the transcript.\",\n      \"method\": \"Sequencing; splice site prediction; RT-PCR to confirm aberrant splicing\",\n      \"journal\": \"Clinical and experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular confirmation of aberrant splicing by RT-PCR, single study\",\n      \"pmids\": [\"23397986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT6C was identified as the probable heterodimer partner for KRT9 in palmoplantar epidermis; KRT6C/KRT9 form a coiled-coil heterodimer through their 2B domains and participate in a protein-protein interaction network regulating cytoskeleton organization and keratinization.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry; proteomics analysis; in silico structural modeling\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP/MS identification of heterodimer partner, single lab, supported by in silico modeling\",\n      \"pmids\": [\"37467889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT9 is required for GBP5-mediated suppression of respiratory syncytial virus (RSV); KRT9 directly interacts with GBP5 (but not RSV-SH protein), and GBP5 acts as a bridge between KRT9 and RSV-SH to trigger RSV-SH transport into microvesicles, inhibiting viral replication. Silencing KRT9 reduces the antiviral effects of GBP5 and interferon-γ. A GBP5-binding domain was mapped on KRT9.\",\n      \"method\": \"Affinity mass spectrometry to identify KRT9 as GBP5-interacting partner; siRNA knockdown of KRT9; co-immunoprecipitation to confirm KRT9-GBP5 direct interaction; antiviral assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal pulldown/MS plus functional KD with defined antiviral phenotype, single lab\",\n      \"pmids\": [\"39835811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT9 expression rises dramatically post-birth in palmoplantar epidermis following transient induction of stress keratin K16. KRT9-null mice show aberrant nuclear YAP1 localization in differentiating keratinocytes. KRT9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm; EPPK-causing pathogenic variants impair this interaction. Pharmacological or genetic inhibition of YAP1 rescues palmoplantar keratoderma in Krt9-null mice.\",\n      \"method\": \"Krt9 knockout mouse model; immunofluorescence for YAP1 localization; co-immunoprecipitation of KRT9 with 14-3-3σ; in vivo YAP1 inhibition rescue experiment; EPPK variant functional analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined cellular phenotype, co-IP for binding partner, rescue experiment; preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KRT9 is a type I keratin expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis that forms a coiled-coil heterodimer with KRT6C via its rod domain; mutations in the conserved helix initiation motif (coil 1A) disrupt heterodimerization and filament integrity to cause EPPK, while in normal palmoplantar skin KRT9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm and suppress hyperproliferative signaling, and also participates in innate antiviral immunity by interacting with GBP5 to facilitate RSV-SH transport into microvesicles.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about canonical KRT9 (keratin 9 protein):\n- KEEP: [6], [21], [41], [43], [44], [49], [50], [51], [52], [55], [56], [57], [61], [63], [65], [68], [70], [77] (preprint)\n- KEEP from curated list: [7], [9], [30], [55]\n\nPapers about H3-K9 histone methylation (alias collision - \"K9\" refers to histone lysine 9, not KRT9):\n- EXCLUDE: [1],[2],[3],[4],[7(corpus)],[8],[9(corpus)],[10],[11],[12],[13],[14],[15],[16],[17],[18],[20],[22],[23],[24],[26],[30(corpus)],[31],[38],[54],[64],[66],[69],[81],[82],[84],[85],[87]\n\nPapers about KSHV ORF K9 (vIRF) - alias collision:\n- EXCLUDE: [5],[19],[34]\n\nPapers about K9 clone antibody (DOG1):\n- EXCLUDE: [25],[37],[42]\n\nPapers about other K9 organisms/strains (bacteria, phage, viruses, etc.):\n- EXCLUDE: [27],[28],[29],[32],[33],[35],[36],[39],[40],[46],[47],[48],[53],[58],[59],[60],[67],[74],[75],[76],[79],[80],[83]\n\nPapers about HERVK9 (endogenous retrovirus):\n- EXCLUDE: [71]\n\nPapers about huntingtin K6/K9 ubiquitination:\n- EXCLUDE: [73]\n\nPapers about canine K9 lymphoma assay:\n- EXCLUDE: [62]\n\nCurated papers - classify:\n- KEEP: [7(curated)=PMID16831889], [30(curated)=PMID7511021], [9(curated)=PMID15324660]\n- The rest are proteomics/interactome papers where KRT9 appeared incidentally - LOW mechanistic value, but check [9] for 14-3-3 binding.