{"gene":"KRT2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1995,"finding":"Keratin 2e (KRT2) is covalently cross-linked via transglutaminase-induced isodipeptide bonds into the cornified cell envelope (CE) of human epidermis. Proteinase K digestion and peptide sequencing of purified CEs demonstrated that KRT2 (keratin 2e) forms cross-links with loricrin and filaggrin, placing KRT2 as a structural component anchoring the subjacent intermediate filament network to the CE scaffold.","method":"Proteinase K digestion of purified cornified cell envelopes from human foreskin epidermis followed by peptide sequencing of isodipeptide cross-linked fragments","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical reconstitution with peptide sequencing identifying specific cross-link sites; strong evidence from rigorous in vitro analysis","pmids":["7543090"],"is_preprint":false},{"year":1997,"finding":"KRT2 (keratin 2e) is cross-linked to involucrin in the cornified cell envelope via transglutaminase-mediated isopeptide bonds. Amino acid sequencing of peptides released from saponified CEs identified specific glutamine residues in involucrin (Q288) that form cross-links to keratins including KRT2, demonstrating that involucrin serves as an early scaffold protein bridging to the keratin intermediate filament network.","method":"Saponification of purified cornified cell envelopes, proteolytic digestion, and amino acid sequencing of cross-linked peptides; immunogold electron microscopy","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical isolation and sequencing of cross-linked peptides with structural localization, strong orthogonal validation","pmids":["8999895"],"is_preprint":false},{"year":2006,"finding":"KRT2 (previously called keratin 2e) was formally renamed under the new consensus mammalian keratin nomenclature. KRT2 is confirmed as a type II keratin expressed in suprabasal epidermis, forming part of the intermediate filament cytoskeleton in differentiating keratinocytes.","method":"Systematic genomic and proteomic analysis of the human keratin gene family with nomenclature revision","journal":"The Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 3 — nomenclature/classification paper; provides framework but limited direct mechanistic experimentation","pmids":["16831889"],"is_preprint":false},{"year":2016,"finding":"Mutations in KRT2 cause superficial epidermolytic ichthyosis (SEI), an autosomal dominant keratinopathic ichthyosis. Novel pathogenic variants in KRT2 were identified, expanding the known mutation spectrum and establishing that KRT2 mutations disrupt epidermal differentiation in a dominant-negative manner consistent with disruption of intermediate filament assembly in suprabasal keratinocytes.","method":"Genetic sequencing of KRT2 in 26 families with keratinopathic ichthyoses; clinical and histopathological correlation","journal":"Acta Dermato-Venereologica","confidence":"Medium","confidence_rationale":"Tier 3 — genetic variant identification with clinical correlation; mechanistic inference from dominant inheritance pattern without direct in vitro reconstitution","pmids":["26581228"],"is_preprint":false},{"year":2020,"finding":"A somatic missense mutation in KRT2 (p.Asn186Asp) was identified at 25% allelic frequency in lesional skin of a patient with epidermolytic nevus, with very low frequency (1.5%) in blood, establishing that somatic KRT2 mutations are sufficient to cause a mosaic epidermal differentiation disorder and that KRT2 functions in a cell-autonomous, dominant-negative manner in suprabasal keratinocytes.","method":"Molecular genetic testing of DNA from lesional skin and blood; allele frequency quantification confirming somatic origin","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 3 — somatic mutation identification with allele frequency analysis; mechanistic implication by dominant-negative inference, not direct biochemical validation","pmids":["33081034"],"is_preprint":false},{"year":2016,"finding":"KRT2 is expressed in alpaca melanocytes in vivo and in vitro, and transfection of KRT2 into alpaca melanocytes increased expression of the melanogenesis regulators MITF, TYR, and TYRP1, as well as melanin production, suggesting KRT2 participates in a regulatory pathway affecting melanogenesis.","method":"Immunohistochemistry, qPCR, Western blot, and transfection of KRT2 into alpaca melanocytes followed by measurement of melanogenic gene expression and melanin production","journal":"Acta Histochemica","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single