{"gene":"CWF19L1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2015,"finding":"hDrn1 (CWF19L1) directly interacts with human Debranching enzyme 1 (hDbr1) through protein-protein interaction, as identified by co-immunoprecipitation followed by mass spectrometry and confirmed by direct interaction assays. hDrn1 also shuttles between the nucleus and the cytoplasm, as hDbr1 does.","method":"Co-immunoprecipitation followed by mass spectrometry; direct protein-protein interaction assay; subcellular localization experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS identification plus direct interaction assay and localization, single lab","pmids":["25671812"],"is_preprint":false},{"year":2014,"finding":"Loss of CWF19L1 function (via morpholino-mediated knockdown in zebrafish) alters cerebellar morphology and causes movement abnormalities, establishing a required role for CWF19L1 in cerebellar development and motor function. A homozygous splice-site mutation (c.964+1G>A) causes exon skipping, reduction in mRNA levels, and protein loss.","method":"Morpholino-mediated knockdown in zebrafish; RT-PCR; immunoblotting","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function model with defined cerebellar phenotype, plus molecular confirmation of splice defect; single lab","pmids":["25361784"],"is_preprint":false},{"year":2020,"finding":"CWF19L1 expression is regulated by H3K27ac (active histone mark) at its promoter, as demonstrated by chromatin immunoprecipitation-quantitative PCR. Upregulation of CWF19L1 leads to degradation of CDK4/6 and results in G1 cell cycle arrest in glioma cells.","method":"ChIP-qPCR; protein mass spectrometry; in vitro and in vivo cell cycle analysis","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR for epigenetic regulation and functional cell cycle readout; single lab, multiple methods","pmids":["32508030"],"is_preprint":false},{"year":2019,"finding":"3'UTR RNA editing sites in CWF19L1 result in increased CWF19L1 protein levels, and altered CWF19L1 expression affects proliferation of human embryonic kidney cells.","method":"Computational identification of RNA editing sites; experimental validation of protein levels; cell proliferation assay","journal":"JCO clinical cancer informatics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single experiment per finding; mechanistic details not fully described in abstract","pmids":["31162949"],"is_preprint":false},{"year":2024,"finding":"CWF19L1 functions as a splicing regulator by interacting with key splicing factors within the nucleus, including components of the U5 small nuclear ribonucleoprotein and the PRPF19 complex. Deficiency of CWF19L1 disrupts alternative splicing of immune-related genes, resulting in diminished expression of cytotoxic molecules and effector cytokines, thereby impairing T cell-mediated antitumor cytotoxicity.","method":"Co-immunoprecipitation; alternative splicing analysis; CWF19L1 knockdown/deficiency with cytotoxicity readouts; gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with splicing factors, loss-of-function with defined molecular and cellular phenotype; single lab, multiple orthogonal methods","pmids":["39542248"],"is_preprint":false},{"year":2025,"finding":"CWF19L2 (a paralog with C-terminal homology to CWF19L1) localizes in a distinct but closely associated pattern relative to CWF19L1 in the nucleus, as shown by super-resolution immunofluorescence imaging. This finding establishes that CWF19L1 and CWF19L2 have distinct but proximate nuclear localizations.","method":"Super-resolution immunofluorescence imaging","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization data for CWF19L1 is incidental to a study focused on CWF19L2; single observation without functional consequence linked to CWF19L1 specifically","pmids":["41422678"],"is_preprint":false}],"current_model":"CWF19L1 (hDrn1) is a nuclear-cytoplasmic shuttling protein that functions as a splicing regulator by interacting with U5 snRNP and PRPF19 complex components; it directly binds the lariat RNA debranching enzyme hDbr1, and its loss disrupts alternative splicing of immune-related genes, impairs T cell cytotoxicity, leads to CDK4/6 degradation and G1 arrest, and is required for normal cerebellar development as demonstrated by zebrafish loss-of-function models."},"narrative":{"mechanistic_narrative":"CWF19L1 (hDrn1) is a nuclear-cytoplasmic shuttling protein that participates in pre-mRNA splicing through physical association with the spliceosomal machinery [PMID:25671812, PMID:39542248]. It directly binds the lariat RNA debranching enzyme hDbr1 and mirrors its nucleocytoplasmic distribution [PMID:25671812], and within the nucleus it interacts with components of the U5 small nuclear ribonucleoprotein and the PRPF19 complex to function as a splicing regulator [PMID:39542248]. Loss of CWF19L1 disrupts alternative splicing of immune-related genes, lowering expression of cytotoxic molecules and effector cytokines and impairing T cell-mediated antitumor cytotoxicity [PMID:39542248]. CWF19L1 is required for normal cerebellar