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"KRT9 was mapped to chromosome 17q21 and three missense mutations (N160K, R162Q, R162W) in the highly conserved coil 1A of the rod domain were identified as causative for epidermolytic palmoplantar keratoderma (EPPK). The coil 1A region is critical for keratin heterodimerization, and mutation of the equivalent arginine in KRT14 and KRT10 likewise causes epidermolysis bullosa simplex and generalized epidermolytic hyperkeratosis, respectively.\",\n      \"method\": \"Gene isolation, chromosomal localization, direct sequencing of PCR products from EPPK patients, restriction enzyme analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original disease-gene discovery with sequencing in multiple unrelated families, replicated across populations in subsequent studies\",\n      \"pmids\": [\"7512862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A single base mutation in the rod domain of keratin 9 cosegregates with EPPK in all affected individuals of a large French pedigree, confirming KRT9 as the causative gene for EPPK; the EPPK locus maps near the type I keratin gene cluster on chromosome 17q.\",\n      \"method\": \"Linkage analysis, partial sequencing of KRT9 rod domain in affected individuals\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent replication of KRT9 rod domain mutations causing EPPK in a separate large pedigree\",\n      \"pmids\": [\"7511021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"KRT9 mutations in EPPK are exclusively located in the helix initiation motif (coil 1A) of the central rod domain, with novel mutations M156T and M156V identified; expression is restricted to suprabasal keratinocytes of palmoplantar epidermis.\",\n      \"method\": \"Direct sequencing of PCR products, restriction enzyme analysis, epidemiological survey\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple independent EPPK kindreds, consistent localization of mutations to helix initiation motif, replicated across labs\",\n      \"pmids\": [\"9856842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The canine KRT9 ortholog spans ~7 kb over eight exons and encodes a protein with 75% identity and 95% similarity to human KRT9 in the rod domain. The C-terminal V2 variable subdomain contains a markedly expanded glycine-loop motif (43 repeats in dog vs. 19 in human), generating a 12 kDa size difference; no KRT9 mutation was found in canine palmoplantar hyperkeratosis in Dogue de Bordeaux.\",\n      \"method\": \"Inverse-PCR cloning, sequence comparison, structural analysis, pedigree screening\",\n      \"journal\": \"Animal genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comparative genomic characterization of ortholog structure and expression, single lab\",\n      \"pmids\": [\"9720175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"New consensus nomenclature established KRT9 as the official symbol for the type I keratin expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis, clarifying its place within the broader keratin gene family.\",\n      \"method\": \"Systematic genomic annotation and nomenclature review\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — nomenclature/annotation paper, no direct functional experiment on KRT9 mechanism\",\n      \"pmids\": [\"16831889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel KRT9 missense mutation at a poorly conserved position (L11V) causes EPPK not through direct protein dysfunction but by activating a cryptic donor splice site, resulting in deletion of 162 amino acids from the mature protein. This demonstrates that mutations outside the conserved rod domain can cause EPPK via a transcriptional/splicing mechanism.\",\n      \"method\": \"Patient sequencing, splice site analysis, RT-PCR to confirm aberrant splicing product\",\n      \"journal\": \"Clinical and experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic demonstration of cryptic splice site activation by direct RT-PCR, single lab\",\n      \"pmids\": [\"23397986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"siRNA specifically targeting the KRT9 R163W mutant allele suppresses mutant KRT9 mRNA and protein expression in HaCaT cells, demonstrating allele-specific silencing as a potential therapeutic strategy for EPPK.