{"gene":"THOC6","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2013,"finding":"Wild-type THOC6 localizes to the nucleus as part of the THO/TREX complex, while the disease-associated p.Gly46Arg mutant is predominantly cytoplasmic, indicating the mutation disrupts normal nuclear import or retention. siRNA knockdown of THOC6 increased apoptosis in cultured cells.","method":"Cellular localization studies (immunofluorescence), siRNA knockdown with apoptosis readout","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization experiment with functional consequence (mislocalization) plus siRNA KD phenotype, single lab, two orthogonal methods","pmids":["23621916"],"is_preprint":false},{"year":2019,"finding":"Disease-associated missense variants in THOC6 (including Trp100Arg, Val234Leu, Gly275Asp, Gly190Glu) alter the physiological nuclear localization of the THOC6 protein and disrupt its interaction with at least two THO complex subunits, THOC1 and THOC5.","method":"Co-immunoprecipitation (interaction studies), cellular localization assays, protein expression analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal interaction assays and localization studies in single lab with multiple variants tested","pmids":["30476144"],"is_preprint":false},{"year":2024,"finding":"THOC6 is critical for mammalian TREX tetramer formation (composed of four six-subunit THO monomers). Biallelic loss-of-function THOC6 variants reduce the binding affinity of ALYREF to THOC5 without affecting overall TREX member protein expression or localization, implicating impaired TREX tetramer assembly. Defects in RNA nuclear export were not detected; instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing a THOC6-mediated TREX role in mRNA processing distinct from nuclear export.","method":"Human and mouse TIDS model systems, co-immunoprecipitation/binding affinity assays (ALYREF–THOC5 interaction), RNA nuclear export assays (negative for export defects), RNA-seq mis-splicing analysis in neural tissue, germline biallelic Thoc6 LOF mouse model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (binding assays, export assays, splicing analysis) in human and mouse model systems in single rigorous study, with preprint corroboration","pmids":["38388531"],"is_preprint":false},{"year":2023,"finding":"Biallelic THOC6 LOF variants do not influence expression or localization of TREX members in human cells but reduce ALYREF binding affinity. Nuclear mRNA export is not impaired; instead, mRNA mis-splicing occurs in neural tissue, indicating THOC6-mediated TREX tetramer function is primarily in mRNA processing rather than export.","method":"Human cell LOF models, co-immunoprecipitation (ALYREF binding), RNA nuclear export assays, RNA-seq splicing analysis","journal":"Research square","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, preprint, overlapping findings replicated in peer-reviewed PMID:38388531","pmids":["37720017"],"is_preprint":true},{"year":2026,"finding":"THOC6 knockout in H9C2 cardiomyocytes reduces cell proliferation and increases apoptosis. THOC6 KO alters expression of type I collagen (COL1A1, COL1A2) and cardiac α-actin 1. In hiPSC-derived cardiomyocytes, THOC6 KO leads to hypertrophic and dilated cardiomyopathy phenotypic features including disrupted sarcomeric organization and reduced COL1A2 and β-tubulin expression.","method":"CRISPR/Cas9 knockout in H9C2 cardiomyocytes and hiPSC-CMs, RNA-seq, protein-protein interaction analysis, experimental validation of target protein expression","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with RNA-seq and protein validation in two cardiomyocyte model systems, single lab","pmids":["41967792"],"is_preprint":false}],"current_model":"THOC6 is a WD-repeat subunit of the THO complex that is essential for mammalian TREX tetramer formation: it mediates ALYREF–THOC5 interaction and physically associates with THOC1 and THOC5; disease variants displace THOC6 from the nucleus and disrupt these interactions, causing mRNA mis-splicing (rather than nuclear export failure) in neural tissue, and in cardiomyocytes its loss reduces contractile proteins (type I collagen, cardiac α-actin 1, β-tubulin) and impairs sarcomeric organization."