{"gene":"SNRNP40","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1998,"finding":"SNRNP40 (WDR57/p40) was identified as a component of the human spliceosome complex through mass spectrometry and EST-database searching of purified spliceosomal particles.","method":"Nanoelectrospray mass spectrometry of purified spliceosome fractions separated by 2D gel electrophoresis","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical purification of intact spliceosome with MS identification, foundational proteomics study","pmids":["9731529"],"is_preprint":false},{"year":2002,"finding":"SNRNP40 was confirmed as a component of functional human spliceosomes, specifically detected in purified C complex spliceosomal particles containing U2, U5, and U6 snRNAs.","method":"Affinity purification of native spliceosomes followed by tandem mass spectrometry","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 — native complex purification with MS confirmation, replicated identification","pmids":["11991638"],"is_preprint":false},{"year":2002,"finding":"SNRNP40 was catalogued as a component of the human spliceosome in a comprehensive proteomic analysis identifying ~145 distinct spliceosomal proteins, confirming its role as a core snRNP-associated protein.","method":"Maltose-binding protein affinity chromatography purification of spliceosomes followed by nanoscale LC-MS/MS","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — comprehensive spliceosome proteomics with rigorous purification, replicated across labs","pmids":["12226669"],"is_preprint":false},{"year":2017,"finding":"SNRNP40 was structurally localized within the human C* spliceosome (activated for step 2 of splicing) by cryo-EM, placing it as part of the U5 snRNP component of the catalytic spliceosome.","method":"Cryo-electron microscopy of human spliceosomal C* complex at near-atomic resolution","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structural determination of intact spliceosome complex","pmids":["28076346"],"is_preprint":false},{"year":2019,"finding":"SNRNP40 is an essential subunit of the U5 snRNP complex of the spliceosome; hypomorphic loss-of-function mutation in mice causes increased splicing errors (predominantly intron retention) in hundreds of mRNAs in hematopoietic stem cells, T cells, and EL4 cells, leading to altered expression of immune-function proteins and a syndromic immunodeficiency phenotype including hypersusceptibility to murine cytomegalovirus and defects in lymphoid development.","method":"Viable hypomorphic mouse mutant; RNA-seq of primary hematopoietic stem cells and T cells; quantitative proteomics of mutant cells","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo KO/hypomorph with defined cellular phenotype plus transcriptome-wide splicing analysis and orthogonal proteomics","pmids":["31427773"],"is_preprint":false},{"year":2016,"finding":"Engineered variable (low) expression of SNRNP40 in breast cancer cells promotes metastatic colonization, identifying SNRNP40 as a spliceosomal gene whose reduced expression confers increased metastatic fitness.","method":"Engineered variable expression in human breast cancer cell lines; in vivo metastasis assays; single-cell RNA-sequencing","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct manipulation (engineered expression) with in vivo phenotypic readout, single lab","pmids":["27138336"],"is_preprint":false}],"current_model":"SNRNP40 is an essential subunit of the U5 small nuclear ribonucleoprotein (snRNP) complex within the spliceosome, where it participates in catalytic pre-mRNA splicing; loss of SNRNP40 function increases splicing errors (predominantly intron retention) across hundreds of mRNAs, with particularly severe consequences in lymphoid cells, causing a syndromic immunodeficiency, and reduced SNRNP40 expression also promotes cancer metastasis."},"narrative":{"teleology":[{"year":1998,"claim":"The composition of the human spliceosome was unknown at the single-protein level; mass spectrometry of purified spliceosomal particles identified SNRNP40 (WDR57/p40) as a spliceosome component, establishing it as a bona fide splicing factor.","evidence":"Nanoelectrospray MS of 2D-gel-separated spliceosome fractions","pmids":["9731529"],"confidence":"High","gaps":["Specific snRNP sub-complex assignment not determined","No functional data on requirement for splicing"]},{"year":2002,"claim":"Whether SNRNP40 was associated with a specific spliceosomal state was unclear; its detection in purified C complex particles and in comprehensive spliceosome proteomes confirmed it as a core snRNP-associated protein present during catalytic stages of splicing.","evidence":"Affinity purification of native C complex spliceosomes followed by LC-MS/MS, replicated across two independent studies","pmids":["11991638","12226669"],"confidence":"High","gaps":["Precise structural position within the spliceosome not resolved","Whether SNRNP40 is required for catalysis or is structural was unknown"]},{"year":2016,"claim":"Whether spliceosomal gene dosage affects cancer biology was poorly explored; engineered reduction of SNRNP40 expression in breast cancer cells promoted metastatic colonization in vivo, revealing that partial spliceosome impairment can confer