{"gene":"GPATCH8","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2024,"finding":"GPATCH8 is required for mutant SF3B1-induced aberrant splicing alterations; silencing GPATCH8 corrected approximately one-third of mutant SF3B1-dependent splicing defects and improved dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors.","method":"Synthetic intron reporter screen to identify trans factors, genetic silencing (knockdown/knockout) in SF3B1-mutant mouse models and primary human hematopoietic progenitors, splicing analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter screen, in vivo mouse model, primary human cells) with defined cellular and molecular phenotypes, replicated across model systems","pmids":["38688280"],"is_preprint":false},{"year":2024,"finding":"GPATCH8 physically interacts with the RNA helicase DHX15, consistent with its role as a G-patch domain-containing protein that activates RNA helicases.","method":"Protein interaction studies (reported in the context of mechanistic characterization of GPATCH8 function in splicing)","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction reported in abstract without specifying Co-IP or pulldown details; single study but functionally contextualized","pmids":["38688280"],"is_preprint":false},{"year":2024,"finding":"GPATCH8 functionally opposes SUGP1 (SURP and G-patch domain containing 1) in branchpoint selection quality control, placing both proteins in the same pathway but with antagonistic roles during SF3B1-mutant mis-splicing.","method":"Genetic epistasis and functional splicing assays in SF3B1-mutant cellular models","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established in cellular models, single lab, functional antagonism demonstrated through splicing readouts","pmids":["38688280"],"is_preprint":false},{"year":2024,"finding":"GPATCH8 is involved in quality control of branchpoint selection during pre-mRNA splicing.","method":"Functional splicing analysis following GPATCH8 silencing in SF3B1-mutant cells","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inferred from splicing correction experiments in defined cellular models, single lab, no in vitro reconstitution","pmids":["38688280"],"is_preprint":false},{"year":2004,"finding":"KIAA0553 (GPATCH8) is highly expressed in adult cardiac tissue (13.1% of adult cardiac library ESTs) compared to fetal cardiac tissue (0.01%), as confirmed by Northern analysis.","method":"EST frequency analysis of cardiac expression libraries confirmed by Northern blot","journal":"Clinical biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Northern blot confirms expression difference but no mechanistic function established; single study, no functional follow-up","pmids":["15498521"],"is_preprint":false}],"current_model":"GPATCH8 is a G-patch domain-containing splicing factor that interacts with the RNA helicase DHX15 and participates in branchpoint selection quality control; it is required for aberrant splicing induced by oncogenic SF3B1 mutations, functionally antagonizing SUGP1, such that its silencing corrects a substantial fraction of mutant SF3B1-dependent mis-splicing events and rescues hematopoietic dysfunction."},"narrative":{"mechanistic_narrative":"GPATCH8 is a G-patch domain-containing splicing factor that participates in the quality control of branchpoint selection during pre-mRNA splicing [PMID:38688280]. It physically interacts with the RNA helicase DHX15, consistent with the canonical role of G-patch proteins in activating RNA helicases [PMID:38688280]. Within the branchpoint quality-control pathway, GPATCH8 functionally antagonizes SUGP1, the two proteins acting in the same pathway with opposing roles during SF3B1-mutant mis-splicing [PMID:38688280]. GPATCH8 is required for the aberrant splicing driven by oncogenic SF3B1 mutations: its silencing corrects roughly one-third of mutant SF3B1-dependent splicing defects and improves dysfunctional hematopoiesis in SF3B1-mutant mouse models and primary human hematopoietic progenitors, identifying it as a tractable node in mutant SF3B1 disease biology [PMID:38688280]. Beyond these splicing functions, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2004,"claim":"Before any functional role was known, the question was simply where GPATCH8 (KIAA0553) is expressed; this established a tissue context but no mechanism.","evidence":"EST frequency analysis of cardiac libraries confirmed by Northern blot","pmids":["15498521"],"confidence":"Low","gaps":["Expression-only observation with no functional follow-up","No molecular activity or interaction partner identified","Differential cardiac expression not linked to any