{"gene":"LUC7L3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2011,"finding":"LUC7L3 (together with RBM25) mediates abnormal splicing of SCN5A (cardiac Na+ channel) mRNA, producing truncated transcripts and reducing full-length SCN5A mRNA and Na+ channel current by ~91% in Jurkat cells and human embryonic stem cell-derived cardiomyocytes. Both splicing factors were elevated in human heart failure tissue, and overexpression of either factor alone was sufficient to increase truncated mRNA and decrease full-length SCN5A transcript.","method":"Gene array profiling of human heart failure vs. normal tissue; overexpression of LUC7L3 and RBM25 in Jurkat cells and hESC-derived cardiomyocytes with quantification of full-length vs. truncated SCN5A mRNA and Na+ channel current (patch-clamp)","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression assay with two orthogonal readouts (mRNA splicing and electrophysiology), single lab, no rescue or mutagenesis experiment reported","pmids":["21859973"],"is_preprint":false}],"current_model":"LUC7L3 is an mRNA splicing factor that, together with RBM25, promotes aberrant truncation of SCN5A (cardiac Na+ channel) pre-mRNA; its upregulation in human heart failure is sufficient to dramatically reduce full-length Na+ channel transcript and current, implicating it as a mediator of arrhythmic risk through pathological alternative splicing."},"narrative":{"mechanistic_narrative":"LUC7L3 is an mRNA splicing factor that, acting together with RBM25, drives aberrant alternative splicing of the cardiac sodium channel gene SCN5A, generating truncated transcripts at the expense of the full-length channel [PMID:21859973]. In human heart failure tissue both factors are elevated, and overexpression of LUC7L3 alone in Jurkat cells and hESC-derived cardiomyocytes is sufficient to increase truncated SCN5A mRNA and reduce full-length transcript and Na+ channel current by ~91%, linking it to pathological remodeling of channel splicing [PMID:21859973]. Beyond this single splicing-regulatory role in SCN5A processing, no further mechanistic detail — including its biochemical mode of substrate recognition or its broader spliceosomal interactions — has been characterized in the available corpus.","teleology":[{"year":2011,"claim":"Whether a specific splicing factor could account for the loss of functional cardiac Na+ channel in heart failure was unknown; this work showed LUC7L3, with RBM25, promotes truncating mis-splicing of SCN5A, establishing it as a candidate mediator of acquired arrhythmic risk.","evidence":"Gene array of human heart failure vs. normal tissue plus overexpression of LUC7L3/RBM25 in Jurkat cells and hESC-derived cardiomyocytes, with quantification of full-length vs. truncated SCN5A mRNA and patch-clamp Na+ current","pmids":["21859973"],"confidence":"Medium","gaps":["No loss-of-function/knockdown or rescue experiment to establish necessity","Direct binding of LUC7L3 to SCN5A pre-mRNA and the cis-elements involved were not defined","Whether LUC7L3 regulates targets beyond SCN5A is untested"]},{"year":null,"claim":"The biochemical mechanism by which LUC7L3 selects splice sites, its spliceosomal partners, and the breadth of its regulated transcripts remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or RNA-binding characterization in the corpus","No genome-wide identification of LUC7L3 splicing targets","Mechanistic relationship to RBM25 (cooperative vs. independent) not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":[],"partners":["RBM25"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95232","full_name":"Luc7-like protein 3","aliases":["Cisplatin resistance-associated-overexpressed protein","Luc7A","Okadaic acid-inducible phosphoprotein OA48-18","cAMP regulatory element-associated protein 1","CRE-associated protein 1","CREAP-1"],"length_aa":432,"mass_kda":51.5,"function":"Binds cAMP regulatory element DNA sequence. 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Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39808224","citation_count":29,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35104,"output_tokens":429,"usd":0.055873,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6708,"output_tokens":1029,"usd":0.029632,"stage2_stop_reason":"end_turn"},"total_usd":0.085505,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"LUC7L3 (together with RBM25) mediates abnormal splicing of SCN5A (cardiac Na+ channel) mRNA, producing truncated transcripts and reducing full-length SCN5A mRNA and Na+ channel current by ~91% in Jurkat cells and human embryonic stem cell-derived cardiomyocytes. Both splicing factors were elevated in human heart failure tissue, and overexpression of either factor alone was sufficient to increase truncated mRNA and decrease full-length SCN5A transcript.\",\n      \"method\": \"Gene array profiling of human heart failure vs. normal tissue; overexpression of LUC7L3 and RBM25 in Jurkat cells and hESC-derived cardiomyocytes with quantification of full-length vs. truncated SCN5A mRNA and Na+ channel current (patch-clamp)\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression assay with two orthogonal readouts (mRNA splicing and electrophysiology), single lab, no rescue or mutagenesis experiment reported\",\n      \"pmids\": [\"21859973\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LUC7L3 is an mRNA splicing factor that, together with RBM25, promotes aberrant truncation of SCN5A (cardiac Na+ channel) pre-mRNA; its upregulation in human heart failure is sufficient to dramatically reduce full-length Na+ channel transcript and current, implicating it as a mediator of arrhythmic risk through pathological alternative splicing.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LUC7L3 is an mRNA splicing factor that, acting together with RBM25, drives aberrant alternative splicing of the cardiac sodium channel gene SCN5A, generating truncated transcripts at the expense of the full-length channel [#0]. In human heart failure tissue both factors are elevated, and overexpression of LUC7L3 alone in Jurkat cells and hESC-derived cardiomyocytes is sufficient to increase truncated SCN5A mRNA and reduce full-length transcript and Na+ channel current by ~91%, linking it to pathological remodeling of channel splicing [#0]. Beyond this single splicing-regulatory role in SCN5A processing, no further mechanistic detail — including its biochemical mode of substrate recognition or its broader spliceosomal interactions — has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Whether a specific splicing factor could account for the loss of functional cardiac Na+ channel in heart failure was unknown; this work showed LUC7L3, with RBM25, promotes truncating mis-splicing of SCN5A, establishing it as a candidate mediator of acquired arrhythmic risk.\",\n      \"evidence\": \"Gene array of human heart failure vs. normal tissue plus overexpression of LUC7L3/RBM25 in Jurkat cells and hESC-derived cardiomyocytes, with quantification of full-length vs. truncated SCN5A mRNA and patch-clamp Na+ current\",\n      \"pmids\": [\"21859973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No loss-of-function/knockdown or rescue experiment to establish necessity\",\n        \"Direct binding of LUC7L3 to SCN5A pre-mRNA and the cis-elements involved were not defined\",\n        \"Whether LUC7L3 regulates targets beyond SCN5A is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical mechanism by which LUC7L3 selects splice sites, its spliceosomal partners, and the breadth of its regulated transcripts remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or RNA-binding characterization in the corpus\",\n        \"No genome-wide identification of LUC7L3 splicing targets\",\n        \"Mechanistic relationship to RBM25 (cooperative vs. independent) not resolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RBM25\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}