metastatic fitness.","evidence":"Engineered variable expression in human breast cancer cell lines with in vivo metastasis assays and single-cell RNA-seq","pmids":["27138336"],"confidence":"Medium","gaps":["Specific mis-spliced transcripts driving metastasis not fully delineated","Not independently replicated in a second cancer type","Mechanism linking partial splicing deficiency to metastatic advantage not resolved"]},{"year":2017,"claim":"The molecular architecture of SNRNP40 within the spliceosome was unknown; cryo-EM of the human C* complex placed SNRNP40 as a U5 snRNP component within the catalytic spliceosome at near-atomic resolution.","evidence":"Cryo-electron microscopy of the human spliceosomal C* complex","pmids":["28076346"],"confidence":"High","gaps":["Contact interfaces with neighboring subunits not fully characterized","Structural role versus catalytic contribution not distinguished"]},{"year":2019,"claim":"Whether SNRNP40 is functionally essential in vivo and which cell types are most vulnerable to its loss was unknown; a hypomorphic mouse mutant demonstrated that reduced SNRNP40 causes widespread intron retention, disrupts immune-protein expression, and produces syndromic immunodeficiency with impaired lymphoid development.","evidence":"Viable hypomorphic mouse mutant with RNA-seq of hematopoietic stem cells and T cells plus quantitative proteomics","pmids":["31427773"],"confidence":"High","gaps":["Why lymphoid cells are preferentially sensitive to SNRNP40 reduction is not mechanistically explained","Whether complete loss is embryonic lethal was not tested","Specific intron-retention events causally driving immunodeficiency not individually validated"]},{"year":null,"claim":"The structural basis for SNRNP40's contribution to spliceosome catalysis, the mechanism underlying cell-type-selective vulnerability to its reduction, and the specific mis-spliced transcripts that drive both immunodeficiency and metastasis remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical reconstitution of SNRNP40's catalytic contribution","Tissue-selective sensitivity mechanism unknown","No therapeutic targeting studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5]}],"complexes":["U5 snRNP","Spliceosomal C complex","Spliceosomal C* complex"],"partners":[],"other_free_text":[]},"mechanistic_narrative":"SNRNP40 is a core subunit of the U5 small nuclear ribonucleoprotein (snRNP) that functions within the spliceosome to catalyze pre-mRNA splicing. Initially identified by mass spectrometry of purified spliceosomal particles [PMID:9731529], SNRNP40 was confirmed in the catalytic C complex containing U2, U5, and U6 snRNAs [PMID:11991638] and structurally resolved within the human C* spliceosome by cryo-EM [PMID:28076346]. Hypomorphic loss of SNRNP40 in mice causes widespread intron retention across hundreds of transcripts, disrupting expression of immune-function proteins and producing a syndromic immunodeficiency with impaired lymphoid development and susceptibility to viral infection [PMID:31427773]. Reduced SNRNP40 expression in breast cancer cells promotes metastatic colonization, linking spliceosome integrity to metastatic fitness [PMID:27138336]."},"prefetch_data":{"uniprot":{"accession":"Q96DI7","full_name":"U5 small nuclear ribonucleoprotein 40 kDa protein","aliases":["38 kDa-splicing factor","Prp8-binding protein","hPRP8BP","U5 snRNP-specific 40 kDa protein","WD repeat-containing protein 57"],"length_aa":357,"mass_kda":39.3,"function":"Required for pre-mRNA splicing as component of the activated spliceosome (PubMed:11991638, PubMed:28076346, PubMed:28502770, PubMed:28781166, PubMed:29301961, PubMed:29360106, PubMed:30315277, PubMed:30705154). Component of the U5 small nuclear ribonucleoprotein (snRNP) complex and the U4/U6-U5 tri-snRNP complex, building blocks of the spliceosome (PubMed:16723661, PubMed:26912367, PubMed:9774689). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (Probable)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96DI7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRNP40","classification":"Common Essential","n_dependent_lines":1095,"n_total_lines":1208,"dependency_fraction":0.9064569536423841},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000060688","cell_line_id":"CID001463","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"PRPF8","stoichiometry":10.0},{"gene":"SNRNP200","stoichiometry":10.0},{"gene":"EFTUD2","stoichiometry":10.0},{"gene":"SNRPD2","stoichiometry":10.0},{"gene":"SF3A2","stoichiometry":4.0},{"gene":"PRPF6","stoichiometry":4.0},{"gene":"SART1","stoichiometry":4.0},{"gene":"PRPF4","stoichiometry":4.0},{"gene":"USP39","stoichiometry":4.0},{"gene":"DDX23","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001463","total_profiled":1310},"omim":[{"mim_id":"617470","title":"UBIQUITIN-SPECIFIC PEPTIDASE-LIKE 1; USPL1","url":"https://www.omim.org/entry/617470"},{"mim_id":"613979","title":"PRE-mRNA-PROCESSING FACTOR 6; PRPF6","url":"https://www.omim.org/entry/613979"},{"mim_id":"607797","title":"SMALL NUCLEAR RIBONUCLEOPROTEIN, 