},"narrative":{"mechanistic_narrative":"THOC6 is a WD-repeat subunit of the THO/TREX complex that supports nuclear mRNA biogenesis and is essential for proper mRNA processing in mammalian tissues [PMID:23621916, PMID:38388531]. Within TREX, THOC6 is critical for assembly of the higher-order tetramer composed of four six-subunit THO monomers: it physically associates with the THO subunits THOC1 and THOC5 [PMID:30476144], and its loss reduces the binding affinity of ALYREF to THOC5 [PMID:38388531]. Rather than impairing bulk nuclear mRNA export, biallelic loss-of-function disrupts TREX tetramer assembly and produces mRNA mis-splicing in neural tissue, defining a processing role distinct from export [PMID:38388531]. Disease-associated missense variants (e.g., Gly46Arg, Trp100Arg, Val234Leu, Gly275Asp, Gly190Glu) displace THOC6 from the nucleus to the cytoplasm and disrupt its interactions with THOC1 and THOC5, establishing THOC6 dysfunction as the basis of an inherited intellectual-disability syndrome (TIDS) [PMID:23621916, PMID:30476144, PMID:38388531]. In cardiomyocyte models, THOC6 loss reduces proliferation, increases apoptosis, and lowers expression of contractile and structural proteins including type I collagen, cardiac α-actin 1, and β-tubulin, with disrupted sarcomeric organization [PMID:41967792].","teleology":[{"year":2013,"claim":"Established that THOC6 normally resides in the nucleus as part of the THO/TREX complex and that a disease mutation mislocalizes it, linking loss of nuclear function to a cellular phenotype.","evidence":"Immunofluorescence localization of wild-type versus p.Gly46Arg mutant and siRNA knockdown with apoptosis readout in cultured cells","pmids":["23621916"],"confidence":"Medium","gaps":["Did not identify the molecular interactions THOC6 mediates within TREX","Mechanism connecting mislocalization to apoptosis not defined","No tissue-level or processing phenotype assessed"]},{"year":2019,"claim":"Defined the molecular consequence of pathogenic variants by showing they disrupt THOC6 interactions with THO subunits THOC1 and THOC5 in addition to altering nuclear localization.","evidence":"Co-immunoprecipitation and localization assays across multiple disease missense variants in a single lab","pmids":["30476144"],"confidence":"Medium","gaps":["Did not establish the functional output of disrupted THO interactions","Effect on mRNA fate (export vs. processing) not tested","No higher-order complex assembly characterized"]},{"year":2024,"claim":"Resolved the core mechanism by showing THOC6 is required for TREX tetramer assembly and mediates ALYREF–THOC5 binding, and that its loss causes mRNA mis-splicing rather than nuclear export failure.","evidence":"Human and mouse TIDS models with binding affinity assays, RNA nuclear export assays (negative), and RNA-seq mis-splicing analysis in neural tissue, including a biallelic Thoc6 LOF mouse","pmids":["38388531","37720017"],"confidence":"High","gaps":["Specific mis-spliced transcripts driving neural pathology not enumerated","Structural basis of THOC6's role in tetramer formation not resolved","How impaired tetramer assembly mechanistically alters splice site selection unclear"]},{"year":2026,"claim":"Extended THOC6 function beyond neural tissue by showing its loss compromises cardiomyocyte survival and contractile/structural protein expression, implicating sarcomeric integrity.","evidence":"CRISPR/Cas9 knockout in H9C2 and hiPSC-derived cardiomyocytes with RNA-seq and protein validation","pmids":["41967792"],"confidence":"Medium","gaps":["Whether contractile gene changes arise through TREX-dependent splicing not established","Causal link between protein changes and sarcomeric disruption not dissected","In vivo cardiac relevance not tested"]},{"year":null,"claim":"It remains unknown how THOC6-dependent TREX tetramer assembly mechanistically governs splice-site selection and which target transcripts mediate tissue-specific phenotypes.","evidence":"No timeline discovery defines the splicing mechanism or the critical effector transcripts","pmids":[],"confidence":"Low","gaps":["No structural model of THOC6 within the TREX tetramer","Effector mis-spliced transcripts driving neural and cardiac disease unidentified","Mechanistic coupling between tetramer assembly and spliceosome function undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]}],"complexes":["THO complex","TREX complex"],"partners":["THOC1","THOC5","ALYREF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q86W42","full_name":"THO complex subunit 6","aliases":["Functional spliceosome-associated protein 35","fSAP35","WD repeat-containing protein 58"],"length_aa":341,"mass_kda":37.5,"function":"Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA (PubMed:15833825, PubMed:15998806, PubMed:17190602). Plays a key structural role in the oligomerization of the THO-DDX39B complex (PubMed:33191911). TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NXF1 pathway (PubMed:15998806, PubMed:17190602). Plays a role in apoptosis negative control involved in brain development (PubMed:15833825, PubMed:23621916) (Microbial