transfection experiment in a non-human model without mechanistic pathway placement; no epistasis or binding partner identified","pmids":["27265811"],"is_preprint":false}],"current_model":"KRT2 encodes a type II suprabasal epidermal keratin that assembles into intermediate filaments in differentiating keratinocytes and is covalently incorporated into the cornified cell envelope via transglutaminase-mediated isodipeptide cross-links with loricrin, filaggrin, and involucrin; dominant-negative mutations in KRT2 disrupt this intermediate filament assembly and cause superficial epidermolytic ichthyosis, while somatic mutations produce mosaic epidermal nevus in a cell-autonomous manner."},"narrative":{"teleology":[{"year":1995,"claim":"Identifying KRT2 as a covalent component of the cornified cell envelope answered how the intermediate filament cytoskeleton is physically connected to the barrier structure of terminally differentiated epidermis.","evidence":"Proteinase K digestion of purified human cornified envelopes with peptide sequencing of isodipeptide cross-linked fragments identified KRT2–loricrin and KRT2–filaggrin cross-links","pmids":["7543090"],"confidence":"High","gaps":["Specific cross-link sites on KRT2 itself were not mapped","The transglutaminase isoform(s) responsible for KRT2 cross-linking were not identified","Functional consequence of losing KRT2 cross-links was not tested"]},{"year":1997,"claim":"Demonstrating that involucrin bridges to KRT2 via transglutaminase-mediated bonds expanded the known CE scaffold architecture, establishing involucrin as an early scaffold connecting to the keratin network.","evidence":"Saponification and proteolytic digestion of purified CEs followed by amino acid sequencing identified involucrin Q288 as a cross-link acceptor for keratins including KRT2; immunogold EM confirmed structural localization","pmids":["8999895"],"confidence":"High","gaps":["Whether KRT2 cross-linking to involucrin is required for CE mechanical integrity was not tested","Temporal order of KRT2 cross-linking relative to other CE components was not resolved"]},{"year":2016,"claim":"Identification of pathogenic KRT2 mutations in superficial epidermolytic ichthyosis families established that KRT2 is essential for normal suprabasal keratinocyte differentiation and that its disruption acts through a dominant-negative mechanism on intermediate filament assembly.","evidence":"Genetic sequencing of KRT2 in 26 keratinopathic ichthyosis families with clinical and histopathological correlation","pmids":["26581228"],"confidence":"Medium","gaps":["No in vitro reconstitution of mutant KRT2 filaments to confirm dominant-negative disruption at the biochemical level","Genotype–phenotype correlations across the mutation spectrum remain incomplete","Whether compensatory upregulation of other type II keratins occurs was not assessed"]},{"year":2020,"claim":"Detection of a somatic KRT2 missense mutation in epidermolytic nevus demonstrated that KRT2 dysfunction is cell-autonomous and that mosaicism for KRT2 variants is sufficient for localized disease.","evidence":"Allele frequency quantification of KRT2 p.Asn186Asp in lesional skin (25%) versus blood (1.5%) confirming somatic origin","pmids":["33081034"],"confidence":"Medium","gaps":["No functional assay of the p.Asn186Asp variant on filament assembly","Threshold allele frequency for phenotypic manifestation was not determined","Mechanism by which this specific variant disrupts intermediate filament architecture is unknown"]},{"year":null,"claim":"The precise structural basis of how KRT2 mutations disrupt intermediate filament assembly and the identity of the transglutaminase isoforms mediating KRT2 incorporation into the cornified envelope remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structural model of KRT2-containing intermediate filaments exists","In vitro reconstitution of disease-causing KRT2 mutants into filament assembly assays has not been reported","The functional redundancy between KRT2 and other suprabasal type II keratins (e.g., KRT1) is not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4]}],"complexes":[],"partners":["LOR","FLG","IVL"],"other_free_text":[]},"mechanistic_narrative":"KRT2 is a type II intermediate filament keratin expressed in suprabasal differentiating keratinocytes that serves as a structural component of the epidermal cytoskeleton and the cornified cell envelope. It is covalently incorporated into the cornified envelope through transglutaminase-mediated isodipeptide cross-links with loricrin, filaggrin, and involucrin, thereby anchoring the intermediate filament network to the envelope scaffold [PMID:7543090, PMID:8999895]. Dominant-negative mutations in KRT2 disrupt intermediate filament assembly in suprabasal keratinocytes and cause superficial epidermolytic ichthyosis, while somatic KRT2 mutations produce mosaic epidermolytic nevus in a cell-autonomous manner [PMID:26581228, PMID:33081034]."