development and motor function, as a homozygous splice-site mutation causing exon skipping and protein loss produces a cerebellar phenotype in patients and zebrafish knockdown alters cerebellar morphology with movement abnormalities [PMID:25361784]. In glioma cells its expression is controlled by H3K27ac at the promoter, and elevated CWF19L1 drives degradation of CDK4/6 and G1 cell cycle arrest [PMID:32508030].","teleology":[{"year":2014,"claim":"Establishing whether CWF19L1 has an essential physiological role, a defined loss-of-function model linked the gene to cerebellar development and a human disease phenotype.","evidence":"Morpholino knockdown in zebrafish with cerebellar/motor readouts plus RT-PCR and immunoblotting confirmation of a patient splice-site mutation","pmids":["25361784"],"confidence":"Medium","gaps":["Molecular mechanism linking CWF19L1 loss to cerebellar defects not defined","No demonstration of which splicing or RNA targets underlie the neurological phenotype"]},{"year":2015,"claim":"To place CWF19L1 in a biochemical pathway, it was shown to directly bind the lariat debranching enzyme hDbr1 and to shuttle between nucleus and cytoplasm, implicating it in RNA lariat/intron metabolism.","evidence":"Co-IP with mass spectrometry, direct interaction assay, and subcellular localization in human cells","pmids":["25671812"],"confidence":"Medium","gaps":["Functional consequence of the hDrn1-hDbr1 interaction on debranching not established","Single-lab interaction without genetic epistasis"]},{"year":2019,"claim":"Addressing post-transcriptional control of the gene itself, 3'UTR RNA editing was found to raise CWF19L1 protein levels and alter cell proliferation.","evidence":"Computational identification of editing sites with protein-level validation and proliferation assays in HEK cells","pmids":["31162949"],"confidence":"Low","gaps":["Single experiment per finding with mechanistic details not described","No link between editing-driven expression changes and a defined molecular pathway"]},{"year":2020,"claim":"Connecting CWF19L1 to cell cycle control, its promoter was shown to be regulated by H3K27ac and its upregulation to trigger CDK4/6 degradation and G1 arrest in glioma.","evidence":"ChIP-qPCR for promoter regulation, mass spectrometry, and in vitro/in vivo cell cycle analysis","pmids":["32508030"],"confidence":"Medium","gaps":["Mechanism by which CWF19L1 promotes CDK4/6 degradation unknown","Relationship between cell-cycle role and splicing function not integrated"]},{"year":2024,"claim":"Defining the core molecular activity, CWF19L1 was shown to act as a splicing regulator interacting with U5 snRNP and PRPF19 complex components, with loss disrupting immune-gene splicing and antitumor T cell cytotoxicity.","evidence":"Co-IP with splicing factors, alternative splicing analysis, and loss-of-function with cytotoxicity and gene-expression readouts","pmids":["39542248"],"confidence":"Medium","gaps":["Direct versus indirect nature of spliceosome association not resolved","Specific splice targets driving the cytotoxicity defect not fully mapped","Single-lab evidence"]},{"year":2025,"claim":"Refining nuclear organization, super-resolution imaging placed CWF19L1 in a distinct but closely associated nuclear pattern relative to its paralog CWF19L2.","evidence":"Super-resolution immunofluorescence imaging","pmids":["41422678"],"confidence":"Low","gaps":["CWF19L1 localization was incidental to a CWF19L2-focused study","No functional consequence tied to CWF19L1 from this observation"]},{"year":null,"claim":"How the splicing/debranching activity, the CDK4/6-degrading cell-cycle role, and the cerebellar developmental requirement of CWF19L1 mechanistically connect into a single pathway remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical mechanism linking splicing function to cell-cycle and developmental phenotypes","No structural model of CWF19L1 or its spliceosome contacts","Direct catalytic activity, if any, undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4]}],"complexes":[],"partners":["DBR1","PRPF19"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q69YN2","full_name":"CWF19-like protein 1","aliases":[],"length_aa":538,"mass_kda":60.6,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q69YN2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CWF19L1","classification":"Not Classified","n_dependent_lines":90,"n_total_lines":1208,"dependency_fraction":0.07450331125827815},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DNAJC17","stoichiometry":0.2},{"gene":"METAP2","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2},{"gene":"SNRPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CWF19L1","total_profiled":1310},"omim":[{"mim_id":"616127","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 17; SCAR17","url":"https://www.omim.org/entry/616127"},{"mim_id":"616120","title":"CWF19-LIKE CELL CYCLE CONTROL FACTOR 1; CWF19L1","url":"https://www.omim.org/entry/616120"},{"mim_id":"611330","title":"SMALL NUCLEOLAR RNA, H/ACA BOX, 