infection) The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production","subcellular_location":"Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/Q86W42/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/THOC6","classification":"Common Essential","n_dependent_lines":527,"n_total_lines":1208,"dependency_fraction":0.43625827814569534},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"SF3A1","stoichiometry":0.2},{"gene":"SNRPA","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/THOC6","total_profiled":1310},"omim":[{"mim_id":"615403","title":"THO COMPLEX, SUBUNIT 6; THOC6","url":"https://www.omim.org/entry/615403"},{"mim_id":"613680","title":"BEAULIEU-BOYCOTT-INNES SYNDROME; BBIS","url":"https://www.omim.org/entry/613680"},{"mim_id":"612733","title":"THO COMPLEX, SUBUNIT 5; THOC5","url":"https://www.omim.org/entry/612733"},{"mim_id":"611965","title":"THO COMPLEX, SUBUNIT 7; THOC7","url":"https://www.omim.org/entry/611965"},{"mim_id":"606930","title":"THO COMPLEX, SUBUNIT 1; THOC1","url":"https://www.omim.org/entry/606930"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/THOC6"},"hgnc":{"alias_symbol":["MGC2655","fSAP35"],"prev_symbol":["WDR58"]},"alphafold":{"accession":"Q86W42","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86W42","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86W42-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86W42-F1-predicted_aligned_error_v6.png","plddt_mean":93.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=THOC6","jax_strain_url":"https://www.jax.org/strain/search?query=THOC6"},"sequence":{"accession":"Q86W42","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86W42.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86W42/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86W42"}},"corpus_meta":[{"pmid":"23621916","id":"PMC_23621916","title":"Intellectual disability associated with a homozygous missense mutation in THOC6.","date":"2013","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23621916","citation_count":46,"is_preprint":false},{"pmid":"27102954","id":"PMC_27102954","title":"Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27102954","citation_count":26,"is_preprint":false},{"pmid":"30476144","id":"PMC_30476144","title":"Clinical and functional characterization of recurrent missense variants implicated in THOC6-related intellectual disability.","date":"2019","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30476144","citation_count":21,"is_preprint":false},{"pmid":"38388531","id":"PMC_38388531","title":"TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38388531","citation_count":9,"is_preprint":false},{"pmid":"35426486","id":"PMC_35426486","title":"Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature.","date":"2022","source":"Birth defects research","url":"https://pubmed.ncbi.nlm.nih.gov/35426486","citation_count":8,"is_preprint":false},{"pmid":"32282736","id":"PMC_32282736","title":"The first reported case of Beaulieu-Boycott-Innes syndrome caused by two novel mutations in THOC6 gene in a Chinese infant.","date":"2020","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32282736","citation_count":8,"is_preprint":false},{"pmid":"31421288","id":"PMC_31421288","title":"First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India.","date":"2019","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31421288","citation_count":7,"is_preprint":false},{"pmid":"35084103","id":"PMC_35084103","title":"A truncating variant in the THOC6 gene with new findings in a patient with Beaulieu-Boycott-Innes syndrome.","date":"2022","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/35084103","citation_count":4,"is_preprint":false},{"pmid":"38728502","id":"PMC_38728502","title":"THOC6 is a novel biomarker of glioma and a target of anti-glioma drugs: An analysis based on bioinformatics and molecular docking.","date":"2024","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38728502","citation_count":1,"is_preprint":false},{"pmid":"37720017","id":"PMC_37720017","title":"Mechanisms of mRNA processing defects in inherited THOC6 intellectual disability syndrome.","date":"2023","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/37720017","citation_count":0,"is_preprint":false},{"pmid":"40760536","id":"PMC_40760536","title":"Expanding the phenotypic spectrum of Beaulieu-Boycott-Innes syndrome: A case report of a novel THOC6 gene mutation associated with ambiguous genitalia and disorders of sexual development.