},"prefetch_data":{"uniprot":{"accession":"P35908","full_name":"Keratin, type II cytoskeletal 2 epidermal","aliases":["Cytokeratin-2e","CK-2e","Epithelial keratin-2e","Keratin-2 epidermis","Keratin-2e","K2e","Type-II keratin Kb2"],"length_aa":639,"mass_kda":65.4,"function":"Probably contributes to terminal cornification (PubMed:1380918). Associated with keratinocyte activation, proliferation and keratinization (PubMed:12598329). Required for maintenance of corneocytes and keratin filaments in suprabasal keratinocytes in the epidermis of the ear, potentially via moderation of expression and localization of keratins and their partner proteins (By similarity). Plays a role in the establishment of the epidermal barrier on plantar skin (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P35908/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KRT2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KRT2","total_profiled":1310},"omim":[{"mim_id":"618084","title":"PEELING SKIN SYNDROME 6; PSS6","url":"https://www.omim.org/entry/618084"},{"mim_id":"609165","title":"ICHTHYOSIS WITH CONFETTI; IWC","url":"https://www.omim.org/entry/609165"},{"mim_id":"607936","title":"PEELING SKIN SYNDROME 4; PSS4","url":"https://www.omim.org/entry/607936"},{"mim_id":"607602","title":"ICHTHYOSIS, ANNULAR EPIDERMOLYTIC, 1; AEI1","url":"https://www.omim.org/entry/607602"},{"mim_id":"600194","title":"KERATIN 2, TYPE II; KRT2","url":"https://www.omim.org/entry/600194"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 1","ntpm":4421.9}],"url":"https://www.proteinatlas.org/search/KRT2"},"hgnc":{"alias_symbol":["KRTE"],"prev_symbol":["KRT2A"]},"alphafold":{"accession":"P35908","domains":[{"cath_id":"1.20.5","chopping":"345-440","consensus_level":"medium","plddt":91.3427,"start":345,"end":440}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35908","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35908-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35908-F1-predicted_aligned_error_v6.png","plddt_mean":63.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRT2","jax_strain_url":"https://www.jax.org/strain/search?query=KRT2"},"sequence":{"accession":"P35908","fasta_url":"https://rest.uniprot.org/uniprotkb/P35908.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35908/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35908"}},"corpus_meta":[{"pmid":"26581228","id":"PMC_26581228","title":"Expanding the Clinical and Genetic 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at N140 and substitution mutations (A431D, L424W) in these conserved positions disrupt hair formation, indicating this domain is critical for keratin intermediate filament function in hair follicles.\",\n      \"method\": \"Positional cloning, mutation analysis across multiple alleles (Ca^J, Ca^9J, Ca^10J, Ca^Rin, Ca^medJ), ENU mutagenesis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — positional cloning with multiple independent alleles converging on same hotspot; no in vitro reconstitution\",\n      \"pmids\": [\"14573483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Missense mutations in the helix initiation motif of Krt71 (formerly Krt2-6g, mouse KRT2 family member) at residues 143 (A→G) and 146 (I→F) cause formation of filamentous aggregates in Henle's and Huxley's layers of the inner root sheath (IRS) of the hair follicle, demonstrating that the helix initiation motif is essential for formation of linear IRS intermediate filaments and proper hair shaft morphology.\",\n      \"method\": \"ENU mutagenesis screen, morphological analysis of hair follicle ultrastructure, molecular mapping of mutations\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent alleles with identical cellular phenotype (filamentous aggregates); no in vitro reconstitution\",\n      \"pmids\": [\"17143583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutations in KRT2 (encoding keratin 2, a suprabasal epidermal keratin) cause superficial epidermolytic ichthyosis, establishing KRT2 as required for normal suprabasal epidermal differentiation and integrity; loss-of-function or dominant-negative mutations lead to epidermolytic hyperkeratosis.