\",\n      \"method\": \"Transfection of wild-type and R163W mutant KRT9 constructs into HaCaT cells, allele-specific siRNA knockdown, qPCR and western blotting\",\n      \"journal\": \"Cancer genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct loss-of-function experiment in human keratinocyte cell line with quantitative readout, single lab\",\n      \"pmids\": [\"27864007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KRT6C was identified as the probable heterodimer partner of KRT9 in palmoplantar epidermis. Co-immunoprecipitation coupled with mass spectrometry identified KRT6C as co-precipitating with KRT9 in a native endogenous environment. In silico modeling shows a typical coiled-coil structure in their 2B domains, and proteomics reveals the KRT6C/KRT9 pair participates in a protein-protein interaction network regulating cytoskeleton organization and keratinization.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry (Co-IP/MS), proteomics network analysis, in silico structural modeling\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/MS identification of heterodimer partner in native tissue, single lab, supported by structural modeling\",\n      \"pmids\": [\"37467889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT9 is required for GBP5-mediated suppression of respiratory syncytial virus (RSV). Affinity mass spectrometry identified KRT9 as a GBP5-interacting protein. Silencing KRT9 reduced the antiviral effects of GBP5 and interferon-γ. A direct interaction between KRT9 and GBP5 was detected (but not between KRT9 and RSV-SH protein directly). A GBP5-binding domain was mapped on KRT9. The data suggest GBP5 acts as a bridge between KRT9 and RSV-SH to trigger RSV-SH transport into microvesicles, inhibiting viral replication.\",\n      \"method\": \"Affinity mass spectrometry, siRNA knockdown, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (affinity MS, Co-IP, KD with functional readout), single lab, novel innate immunity role\",\n      \"pmids\": [\"39835811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KRT9 expression in palmoplantar epidermis rises dramatically post-birth following a transient induction of stress-related keratin K16, and onset of Krt9 expression is dependent on K16. Krt9-null mice exhibit elevated K16 and aberrant nuclear-localized YAP1 by postnatal day 3. K9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm, suppressing YAP1 nuclear activity. EPPK-causing pathogenic variants of K9 impair 14-3-3σ binding and YAP1 cytoplasmic sequestration. Pharmacological or genetic inhibition of YAP1 in vivo rescues palmoplantar keratoderma in Krt9-null mice.\",\n      \"method\": \"Krt9 knockout mouse model, immunofluorescence for YAP1 localization, co-immunoprecipitation (K9 with 14-3-3σ), in vivo YAP1 inhibitor treatment, postnatal expression profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with defined cellular phenotype, direct protein interaction (Co-IP), in vivo rescue, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The R162W mutation in KRT9 represents a mutational hotspot; confirmed in five unrelated families from multiple geographic backgrounds, and the corresponding arginine is conserved across keratin family members KRT14 and KRT10 where equivalent mutations cause other blistering/keratinizing disorders.\",\n      \"method\": \"RT-PCR, direct sequencing, restriction enzyme analysis across multiple unrelated EPPK families\",\n      \"journal\": \"European journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — convergent genetic evidence from multiple independent families establishing hotspot mutation in conserved rod domain residue\",\n      \"pmids\": [\"15564199\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT9 encodes a type I keratin expressed exclusively in suprabasal keratinocytes of palmoplantar epidermis, where it heterodimerizes with KRT6C via coiled-coil interactions in the rod domain to form intermediate filaments; pathogenic mutations cluster in the helix initiation motif (coil 1A) of the rod domain and disrupt filament integrity, causing EPPK. Beyond structural roles, K9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm of differentiating keratinocytes—loss of K9 causes aberrant nuclear YAP1 accumulation and hyperkeratosis that is rescued by YAP1 inhibition in vivo—and K9 also participates in innate antiviral immunity by binding GBP5 to facilitate RSV-SH protein transport into microvesicles.