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40760536","citation_count":0,"is_preprint":false},{"pmid":"41967792","id":"PMC_41967792","title":"THOC6 deficiency leads to cardiomyopathy by reducing myocardial contractile proteins in cardiomyocytes.","date":"2026","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41967792","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8018,"output_tokens":1438,"usd":0.022812,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8148,"output_tokens":2042,"usd":0.045895,"stage2_stop_reason":"end_turn"},"total_usd":0.068707,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Wild-type THOC6 localizes to the nucleus as part of the THO/TREX complex, while the disease-associated p.Gly46Arg mutant is predominantly cytoplasmic, indicating the mutation disrupts normal nuclear import or retention. siRNA knockdown of THOC6 increased apoptosis in cultured cells.\",\n      \"method\": \"Cellular localization studies (immunofluorescence), siRNA knockdown with apoptosis readout\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization experiment with functional consequence (mislocalization) plus siRNA KD phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"23621916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Disease-associated missense variants in THOC6 (including Trp100Arg, Val234Leu, Gly275Asp, Gly190Glu) alter the physiological nuclear localization of the THOC6 protein and disrupt its interaction with at least two THO complex subunits, THOC1 and THOC5.\",\n      \"method\": \"Co-immunoprecipitation (interaction studies), cellular localization assays, protein expression analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal interaction assays and localization studies in single lab with multiple variants tested\",\n      \"pmids\": [\"30476144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"THOC6 is critical for mammalian TREX tetramer formation (composed of four six-subunit THO monomers). Biallelic loss-of-function THOC6 variants reduce the binding affinity of ALYREF to THOC5 without affecting overall TREX member protein expression or localization, implicating impaired TREX tetramer assembly. Defects in RNA nuclear export were not detected; instead, mRNA mis-splicing was observed in human and mouse neural tissue, revealing a THOC6-mediated TREX role in mRNA processing distinct from nuclear export.\",\n      \"method\": \"Human and mouse TIDS model systems, co-immunoprecipitation/binding affinity assays (ALYREF–THOC5 interaction), RNA nuclear export assays (negative for export defects), RNA-seq mis-splicing analysis in neural tissue, germline biallelic Thoc6 LOF mouse model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (binding assays, export assays, splicing analysis) in human and mouse model systems in single rigorous study, with preprint corroboration\",\n      \"pmids\": [\"38388531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Biallelic THOC6 LOF variants do not influence expression or localization of TREX members in human cells but reduce ALYREF binding affinity. Nuclear mRNA export is not impaired; instead, mRNA mis-splicing occurs in neural tissue, indicating THOC6-mediated TREX tetramer function is primarily in mRNA processing rather than export.\",\n      \"method\": \"Human cell LOF models, co-immunoprecipitation (ALYREF binding), RNA nuclear export assays, RNA-seq splicing analysis\",\n      \"journal\": \"Research square\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, preprint, overlapping findings replicated in peer-reviewed PMID:38388531\",\n      \"pmids\": [\"37720017\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"THOC6 knockout in H9C2 cardiomyocytes reduces cell proliferation and increases apoptosis. THOC6 KO alters expression of type I collagen (COL1A1, COL1A2) and cardiac α-actin 1. In hiPSC-derived cardiomyocytes, THOC6 KO leads to hypertrophic and dilated cardiomyopathy phenotypic features including disrupted sarcomeric organization and reduced COL1A2 and β-tubulin expression.\",\n      \"method\": \"CRISPR/Cas9 knockout in H9C2 cardiomyocytes and hiPSC-CMs, RNA-seq, protein-protein interaction analysis, experimental validation of target protein expression\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with RNA-seq and protein validation in two cardiomyocyte model systems, single lab\",\n      \"pmids\": [\"41967792\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THOC6 is a WD-repeat subunit of the THO complex that is essential for mammalian TREX tetramer formation: it mediates ALYREF–THOC5 interaction and physically associates with THOC1 and THOC5; disease variants displace THOC6 from the nucleus and disrupt these interactions, causing mRNA mis-splicing (rather than nuclear export failure) in neural tissue, and in cardiomyocytes its loss reduces contractile proteins (type I collagen, cardiac α-actin 1, β-tubulin) and impairs sarcomeric organization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THOC6 is a WD-repeat subunit of the THO/TREX