\",\n      \"method\": \"Genetic sequencing of patients with keratinopathic ichthyosis, identification of novel pathogenic KRT2 variants\",\n      \"journal\": \"Acta dermato-venereologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple independent patient mutations establish causality; no in vitro mechanistic assay\",\n      \"pmids\": [\"26581228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A somatic missense mutation (p.Asn186Asp) in KRT2 detected in lesional skin (25% allelic frequency) but only minimally in blood (1.5%) causes epidermolytic nevus, demonstrating that KRT2 mutations act in a cell-autonomous manner in suprabasal keratinocytes to disrupt epidermal structure.\",\n      \"method\": \"Molecular genetic testing of lesional skin vs. blood DNA, allelic frequency quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — somatic mosaicism analysis provides cell-autonomous localization of function; single case with molecular quantification\",\n      \"pmids\": [\"33081034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRT2 overexpression in alpaca melanocytes upregulates MITF, tyrosinase (TYR), and TYRP1 expression and increases melanin production, indicating KRT2 plays a functional role in melanogenesis regulation within melanocytes.\",\n      \"method\": \"Transfection of KRT2 into alpaca melanocytes, qPCR, Western blot, melanin quantification\",\n      \"journal\": \"Acta histochemica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single species (alpaca), overexpression without pathway mechanistic detail; no reciprocal or loss-of-function validation\",\n      \"pmids\": [\"27265811\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT2 encodes a type II suprabasal epidermal keratin whose conserved alpha-helical rod domain and helix initiation motif are essential for the formation of linear intermediate filaments in differentiating keratinocytes; dominant or somatic mutations in KRT2 disrupt this filament network in a cell-autonomous fashion, causing epidermolytic hyperkeratosis and superficial epidermolytic ichthyosis, while overexpression studies suggest an additional modulatory role in melanogenesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:26581228 — KRT2 mutations in keratinopathic ichthyosis → KEEP\n2. PMID:14573483 — mK6irs1/Krt2-6g (mouse Krt71, not KRT2) → EXCLUDE (symbol collision; Krt2-6g is an old alias for Krt71, not the canonical KRT2)\n3. PMID:17143583 — Krt71 (formerly Krt2-6g) → EXCLUDE (same as above)\n4. PMID:33081034 — KRT2 somatic mutation in epidermolytic nevus → KEEP\n5. PMID:27265811 — KRT2 in alpaca melanogenesis → KEEP (but largely expression/functional correlation; check for mechanism)\n6. PMID:1379621 — Genetic linkage of Krt-2 mouse locus → EXCLUDE (linkage mapping only, no mechanistic finding about KRT2 protein)\n7. PMID:35887135 — SEI due to KRT2 mutation p.Glu487Lys → KEEP (clinical/genetic, minimal mechanism)\n8. PMID:33555633 — Epidermolytic epidermal nevus due to somatic KRT2 mutation → KEEP (clinical)\n9. PMID:22435621 — KRT2.13 sheep wool gene → EXCLUDE (symbol collision; KRT2.13 is a wool keratin, not human KRT2)\n10. PMID:39619568 — ABHD1 regulates KRT1 and KRT2 in DR → KEEP (mechanistic context)\n11. PMID:39761764 — KRT2 in sheep horn → EXCLUDE (non-human, largely computational/expression)\n\nGene2pubmed curated papers:\n- PMID:7543090 — Steinert & Marekov 1995: keratin IF cross-linked into cornified cell envelope → KEEP (mentions keratin 2e directly)\n- PMID:8999895 — Steinert & Marekov 1997: involucrin cross-linked to keratins in CE → KEEP\n- PMID:16831889 — New consensus keratin nomenclature → KEEP (nomenclature, minimal mechanism)\n- All others (interactome maps, VIRMA m6A, Bcr-Abl, 14-3-3sigma, etc.) → EXCLUDE (off-target, no KRT2 mechanistic content)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"Keratin 2e (KRT2) is covalently cross-linked via transglutaminase-induced isodipeptide bonds into the cornified cell envelope (CE) of human epidermis. Proteinase K digestion and peptide sequencing of purified CEs demonstrated that KRT2 (keratin 2e) forms cross-links with loricrin and filaggrin, placing KRT2 as a structural component anchoring the subjacent intermediate filament network to the CE scaffold.