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT9 is a type I keratin whose expression is restricted to suprabasal keratinocytes of palmoplantar epidermis, where it functions both as a structural intermediate filament component and as a signaling scaffold that restrains keratinocyte proliferation. KRT9 forms a coiled-coil heterodimer with KRT6C through their rod domains to organize the palmoplantar cytoskeleton [PMID:37467889], and its highly conserved helix initiation motif (coil 1A) is essential for filament integrity, as missense mutations at this hotspot (e.g., N160K, R162Q, R162W, M156T) cause epidermolytic palmoplantar keratoderma (EPPK) [PMID:7512862, PMID:9856842]. Beyond its structural role, KRT9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm of differentiating keratinocytes, suppressing hyperproliferative signaling; loss of KRT9 leads to aberrant nuclear YAP1 accumulation, and pharmacological YAP1 inhibition rescues the keratoderma phenotype in Krt9-null mice. KRT9 also participates in innate antiviral defense by directly binding GBP5, which bridges KRT9 to the RSV small hydrophobic protein for export into microvesicles, thereby inhibiting viral replication [PMID:39835811].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of KRT9 coil 1A mutations in EPPK families established that a specific structural domain of a palmoplantar-restricted keratin is essential for filament integrity and skin homeostasis, founding the molecular basis of this genodermatosis.\",\n      \"evidence\": \"Direct sequencing of PCR products from multiple unrelated EPPK kindreds, mapping mutations N160K, R162Q, R162W to chromosome 17q21\",\n      \"pmids\": [\"7512862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which coil 1A mutations disrupt filament assembly was not resolved at a structural level\",\n        \"The type II keratin partner for KRT9 was unknown\",\n        \"Whether KRT9 has functions beyond structural support was not addressed\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Replication across additional EPPK families confirmed the helix initiation motif as the sole mutation hotspot in KRT9 and expanded the allelic series (M156T, M156V), reinforcing a dominant-negative mechanism for filament disruption.\",\n      \"evidence\": \"Independent sequencing and restriction enzyme analysis across multiple kindreds; epidemiological survey\",\n      \"pmids\": [\"9856842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vitro filament assembly assay was performed to directly test dominant-negative mechanism\",\n        \"Genotype–phenotype correlation beyond the coil 1A region was unexplored\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that a missense change outside the rod domain (V11) causes EPPK by activating a cryptic splice site revealed that KRT9 pathogenesis extends beyond simple amino acid substitutions to include mRNA mis-splicing as a disease mechanism.\",\n      \"evidence\": \"Splice site prediction followed by RT-PCR confirmation of aberrant transcript deleting 162 amino acids\",\n      \"pmids\": [\"23397986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only a single family was studied; independent replication would strengthen generalizability\",\n        \"Protein-level consequences of the truncated transcript were not characterized\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of KRT6C as the heterodimer partner of KRT9 resolved the long-standing question of which type II keratin pairs with KRT9 in palmoplantar skin and placed the KRT6C/KRT9 pair within a cytoskeleton-organizing protein network.\",\n      \"evidence\": \"Co-immunoprecipitation coupled with mass spectrometry from palmoplantar tissue; in silico coiled-coil modeling of the 2B domain interface\",\n      \"pmids\": [\"37467889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Heterodimerization was supported by co-IP/MS and modeling but not by in vitro reconstitution of purified proteins\",\n        \"Whether KRT6C is the exclusive or predominant partner versus other type II keratins was not resolved\",\n        \"Structural basis of how EPPK mutations in coil 1A affect heterodimerization with KRT6C specifically was not tested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that KRT9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm established a non-structural signaling function: KRT9 acts as an anti-proliferative scaffold in differentiating palmoplantar keratinocytes, and loss of this function is the proximal cause of EPPK pathology.