40-KD; SNRNP40","url":"https://www.omim.org/entry/607797"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRNP40"},"hgnc":{"alias_symbol":["PRP8BP","SPF38","PRPF8BP","HPRP8BP"],"prev_symbol":["WDR57"]},"alphafold":{"accession":"Q96DI7","domains":[{"cath_id":"2.130.10.10","chopping":"58-354","consensus_level":"medium","plddt":93.3829,"start":58,"end":354}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DI7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DI7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96DI7-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRNP40","jax_strain_url":"https://www.jax.org/strain/search?query=SNRNP40"},"sequence":{"accession":"Q96DI7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96DI7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96DI7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96DI7"}},"corpus_meta":[{"pmid":"27138336","id":"PMC_27138336","title":"Highly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27138336","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33584830","id":"PMC_33584830","title":"The Role of the U5 snRNP in Genetic Disorders and Cancer.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33584830","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32114312","id":"PMC_32114312","title":"Analysis of testis metabolome and transcriptome from the oriental river prawn (Macrobrachium nipponense) in response to different temperatures and illumination times.","date":"2020","source":"Comparative biochemistry and physiology. 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causes increased splicing errors (predominantly intron retention) in several hundred mRNAs in hematopoietic stem cells and T cells, leading to altered expression of proteins associated with immune cell function and a syndromic immunodeficiency phenotype.\",\n      \"method\": \"Hypomorphic mouse mutant (ENU screen), RNA-seq splicing analysis, hematopoietic stem cell and T cell functional assays, bone marrow transplantation (cell-intrinsic defect demonstration)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO/hypomorph with defined cellular phenotype, multiple orthogonal methods (genetics, transcriptomics, cell biology), replicated across multiple cell types\",\n      \"pmids\": [\"31427773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Variable (low) expression of SNRNP40, a spliceosomal gene, promotes breast cancer metastasis; engineered low expression of SNRNP40 increases metastatic colonization, placing SNRNP40 as a functionally relevant spliceosomal component whose expression level affects cancer cell fitness.\",\n      \"method\": \"Engineered variable expression (lentiviral), in vivo metastasis assays, single-cell RNA-sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo functional assay with engineered expression, but mechanistic pathway not fully delineated\",\n      \"pmids\": [\"27138336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNRNP40 is a component of the U5 snRNP within the spliceosome; somatic mutations or altered expression of SNRNP40 are associated with human cancers, consistent with its role in pre-mRNA splicing as part of the U5 snRNP complex.\",\n      \"method\": \"Literature review synthesizing genetic and functional data on U5 snRNP proteins\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review synthesizing published functional data, no new primary experiment\",\n      \"pmids\": [\"33584830\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRNP40 is an essential subunit of the U5 snRNP complex of the spliceosome that is required for accurate pre-mRNA splicing; its deficiency causes widespread intron retention in hundreds of mRNAs, leading to altered protein expression and, in vivo, a cell-intrinsic syndromic immunodeficiency in mice, while variable low expression in cancer cells promotes metastatic colonization.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SNRNP40 (WDR57/p40) was identified as a component of the human spliceosome complex through mass spectrometry and EST-database searching of purified spliceosomal particles.\",\n      \"method\": \"Nanoelectrospray mass spectrometry of purified spliceosome fractions separated by 2D gel electrophoresis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical purification of intact spliceosome with MS identification, foundational proteomics study\",\n      \"pmids\": [\"9731529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SNRNP40 was confirmed as a component of functional human spliceosomes, specifically detected in purified C complex spliceosomal particles containing U2, U5, and U6 snRNAs.\",\n      \"method\": \"Affinity purification of native spliceosomes followed by tandem mass spectrometry\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — native complex purification with MS confirmation, replicated identification\",\n      \"pmids\": [\"11991638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SNRNP40 was catalogued as a component of the human spliceosome in a comprehensive proteomic analysis identifying ~145 distinct spliceosomal proteins, confirming its role as a core snRNP-associated protein.