\",\n      \"method\": \"Proteinase K digestion of purified cornified cell envelopes from human foreskin epidermis followed by peptide sequencing of isodipeptide cross-linked fragments\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical reconstitution with peptide sequencing identifying specific cross-link sites; strong evidence from rigorous in vitro analysis\",\n      \"pmids\": [\"7543090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KRT2 (keratin 2e) is cross-linked to involucrin in the cornified cell envelope via transglutaminase-mediated isopeptide bonds. Amino acid sequencing of peptides released from saponified CEs identified specific glutamine residues in involucrin (Q288) that form cross-links to keratins including KRT2, demonstrating that involucrin serves as an early scaffold protein bridging to the keratin intermediate filament network.\",\n      \"method\": \"Saponification of purified cornified cell envelopes, proteolytic digestion, and amino acid sequencing of cross-linked peptides; immunogold electron microscopy\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical isolation and sequencing of cross-linked peptides with structural localization, strong orthogonal validation\",\n      \"pmids\": [\"8999895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"KRT2 (previously called keratin 2e) was formally renamed under the new consensus mammalian keratin nomenclature. KRT2 is confirmed as a type II keratin expressed in suprabasal epidermis, forming part of the intermediate filament cytoskeleton in differentiating keratinocytes.\",\n      \"method\": \"Systematic genomic and proteomic analysis of the human keratin gene family with nomenclature revision\",\n      \"journal\": \"The Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — nomenclature/classification paper; provides framework but limited direct mechanistic experimentation\",\n      \"pmids\": [\"16831889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutations in KRT2 cause superficial epidermolytic ichthyosis (SEI), an autosomal dominant keratinopathic ichthyosis. Novel pathogenic variants in KRT2 were identified, expanding the known mutation spectrum and establishing that KRT2 mutations disrupt epidermal differentiation in a dominant-negative manner consistent with disruption of intermediate filament assembly in suprabasal keratinocytes.\",\n      \"method\": \"Genetic sequencing of KRT2 in 26 families with keratinopathic ichthyoses; clinical and histopathological correlation\",\n      \"journal\": \"Acta Dermato-Venereologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — genetic variant identification with clinical correlation; mechanistic inference from dominant inheritance pattern without direct in vitro reconstitution\",\n      \"pmids\": [\"26581228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A somatic missense mutation in KRT2 (p.Asn186Asp) was identified at 25% allelic frequency in lesional skin of a patient with epidermolytic nevus, with very low frequency (1.5%) in blood, establishing that somatic KRT2 mutations are sufficient to cause a mosaic epidermal differentiation disorder and that KRT2 functions in a cell-autonomous, dominant-negative manner in suprabasal keratinocytes.\",\n      \"method\": \"Molecular genetic testing of DNA from lesional skin and blood; allele frequency quantification confirming somatic origin\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — somatic mutation identification with allele frequency analysis; mechanistic implication by dominant-negative inference, not direct biochemical validation\",\n      \"pmids\": [\"33081034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KRT2 is expressed in alpaca melanocytes in vivo and in vitro, and transfection of KRT2 into alpaca melanocytes increased expression of the melanogenesis regulators MITF, TYR, and TYRP1, as well as melanin production, suggesting KRT2 participates in a regulatory pathway affecting melanogenesis.\",\n      \"method\": \"Immunohistochemistry, qPCR, Western blot, and transfection of KRT2 into alpaca melanocytes followed by measurement of melanogenic gene expression and melanin production\",\n      \"journal\": \"Acta Histochemica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single transfection experiment in a non-human model without mechanistic pathway placement; no epistasis or binding partner identified\",\n      \"pmids\": [\"27265811\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRT2 encodes a type II suprabasal epidermal keratin that assembles into intermediate filaments in differentiating keratinocytes and is covalently incorporated into the cornified cell envelope via transglutaminase-mediated isodipeptide cross-links with loricrin, filaggrin, and involucrin; dominant-negative mutations in KRT2 disrupt this intermediate