\",\n      \"evidence\": \"Krt9 knockout mouse with aberrant nuclear YAP1; co-IP of KRT9 with 14-3-3σ; rescue of keratoderma by pharmacological/genetic YAP1 inhibition; EPPK variants impair KRT9–14-3-3σ interaction (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Preprint not yet peer-reviewed; awaits independent validation\",\n        \"Direct binding interface between KRT9 and 14-3-3σ has not been structurally defined\",\n        \"Whether the YAP1-sequestration mechanism operates in human palmoplantar epidermis in vivo is inferred from mouse data\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Finding that KRT9 directly binds GBP5 and is required for GBP5-mediated export of the RSV small hydrophobic protein into microvesicles extended KRT9 function to innate antiviral immunity, an unexpected role for a tissue-restricted keratin.\",\n      \"evidence\": \"Affinity mass spectrometry identifying KRT9 as GBP5 interactor; reciprocal co-IP; siRNA knockdown of KRT9 reducing interferon-γ/GBP5 antiviral activity against RSV\",\n      \"pmids\": [\"39835811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; independent replication needed\",\n        \"The GBP5-binding domain on KRT9 was mapped but structural detail is lacking\",\n        \"Physiological relevance in palmoplantar tissue versus cultured cell lines is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions include the atomic-resolution structure of the KRT9/KRT6C heterodimer, how EPPK mutations quantitatively impair both filament assembly and YAP1-sequestration in human tissue, and whether KRT9's antiviral role is physiologically relevant in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of KRT9-containing filaments exists\",\n        \"Relative contributions of filament disruption versus YAP1 mis-localization to EPPK pathology are unresolved\",\n        \"In vivo antiviral function of KRT9 has not been tested in animal models\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"KRT9/KRT6C heterodimer\"\n    ],\n    \"partners\": [\n      \"KRT6C\",\n      \"GBP5\",\n      \"SFN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"KRT9 is a type I intermediate filament keratin expressed exclusively in the suprabasal keratinocytes of palmoplantar epidermis, where it heterodimerizes with KRT6C via coiled-coil rod domain interactions to form cytoskeletal filaments essential for mechanical resilience [PMID:37467889]. Pathogenic missense mutations clustering in the helix initiation motif (coil 1A) of the rod domain cause epidermolytic palmoplantar keratoderma (EPPK), with R162W representing a recurrent mutational hotspot conserved across type I keratins [PMID:7512862, PMID:15564199]. Beyond its structural role, KRT9 interacts with 14-3-3σ to sequester YAP1 in the cytoplasm of differentiating keratinocytes; loss of KRT9 leads to aberrant nuclear YAP1 accumulation and hyperkeratosis that is rescued by YAP1 inhibition in vivo. KRT9 also participates in innate antiviral defense by binding GBP5, facilitating GBP5-mediated transport of RSV-SH protein into microvesicles and thereby suppressing respiratory syncytial virus replication [PMID:39835811].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of KRT9 as the causative gene for EPPK established that coil 1A rod domain integrity is essential for palmoplantar keratin function, answering which gene underlies this site-restricted genodermatosis.\",\n      \"evidence\": \"Sequencing of EPPK patients in multiple unrelated families identified missense mutations (N160K, R162Q, R162W) in the coil 1A helix initiation motif; confirmed by linkage in an independent French pedigree\",\n      \"pmids\": [\"7512862\", \"7511021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Heterodimer partner of KRT9 in vivo was unknown\",\n        \"No animal model to assess phenotype of total KRT9 loss\",\n        \"Mechanism by which rod domain mutations disrupt filament assembly not resolved at atomic level\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Systematic survey of EPPK kindreds confirmed that all pathogenic KRT9 mutations map exclusively to the helix initiation motif and that KRT9 expression is restricted to suprabasal palmoplantar keratinocytes, defining the genotype-phenotype constraint.\",\n      \"evidence\": \"Direct sequencing across multiple EPPK families identifying novel mutations M156T/M156V; epidemiological survey of expression pattern\",\n      \"pmids\": [\"9856842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mutations outside the rod domain had not been evaluated for pathogenicity\",\n        \"No functional assay to test mutant filament assembly in vitro\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Confirmation of R162W as a recurrent mutational hotspot across geographically diverse families reinforced the functional criticality of this conserved arginine in the coil 1A domain.