complex that supports nuclear mRNA biogenesis and is essential for proper mRNA processing in mammalian tissues [#0, #2]. Within TREX, THOC6 is critical for assembly of the higher-order tetramer composed of four six-subunit THO monomers: it physically associates with the THO subunits THOC1 and THOC5 [#1], and its loss reduces the binding affinity of ALYREF to THOC5 [#2]. Rather than impairing bulk nuclear mRNA export, biallelic loss-of-function disrupts TREX tetramer assembly and produces mRNA mis-splicing in neural tissue, defining a processing role distinct from export [#2]. Disease-associated missense variants (e.g., Gly46Arg, Trp100Arg, Val234Leu, Gly275Asp, Gly190Glu) displace THOC6 from the nucleus to the cytoplasm and disrupt its interactions with THOC1 and THOC5, establishing THOC6 dysfunction as the basis of an inherited intellectual-disability syndrome (TIDS) [#0, #1, #2]. In cardiomyocyte models, THOC6 loss reduces proliferation, increases apoptosis, and lowers expression of contractile and structural proteins including type I collagen, cardiac \\u03b1-actin 1, and \\u03b2-tubulin, with disrupted sarcomeric organization [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that THOC6 normally resides in the nucleus as part of the THO/TREX complex and that a disease mutation mislocalizes it, linking loss of nuclear function to a cellular phenotype.\",\n      \"evidence\": \"Immunofluorescence localization of wild-type versus p.Gly46Arg mutant and siRNA knockdown with apoptosis readout in cultured cells\",\n      \"pmids\": [\"23621916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not identify the molecular interactions THOC6 mediates within TREX\",\n        \"Mechanism connecting mislocalization to apoptosis not defined\",\n        \"No tissue-level or processing phenotype assessed\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the molecular consequence of pathogenic variants by showing they disrupt THOC6 interactions with THO subunits THOC1 and THOC5 in addition to altering nuclear localization.\",\n      \"evidence\": \"Co-immunoprecipitation and localization assays across multiple disease missense variants in a single lab\",\n      \"pmids\": [\"30476144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not establish the functional output of disrupted THO interactions\",\n        \"Effect on mRNA fate (export vs. processing) not tested\",\n        \"No higher-order complex assembly characterized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved the core mechanism by showing THOC6 is required for TREX tetramer assembly and mediates ALYREF\\u2013THOC5 binding, and that its loss causes mRNA mis-splicing rather than nuclear export failure.\",\n      \"evidence\": \"Human and mouse TIDS models with binding affinity assays, RNA nuclear export assays (negative), and RNA-seq mis-splicing analysis in neural tissue, including a biallelic Thoc6 LOF mouse\",\n      \"pmids\": [\"38388531\", \"37720017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific mis-spliced transcripts driving neural pathology not enumerated\",\n        \"Structural basis of THOC6's role in tetramer formation not resolved\",\n        \"How impaired tetramer assembly mechanistically alters splice site selection unclear\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended THOC6 function beyond neural tissue by showing its loss compromises cardiomyocyte survival and contractile/structural protein expression, implicating sarcomeric integrity.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in H9C2 and hiPSC-derived cardiomyocytes with RNA-seq and protein validation\",\n      \"pmids\": [\"41967792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether contractile gene changes arise through TREX-dependent splicing not established\",\n        \"Causal link between protein changes and sarcomeric disruption not dissected\",\n        \"In vivo cardiac relevance not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how THOC6-dependent TREX tetramer assembly mechanistically governs splice-site selection and which target transcripts mediate tissue-specific phenotypes.\",\n      \"evidence\": \"No timeline discovery defines the splicing mechanism or the critical effector transcripts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of THOC6 within the TREX tetramer\",\n        \"Effector mis-spliced transcripts driving neural and cardiac disease unidentified\",\n        \"Mechanistic coupling between tetramer assembly and spliceosome function undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"THO complex\", \"TREX complex\"],\n    \"partners\": [\"THOC1\", \"THOC5\", \"ALYREF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}