filament assembly and cause superficial epidermolytic ichthyosis, while somatic mutations produce mosaic epidermal nevus in a cell-autonomous manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KRT2 encodes a type II intermediate filament keratin expressed in suprabasal epidermal keratinocytes, where it is essential for maintaining epidermal structural integrity during terminal differentiation. Mutations in the conserved alpha-helical rod domain and helix initiation motif disrupt the assembly of linear intermediate filaments, leading to filamentous aggregates and epidermolysis [PMID:14573483, PMID:17143583]. Dominant and somatic missense mutations in KRT2 cause superficial epidermolytic ichthyosis (epidermolytic hyperkeratosis) in a cell-autonomous manner in suprabasal keratinocytes [PMID:26581228, PMID:33081034].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Positional cloning of multiple independent mouse alleles revealed that the alpha-helical rod domain (1A and 2B subdomains) of the KRT2 family member Krt2-6g harbors a mutation hotspot critical for keratin intermediate filament function, establishing the structural basis of filament assembly for this keratin subfamily.\",\n      \"evidence\": \"Positional cloning and mutation analysis across five ENU-induced alleles in mouse\",\n      \"pmids\": [\"14573483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro filament reconstitution to demonstrate direct assembly defect\",\n        \"Mouse Krt2-6g is a hair follicle keratin; relevance to human epidermal KRT2 inferred by homology\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Two additional independent alleles pinpointed the helix initiation motif as essential for linear intermediate filament formation, showing that mutations at this site convert filaments into aggregates in the inner root sheath, refining the domain-level requirements for filament polymerization.\",\n      \"evidence\": \"ENU mutagenesis screen with ultrastructural analysis of hair follicle inner root sheath in mouse\",\n      \"pmids\": [\"17143583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Filament aggregation observed morphologically; biochemical mechanism of assembly failure not characterized\",\n        \"Function in epidermal (non-follicular) keratinocytes not addressed\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of pathogenic KRT2 variants in patients with keratinopathic ichthyosis established that human KRT2 is required for suprabasal epidermal differentiation and that its disruption causes superficial epidermolytic ichthyosis, linking the mouse structural studies to a defined human Mendelian disease.\",\n      \"evidence\": \"Genetic sequencing of keratinopathic ichthyosis patients identifying novel KRT2 variants\",\n      \"pmids\": [\"26581228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro or cell-based functional assays to characterize individual variant effects on filament network\",\n        \"Genotype-phenotype correlation across the rod domain not systematically established\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Detection of a somatic KRT2 missense mutation enriched in lesional epidermis but nearly absent in blood demonstrated that KRT2 acts cell-autonomously in suprabasal keratinocytes, ruling out non-cell-autonomous contributions to the epidermolytic phenotype.\",\n      \"evidence\": \"Allelic frequency quantification of p.Asn186Asp in lesional skin vs. blood DNA from an epidermolytic nevus patient\",\n      \"pmids\": [\"33081034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case report; broader somatic mutation spectrum not surveyed\",\n        \"Mechanism by which this specific substitution disrupts filament assembly not determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the biochemical mechanism by which specific rod-domain mutations prevent linear filament polymerization, the structural basis of KRT2 heterodimer and filament assembly at atomic resolution, and whether KRT2 has non-structural signaling roles in keratinocytes beyond overexpression-based observations in melanocytes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No in vitro reconstitution or structural model of KRT2 filament assembly\",\n        \"Overexpression-based melanogenesis role lacks loss-of-function validation and pathway mechanism\",\n        \"No systematic mutagenesis mapping critical residues across the full rod domain\"\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\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"KRT2 is a type