12; SNORA12","url":"https://www.omim.org/entry/611330"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CWF19L1"},"hgnc":{"alias_symbol":["FLJ10998","hDrn1"],"prev_symbol":[]},"alphafold":{"accession":"Q69YN2","domains":[{"cath_id":"3.60.21.10","chopping":"5-254","consensus_level":"high","plddt":90.1788,"start":5,"end":254},{"cath_id":"3.30.428.10","chopping":"338-531","consensus_level":"high","plddt":90.374,"start":338,"end":531}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q69YN2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q69YN2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q69YN2-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CWF19L1","jax_strain_url":"https://www.jax.org/strain/search?query=CWF19L1"},"sequence":{"accession":"Q69YN2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q69YN2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q69YN2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q69YN2"}},"corpus_meta":[{"pmid":"23477746","id":"PMC_23477746","title":"The ERLIN1-CHUK-CWF19L1 gene cluster influences liver fat deposition and hepatic inflammation in the NHLBI Family Heart Study.","date":"2013","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/23477746","citation_count":43,"is_preprint":false},{"pmid":"34558842","id":"PMC_34558842","title":"Association of Genetic Risk Score With NAFLD in An Ethnically Diverse Cohort.","date":"2021","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/34558842","citation_count":41,"is_preprint":false},{"pmid":"32508030","id":"PMC_32508030","title":"HOTAIR-EZH2 inhibitor AC1Q3QWB upregulates CWF19L1 and enhances cell cycle inhibition of CDK4/6 inhibitor palbociclib in glioma.","date":"2020","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32508030","citation_count":29,"is_preprint":false},{"pmid":"25361784","id":"PMC_25361784","title":"Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome.","date":"2014","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25361784","citation_count":27,"is_preprint":false},{"pmid":"26197978","id":"PMC_26197978","title":"Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy.","date":"2015","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/26197978","citation_count":19,"is_preprint":false},{"pmid":"37540242","id":"PMC_37540242","title":"Transcriptome-wide association study-derived genes as potential visceral adipose tissue-specific targets for type 2 diabetes.","date":"2023","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/37540242","citation_count":16,"is_preprint":false},{"pmid":"27016154","id":"PMC_27016154","title":"Exome sequencing reveals a novel CWF19L1 mutation associated with intellectual disability and cerebellar atrophy.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27016154","citation_count":14,"is_preprint":false},{"pmid":"25671812","id":"PMC_25671812","title":"Identification of the specific interactors of the human lariat RNA debranching enzyme 1 protein.","date":"2015","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25671812","citation_count":13,"is_preprint":false},{"pmid":"36530930","id":"PMC_36530930","title":"Diagnostic Efficacy of Genetic Studies in a Series of Hereditary Cerebellar Ataxias in Eastern Spain.","date":"2022","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36530930","citation_count":11,"is_preprint":false},{"pmid":"33012273","id":"PMC_33012273","title":"A Novel Variant in CWF19L1 Gene in a Family with Late-Onset Autosomal Recessive Cerebellar Ataxia 17.","date":"2020","source":"Neurological research","url":"https://pubmed.ncbi.nlm.nih.gov/33012273","citation_count":8,"is_preprint":false},{"pmid":"31162949","id":"PMC_31162949","title":"Clinical Relevance of Noncoding Adenosine-to-Inosine RNA Editing in Multiple Human Cancers.","date":"2019","source":"JCO clinical cancer informatics","url":"https://pubmed.ncbi.nlm.nih.gov/31162949","citation_count":8,"is_preprint":false},{"pmid":"39542248","id":"PMC_39542248","title":"CWF19L1 promotes T-cell cytotoxicity through the regulation of alternative splicing.","date":"2024","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39542248","citation_count":3,"is_preprint":false},{"pmid":"36357319","id":"PMC_36357319","title":"Heterozygous pathogenic variants in CWF19L1 in a Chinese family with spinocerebellar ataxia, autosomal recessive 17.","date":"2022","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/36357319","citation_count":3,"is_preprint":false},{"pmid":"37752213","id":"PMC_37752213","title":"Novel CWF19L1 mutations in patients with spinocerebellar ataxia, autosomal recessive 17.","date":"2023","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37752213","citation_count":1,"is_preprint":false},{"pmid":"35714975","id":"PMC_35714975","title":"Expression patterns and functional analysis of porcine lnc-34015.","date":"2022","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35714975","citation_count":1,"is_preprint":false},{"pmid":"41422678","id":"PMC_41422678","title":"NVL2-interacting protein CWF19L2 is required for debranching of intron-derived lariat