\",\n      \"evidence\": \"RT-PCR and sequencing in five unrelated EPPK families from multiple ethnic backgrounds\",\n      \"pmids\": [\"15564199\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro assembly assay comparing wild-type vs R162W filaments\",\n        \"No structural explanation for why arginine at this position is indispensable\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that a mutation outside the rod domain (L11V) causes EPPK by activating a cryptic splice site revealed a splicing-mediated pathogenic mechanism, expanding the mutational landscape beyond missense changes in coil 1A.\",\n      \"evidence\": \"RT-PCR demonstrating aberrant splicing product with 162-amino-acid deletion in patient keratinocytes\",\n      \"pmids\": [\"23397986\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single family; frequency of splice-site-mediated EPPK unknown\",\n        \"Effect of truncated protein on filament network not directly visualized\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Allele-specific siRNA silencing of the R163W mutant demonstrated that selective knockdown of the dominant-negative allele is feasible, establishing proof-of-concept for a therapeutic strategy targeting EPPK at the mRNA level.\",\n      \"evidence\": \"Transfection of wild-type and R163W KRT9 into HaCaT cells with allele-specific siRNA, qPCR and western blot readout\",\n      \"pmids\": [\"27864007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Performed in an immortalized cell line, not primary palmoplantar keratinocytes\",\n        \"No in vivo delivery or phenotype rescue demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of KRT6C as the endogenous heterodimer partner of KRT9 resolved a long-standing question about which type II keratin pairs with KRT9 in palmoplantar epidermis.\",\n      \"evidence\": \"Co-immunoprecipitation coupled with mass spectrometry from native palmoplantar tissue; coiled-coil modeling of KRT6C/KRT9 2B domains\",\n      \"pmids\": [\"37467889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No reciprocal IP or in vitro reconstitution of heterodimer\",\n        \"Functional consequence of disrupting the KRT6C–KRT9 pair specifically is untested\",\n        \"Single lab; awaits independent validation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"KRT9 was shown to function in innate antiviral immunity by interacting with GBP5 to facilitate transport of RSV-SH protein into microvesicles, establishing a non-structural role for this keratin.\",\n      \"evidence\": \"Affinity mass spectrometry, co-IP, domain mapping, and siRNA knockdown with functional readout of RSV replication\",\n      \"pmids\": [\"39835811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"KRT9 is palmoplantar-restricted, so physiological relevance of antiviral function in vivo needs clarification\",\n        \"Mechanism of microvesicle cargo loading by KRT9–GBP5 not defined\",\n        \"Single lab finding; not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"KRT9 was found to regulate YAP1 cytoplasmic sequestration via 14-3-3σ interaction, directly linking intermediate filament identity to Hippo pathway control and explaining the hyperproliferative pathology in EPPK.\",\n      \"evidence\": \"Krt9 knockout mice, co-IP of K9 with 14-3-3σ, YAP1 immunofluorescence, in vivo rescue by YAP1 inhibition (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Preprint; not yet peer-reviewed\",\n        \"Whether EPPK patient mutations uniformly disrupt 14-3-3σ binding quantitatively is not fully characterized\",\n        \"Downstream transcriptional targets of nuclear YAP1 in palmoplantar keratinocytes not defined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the atomic-resolution structure of the KRT9–KRT6C heterodimer, the full spectrum of signaling functions mediated by the KRT9–14-3-3σ complex, and whether the antiviral role of KRT9 via GBP5 operates in tissues beyond its canonical palmoplantar expression domain.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of KRT9-containing intermediate filaments\",\n        \"In vivo relevance of KRT9–GBP5 antiviral axis unresolved\",\n        \"Whether YAP1 sequestration is the sole signaling function of KRT9 is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1, 2, 5, 10]}\n    ],\n    \"complexes\": [\n      \"KRT9–KRT6C intermediate filament heterodimer\"\n    ],\n    \"partners\": [\n      \"KRT6C\",\n      \"GBP5\",\n      \"SFN\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}