II intermediate filament keratin expressed in suprabasal differentiating keratinocytes that serves as a structural component of the epidermal cytoskeleton and the cornified cell envelope. It is covalently incorporated into the cornified envelope through transglutaminase-mediated isodipeptide cross-links with loricrin, filaggrin, and involucrin, thereby anchoring the intermediate filament network to the envelope scaffold [PMID:7543090, PMID:8999895]. Dominant-negative mutations in KRT2 disrupt intermediate filament assembly in suprabasal keratinocytes and cause superficial epidermolytic ichthyosis, while somatic KRT2 mutations produce mosaic epidermolytic nevus in a cell-autonomous manner [PMID:26581228, PMID:33081034].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identifying KRT2 as a covalent component of the cornified cell envelope answered how the intermediate filament cytoskeleton is physically connected to the barrier structure of terminally differentiated epidermis.\",\n      \"evidence\": \"Proteinase K digestion of purified human cornified envelopes with peptide sequencing of isodipeptide cross-linked fragments identified KRT2–loricrin and KRT2–filaggrin cross-links\",\n      \"pmids\": [\"7543090\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific cross-link sites on KRT2 itself were not mapped\",\n        \"The transglutaminase isoform(s) responsible for KRT2 cross-linking were not identified\",\n        \"Functional consequence of losing KRT2 cross-links was not tested\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that involucrin bridges to KRT2 via transglutaminase-mediated bonds expanded the known CE scaffold architecture, establishing involucrin as an early scaffold connecting to the keratin network.\",\n      \"evidence\": \"Saponification and proteolytic digestion of purified CEs followed by amino acid sequencing identified involucrin Q288 as a cross-link acceptor for keratins including KRT2; immunogold EM confirmed structural localization\",\n      \"pmids\": [\"8999895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether KRT2 cross-linking to involucrin is required for CE mechanical integrity was not tested\",\n        \"Temporal order of KRT2 cross-linking relative to other CE components was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of pathogenic KRT2 mutations in superficial epidermolytic ichthyosis families established that KRT2 is essential for normal suprabasal keratinocyte differentiation and that its disruption acts through a dominant-negative mechanism on intermediate filament assembly.\",\n      \"evidence\": \"Genetic sequencing of KRT2 in 26 keratinopathic ichthyosis families with clinical and histopathological correlation\",\n      \"pmids\": [\"26581228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of mutant KRT2 filaments to confirm dominant-negative disruption at the biochemical level\",\n        \"Genotype–phenotype correlations across the mutation spectrum remain incomplete\",\n        \"Whether compensatory upregulation of other type II keratins occurs was not assessed\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Detection of a somatic KRT2 missense mutation in epidermolytic nevus demonstrated that KRT2 dysfunction is cell-autonomous and that mosaicism for KRT2 variants is sufficient for localized disease.\",\n      \"evidence\": \"Allele frequency quantification of KRT2 p.Asn186Asp in lesional skin (25%) versus blood (1.5%) confirming somatic origin\",\n      \"pmids\": [\"33081034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay of the p.Asn186Asp variant on filament assembly\",\n        \"Threshold allele frequency for phenotypic manifestation was not determined\",\n        \"Mechanism by which this specific variant disrupts intermediate filament architecture is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise structural basis of how KRT2 mutations disrupt intermediate filament assembly and the identity of the transglutaminase isoforms mediating KRT2 incorporation into the cornified envelope remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structural model of KRT2-containing intermediate filaments exists\",\n        \"In vitro reconstitution of disease-causing KRT2 mutants into filament assembly assays has not been reported\",\n        \"The functional redundancy between KRT2 and other suprabasal type II keratins (e.g., KRT1) is not defined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LOR\",\n      \"FLG\",\n      \"IVL\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}