RNAs.","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/41422678","citation_count":0,"is_preprint":false},{"pmid":"37976965","id":"PMC_37976965","title":"Identification of lncRNA-based regulatory mechanisms of Takifugu rubripes growth traits in fast and slow-growing family lines.","date":"2023","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/37976965","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11545,"output_tokens":1497,"usd":0.028545,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8213,"output_tokens":2236,"usd":0.048482,"stage2_stop_reason":"end_turn"},"total_usd":0.077027,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"hDrn1 (CWF19L1) directly interacts with human Debranching enzyme 1 (hDbr1) through protein-protein interaction, as identified by co-immunoprecipitation followed by mass spectrometry and confirmed by direct interaction assays. hDrn1 also shuttles between the nucleus and the cytoplasm, as hDbr1 does.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry; direct protein-protein interaction assay; subcellular localization experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS identification plus direct interaction assay and localization, single lab\",\n      \"pmids\": [\"25671812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of CWF19L1 function (via morpholino-mediated knockdown in zebrafish) alters cerebellar morphology and causes movement abnormalities, establishing a required role for CWF19L1 in cerebellar development and motor function. A homozygous splice-site mutation (c.964+1G>A) causes exon skipping, reduction in mRNA levels, and protein loss.\",\n      \"method\": \"Morpholino-mediated knockdown in zebrafish; RT-PCR; immunoblotting\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function model with defined cerebellar phenotype, plus molecular confirmation of splice defect; single lab\",\n      \"pmids\": [\"25361784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CWF19L1 expression is regulated by H3K27ac (active histone mark) at its promoter, as demonstrated by chromatin immunoprecipitation-quantitative PCR. Upregulation of CWF19L1 leads to degradation of CDK4/6 and results in G1 cell cycle arrest in glioma cells.\",\n      \"method\": \"ChIP-qPCR; protein mass spectrometry; in vitro and in vivo cell cycle analysis\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR for epigenetic regulation and functional cell cycle readout; single lab, multiple methods\",\n      \"pmids\": [\"32508030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"3'UTR RNA editing sites in CWF19L1 result in increased CWF19L1 protein levels, and altered CWF19L1 expression affects proliferation of human embryonic kidney cells.\",\n      \"method\": \"Computational identification of RNA editing sites; experimental validation of protein levels; cell proliferation assay\",\n      \"journal\": \"JCO clinical cancer informatics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single experiment per finding; mechanistic details not fully described in abstract\",\n      \"pmids\": [\"31162949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CWF19L1 functions as a splicing regulator by interacting with key splicing factors within the nucleus, including components of the U5 small nuclear ribonucleoprotein and the PRPF19 complex. Deficiency of CWF19L1 disrupts alternative splicing of immune-related genes, resulting in diminished expression of cytotoxic molecules and effector cytokines, thereby impairing T cell-mediated antitumor cytotoxicity.\",\n      \"method\": \"Co-immunoprecipitation; alternative splicing analysis; CWF19L1 knockdown/deficiency with cytotoxicity readouts; gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with splicing factors, loss-of-function with defined molecular and cellular phenotype; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39542248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CWF19L2 (a paralog with C-terminal homology to CWF19L1) localizes in a distinct but closely associated pattern relative to CWF19L1 in the nucleus, as shown by super-resolution immunofluorescence imaging. This finding establishes that CWF19L1 and CWF19L2 have distinct but proximate nuclear localizations.\",\n      \"method\": \"Super-resolution immunofluorescence imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization data for CWF19L1 is incidental to a study focused on CWF19L2; single observation without functional consequence linked to CWF19L1 specifically\",\n      \"pmids\": [\"41422678\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CWF19L1 (hDrn1) is a nuclear-cytoplasmic shuttling protein that functions as a splicing regulator by interacting with U5 snRNP and PRPF19 complex components; it directly binds the lariat RNA debranching enzyme hDbr1, and its loss disrupts alternative splicing of immune-related genes, impairs T cell cytotoxicity, leads to CDK4/6 degradation and G1 arrest, and is required for normal cerebellar development as demonstrated by zebrafish loss-of-function models.