\",\n      \"method\": \"Maltose-binding protein affinity chromatography purification of spliceosomes followed by nanoscale LC-MS/MS\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — comprehensive spliceosome proteomics with rigorous purification, replicated across labs\",\n      \"pmids\": [\"12226669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNRNP40 was structurally localized within the human C* spliceosome (activated for step 2 of splicing) by cryo-EM, placing it as part of the U5 snRNP component of the catalytic spliceosome.\",\n      \"method\": \"Cryo-electron microscopy of human spliceosomal C* complex at near-atomic resolution\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structural determination of intact spliceosome complex\",\n      \"pmids\": [\"28076346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNRNP40 is an essential subunit of the U5 snRNP complex of the spliceosome; hypomorphic loss-of-function mutation in mice causes increased splicing errors (predominantly intron retention) in hundreds of mRNAs in hematopoietic stem cells, T cells, and EL4 cells, leading to altered expression of immune-function proteins and a syndromic immunodeficiency phenotype including hypersusceptibility to murine cytomegalovirus and defects in lymphoid development.\",\n      \"method\": \"Viable hypomorphic mouse mutant; RNA-seq of primary hematopoietic stem cells and T cells; quantitative proteomics of mutant cells\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo KO/hypomorph with defined cellular phenotype plus transcriptome-wide splicing analysis and orthogonal proteomics\",\n      \"pmids\": [\"31427773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Engineered variable (low) expression of SNRNP40 in breast cancer cells promotes metastatic colonization, identifying SNRNP40 as a spliceosomal gene whose reduced expression confers increased metastatic fitness.\",\n      \"method\": \"Engineered variable expression in human breast cancer cell lines; in vivo metastasis assays; single-cell RNA-sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct manipulation (engineered expression) with in vivo phenotypic readout, single lab\",\n      \"pmids\": [\"27138336\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRNP40 is an essential subunit of the U5 small nuclear ribonucleoprotein (snRNP) complex within the spliceosome, where it participates in catalytic pre-mRNA splicing; loss of SNRNP40 function increases splicing errors (predominantly intron retention) across hundreds of mRNAs, with particularly severe consequences in lymphoid cells, causing a syndromic immunodeficiency, and reduced SNRNP40 expression also promotes cancer metastasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNRNP40 is a structural subunit of the U5 small nuclear ribonucleoprotein (snRNP) complex of the spliceosome, required for accurate pre-mRNA splicing. Hypomorphic loss-of-function in mice causes widespread intron retention across hundreds of mRNAs in hematopoietic stem cells and T cells, leading to altered expression of immune-associated proteins and a cell-intrinsic syndromic immunodeficiency [PMID:31427773]. Engineered low expression of SNRNP40 in breast cancer cells promotes metastatic colonization in vivo, indicating that graded reduction in spliceosomal capacity can be co-opted for malignant fitness [PMID:27138336].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"It was unknown whether subtle variation in expression of core spliceosomal components could influence cancer phenotypes; engineered low SNRNP40 expression was shown to enhance breast cancer metastatic colonization, establishing that suboptimal spliceosome dosage can be functionally selected in tumors.\",\n      \"evidence\": \"Lentiviral variable-expression system with in vivo metastasis assays and single-cell RNA-seq in breast cancer models\",\n      \"pmids\": [\"27138336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific splicing targets mediating metastatic advantage not identified\",\n        \"Whether the metastasis effect is U5-specific or reflects general spliceosome insufficiency is unknown\",\n        \"No mechanistic link to particular signaling or adhesion pathways was established\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The in vivo requirement of SNRNP40 for splicing fidelity and immune cell development was unknown; a hypomorphic mouse mutant revealed that reduced SNRNP40 function causes intron retention in hundreds of transcripts in hematopoietic cells, producing a syndromic immunodeficiency that is cell-intrinsic.\",\n      \"evidence\": \"ENU-derived hypomorphic mouse mutant, RNA-seq splicing analysis in HSCs and T cells, bone marrow transplantation demonstrating cell-intrinsic defect\",\n      \"pmids\": [\"31427773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which specific mis-spliced transcripts are causally responsible for the immune phenotype is not resolved\",\n        \"Whether complete loss of SNRNP40 is cell-lethal has not been tested\",\n        \"Structural basis for how SNRNP40 contributes to U5 snRNP catalytic function is uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular contacts of SNRNP40 within the U5 snRNP, its mechanism of substrate RNA recognition, and the specific mis-spliced transcripts that causally drive the immunodeficiency and metastasis phenotypes remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structural data defining SNRNP40's position or contacts within the U5 snRNP\",\n        \"No identification of causal mis-spliced targets in either the immune or cancer context\",\n        \"No human Mendelian disease formally linked to SNRNP40 mutations\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"U5 snRNP\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"SNRNP40 is a core subunit of the U5 small nuclear ribonucleoprotein (snRNP) that functions within the spliceosome to catalyze pre-mRNA splicing. Initially identified by mass spectrometry of purified spliceosomal particles [PMID:9731529], SNRNP40 was confirmed in the catalytic C complex containing U2, U5, and U6 snRNAs [PMID:11991638] and structurally resolved within the human C* spliceosome by cryo-EM [PMID:28076346]. Hypomorphic loss of SNRNP40 in mice causes widespread intron retention across hundreds of transcripts, disrupting expression of immune-function proteins and producing a syndromic immunodeficiency with impaired lymphoid development and susceptibility to viral infection [PMID:31427773]. Reduced SNRNP40 expression in breast cancer cells promotes metastatic colonization, linking spliceosome integrity to metastatic fitness [PMID:27138336].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The composition of the human spliceosome was unknown at the single-protein level; mass spectrometry of purified spliceosomal particles identified SNRNP40 (WDR57/p40) as a spliceosome component, establishing it as a bona fide splicing factor.\",\n      \"evidence\": \"Nanoelectrospray MS of 2D-gel-separated spliceosome fractions\",\n      \"pmids\": [\"9731529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific snRNP sub-complex assignment not determined\", \"No functional data on requirement for splicing\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Whether SNRNP40 was associated with a specific spliceosomal state was unclear; its detection in purified C complex particles and in comprehensive spliceosome proteomes confirmed it as a core snRNP-associated protein present during catalytic stages of splicing.\",\n      \"evidence\": \"Affinity purification of native C complex spliceosomes followed by LC-MS/MS, replicated across two independent studies\",\n      \"pmids\": [\"11991638\", \"12226669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise structural position within the spliceosome not resolved\", \"Whether SNRNP40 is required for catalysis or is structural was unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether spliceosomal gene dosage affects cancer biology was poorly explored; engineered reduction of SNRNP40 expression in breast cancer cells promoted metastatic colonization in vivo, revealing that partial spliceosome impairment can confer metastatic fitness.\",\n      \"evidence\": \"Engineered variable expression in human breast cancer cell lines with in vivo metastasis assays and single-cell RNA-seq\",\n      \"pmids\": [\"27138336\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific mis-spliced transcripts driving metastasis not fully delineated\", \"Not independently replicated in a second cancer type\", \"Mechanism linking partial splicing deficiency to metastatic advantage not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The molecular architecture of SNRNP40 within the spliceosome was unknown; cryo-EM of the human C* complex placed SNRNP40 as a U5 snRNP component within the catalytic spliceosome at near-atomic resolution.\",\n      \"evidence\": \"Cryo-electron microscopy of the human spliceosomal C* complex\",\n      \"pmids\": [\"28076346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contact interfaces with neighboring subunits not fully characterized\", \"Structural role versus catalytic contribution not distinguished\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether SNRNP40 is functionally essential in vivo and which cell types are most vulnerable to its loss was unknown; a hypomorphic mouse mutant demonstrated that reduced SNRNP40 causes widespread intron retention, disrupts immune-protein expression, and produces syndromic immunodeficiency with impaired lymphoid development.\",\n      \"evidence\": \"Viable hypomorphic mouse mutant with RNA-seq of hematopoietic stem cells and T cells plus quantitative proteomics\",\n      \"pmids\": [\"31427773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why lymphoid cells are preferentially sensitive to SNRNP40 reduction is not mechanistically explained\", \"Whether complete loss is embryonic lethal was not tested\", \"Specific intron-retention events causally driving immunodeficiency not individually validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for SNRNP40's contribution to spliceosome catalysis, the mechanism underlying cell-type-selective vulnerability to its reduction, and the specific mis-spliced transcripts that drive both immunodeficiency and metastasis remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No biochemical reconstitution of SNRNP40's catalytic contribution\", \"Tissue-selective sensitivity mechanism unknown\", \"No therapeutic targeting studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\n      \"U5 snRNP\",\n      \"Spliceosomal C complex\",\n      \"Spliceosomal C* complex\"\n    ],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}