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CWF19L1 (hDrn1) is a nuclear-cytoplasmic shuttling protein that participates in pre-mRNA splicing through physical association with the spliceosomal machinery [#0, #4]. It directly binds the lariat RNA debranching enzyme hDbr1 and mirrors its nucleocytoplasmic distribution [#0], and within the nucleus it interacts with components of the U5 small nuclear ribonucleoprotein and the PRPF19 complex to function as a splicing regulator [#4]. Loss of CWF19L1 disrupts alternative splicing of immune-related genes, lowering expression of cytotoxic molecules and effector cytokines and impairing T cell-mediated antitumor cytotoxicity [#4]. CWF19L1 is required for normal cerebellar development and motor function, as a homozygous splice-site mutation causing exon skipping and protein loss produces a cerebellar phenotype in patients and zebrafish knockdown alters cerebellar morphology with movement abnormalities [#1]. In glioma cells its expression is controlled by H3K27ac at the promoter, and elevated CWF19L1 drives degradation of CDK4/6 and G1 cell cycle arrest [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing whether CWF19L1 has an essential physiological role, a defined loss-of-function model linked the gene to cerebellar development and a human disease phenotype.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with cerebellar/motor readouts plus RT-PCR and immunoblotting confirmation of a patient splice-site mutation\",\n      \"pmids\": [\"25361784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking CWF19L1 loss to cerebellar defects not defined\", \"No demonstration of which splicing or RNA targets underlie the neurological phenotype\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"To place CWF19L1 in a biochemical pathway, it was shown to directly bind the lariat debranching enzyme hDbr1 and to shuttle between nucleus and cytoplasm, implicating it in RNA lariat/intron metabolism.\",\n      \"evidence\": \"Co-IP with mass spectrometry, direct interaction assay, and subcellular localization in human cells\",\n      \"pmids\": [\"25671812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the hDrn1-hDbr1 interaction on debranching not established\", \"Single-lab interaction without genetic epistasis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Addressing post-transcriptional control of the gene itself, 3'UTR RNA editing was found to raise CWF19L1 protein levels and alter cell proliferation.\",\n      \"evidence\": \"Computational identification of editing sites with protein-level validation and proliferation assays in HEK cells\",\n      \"pmids\": [\"31162949\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single experiment per finding with mechanistic details not described\", \"No link between editing-driven expression changes and a defined molecular pathway\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connecting CWF19L1 to cell cycle control, its promoter was shown to be regulated by H3K27ac and its upregulation to trigger CDK4/6 degradation and G1 arrest in glioma.\",\n      \"evidence\": \"ChIP-qPCR for promoter regulation, mass spectrometry, and in vitro/in vivo cell cycle analysis\",\n      \"pmids\": [\"32508030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CWF19L1 promotes CDK4/6 degradation unknown\", \"Relationship between cell-cycle role and splicing function not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining the core molecular activity, CWF19L1 was shown to act as a splicing regulator interacting with U5 snRNP and PRPF19 complex components, with loss disrupting immune-gene splicing and antitumor T cell cytotoxicity.\",\n      \"evidence\": \"Co-IP with splicing factors, alternative splicing analysis, and loss-of-function with cytotoxicity and gene-expression readouts\",\n      \"pmids\": [\"39542248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect nature of spliceosome association not resolved\", \"Specific splice targets driving the cytotoxicity defect not fully mapped\", \"Single-lab evidence\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Refining nuclear organization, super-resolution imaging placed CWF19L1 in a distinct but closely associated nuclear pattern relative to its paralog CWF19L2.\",\n      \"evidence\": \"Super-resolution immunofluorescence imaging\",\n      \"pmids\": [\"41422678\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"CWF19L1 localization was incidental to a CWF19L2-focused study\", \"No functional consequence tied to CWF19L1 from this observation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the splicing/debranching activity, the CDK4/6-degrading cell-cycle role, and the cerebellar developmental requirement of CWF19L1 mechanistically connect into a single pathway remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying biochemical mechanism linking splicing function to cell-cycle and developmental phenotypes\", \"No structural model of CWF19L1 or its spliceosome contacts\", \"Direct catalytic activity, if any, undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DBR1\", \"PRPF19\"]\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":5,"faith_pct":80.0}}