phenotype"]},{"year":2024,"claim":"A reporter screen and in vivo genetics addressed whether any trans factor is required for oncogenic SF3B1-driven mis-splicing, showing GPATCH8 is necessary and that its loss reverses both splicing defects and hematopoietic dysfunction.","evidence":"Synthetic intron reporter screen, genetic silencing in SF3B1-mutant mouse models and primary human hematopoietic progenitors, splicing analysis","pmids":["38688280"],"confidence":"High","gaps":["Only ~one-third of mis-splicing events corrected, leaving other contributing factors undefined","Direct biochemical mechanism of how GPATCH8 acts on the spliceosome not reconstituted"]},{"year":2024,"claim":"To place GPATCH8 mechanistically, its interaction with the RNA helicase DHX15 was examined, linking it to helicase activation during splicing.","evidence":"Protein interaction studies in the context of splicing function characterization","pmids":["38688280"],"confidence":"Medium","gaps":["Interaction reported without specified Co-IP or pulldown detail and no reciprocal validation","Helicase-activating activity inferred from G-patch context rather than directly assayed"]},{"year":2024,"claim":"Epistasis experiments addressed how GPATCH8 relates to other branchpoint factors, establishing it as a functional antagonist of SUGP1 within the same quality-control pathway.","evidence":"Genetic epistasis and functional splicing assays in SF3B1-mutant cellular models","pmids":["38688280"],"confidence":"Medium","gaps":["Single-lab cellular epistasis without in vitro reconstitution","Molecular basis of the antagonism with SUGP1 not defined","Whether antagonism operates in wild-type SF3B1 contexts unclear"]},{"year":null,"claim":"The direct biochemical mechanism by which GPATCH8, via DHX15, enforces branchpoint selection quality control and counteracts SUGP1 remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution of GPATCH8/DHX15 activity on the spliceosome","No structural model of GPATCH8 within the branchpoint recognition machinery","Mechanism of antagonism with SUGP1 at the molecular level undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3]}],"complexes":[],"partners":["DHX15","SUGP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKJ3","full_name":"G patch domain-containing protein 8","aliases":[],"length_aa":1502,"mass_kda":164.2,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UKJ3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPATCH8","classification":"Not Classified","n_dependent_lines":47,"n_total_lines":1208,"dependency_fraction":0.03890728476821192},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPATCH8","total_profiled":1310},"omim":[{"mim_id":"614396","title":"G-PATCH DOMAIN-CONTAINING PROTEIN 8; GPATCH8","url":"https://www.omim.org/entry/614396"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GPATCH8"},"hgnc":{"alias_symbol":[],"prev_symbol":["KIAA0553","GPATC8"]},"alphafold":{"accession":"Q9UKJ3","domains":[{"cath_id":"-","chopping":"37-78","consensus_level":"medium","plddt":79.6879,"start":37,"end":78},{"cath_id":"1.20.5","chopping":"107-136","consensus_level":"medium","plddt":87.5747,"start":107,"end":136},{"cath_id":"1.20.5","chopping":"146-200","consensus_level":"medium","plddt":89.8898,"start":146,"end":200}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKJ3-F1-predicted_aligned_error_v6.png","plddt_mean":45.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPATCH8","jax_strain_url":"https://www.jax.org/strain/search?query=GPATCH8"},"sequence":{"accession":"Q9UKJ3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKJ3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKJ3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKJ3"}},"corpus_meta":[{"pmid":"38688280","id":"PMC_38688280","title":"GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies.","date":"2024","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38688280","citation_count":37,"is_preprint":false},{"pmid":"10477733","id":"PMC_10477733","title":"The human platelet alphaIIb gene is not closely linked to its integrin partner beta3.","date":"1999","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10477733","citation_count":30,"is_preprint":false},{"pmid":"32591784","id":"PMC_32591784","title":"Using off-target data from whole-exome sequencing to improve genotyping accuracy, association analysis and polygenic risk prediction.","date":"2021","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/32591784","citation_count":11,"is_preprint":false},{"pmid":"37474895","id":"PMC_37474895","title":"Identification of the susceptible genes and mechanism underlying the comorbid presence of coronary artery disease and rheumatoid arthritis: a network modularization analysis.","date":"2023","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37474895","citation_count":9,"is_preprint":false},{"pmid":"21594610","id":"PMC_21594610","title":"Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21594610","citation_count":6,"is_preprint":false},{"pmid":"39062728","id":"PMC_39062728","title":"Hepatopancreas Transcriptome Analysis of Spinibarbus sinensis to Reveal Different Growth-Related Genes.","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39062728","citation_count":5,"is_preprint":false},{"pmid":"38762373","id":"PMC_38762373","title":"(G)Patching up mis-splicing in cancer.","date":"2024","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38762373","citation_count":3,"is_preprint":false},{"pmid":"15498521","id":"PMC_15498521","title":"Venn analysis as part of a bioinformatic approach to prioritize expressed sequence tags from cardiac libraries.","date":"2004","source":"Clinical biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15498521","citation_count":2,"is_preprint":false},{"pmid":"40694934","id":"PMC_40694934","title":"Gonadal sex differentiation in Eleutheronema tetradactylum: Histological features and transcriptomic insights from mature gonads.","date":"2025","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/40694934","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6728,"output_tokens":1043,"usd":0.017914,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7631,"output_tokens":1697,"usd":0.04029,"stage2_stop_reason":"end_turn"},"total_usd":0.058204,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"GPATCH8 is required for mutant SF3B1-induced aberrant splicing alterations; silencing GPATCH8 corrected approximately one-third of mutant SF3B1-dependent splicing defects and improved dysfunctional hematopoiesis in SF3B1-mutant mice and primary human progenitors.\",\n      \"method\": \"Synthetic intron reporter screen to identify trans factors, genetic silencing (knockdown/knockout) in SF3B1-mutant mouse models and primary human hematopoietic progenitors, splicing analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter screen, in vivo mouse model, primary human cells) with defined cellular and molecular phenotypes, replicated across model systems\",\n      \"pmids\": [\"38688280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPATCH8 physically interacts with the RNA helicase DHX15, consistent with its role as a G-patch domain-containing protein that activates RNA helicases.\",\n      \"method\": \"Protein interaction studies (reported in the context of mechanistic characterization of GPATCH8 function in splicing)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction reported in abstract without specifying Co-IP or pulldown details; single study but functionally contextualized\",\n      \"pmids\": [\"38688280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPATCH8 functionally opposes SUGP1 (SURP and G-patch domain containing 1) in branchpoint selection quality control, placing both proteins in the same pathway but with antagonistic roles during SF3B1-mutant mis-splicing.\",\n      \"method\": \"Genetic epistasis and functional splicing assays in SF3B1-mutant cellular models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established in cellular models, single lab, functional antagonism demonstrated through splicing readouts\",\n      \"pmids\": [\"38688280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPATCH8 is involved in quality control of branchpoint selection during pre-mRNA splicing.\",\n      \"method\": \"Functional splicing analysis following GPATCH8 silencing in SF3B1-mutant cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inferred from splicing correction experiments in defined cellular models, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"38688280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KIAA0553 (GPATCH8) is highly expressed in adult cardiac tissue (13.1% of adult cardiac library ESTs) compared to fetal cardiac tissue (0.01%), as confirmed by Northern analysis.\",\n      \"method\": \"EST frequency analysis of cardiac expression libraries confirmed by Northern blot\",\n      \"journal\": \"Clinical biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Northern blot confirms expression difference but no mechanistic function established; single study, no functional follow-up\",\n      \"pmids\": [\"15498521\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPATCH8 is a G-patch domain-containing splicing factor that interacts with the RNA helicase DHX15 and participates in branchpoint selection quality control; it is required for aberrant splicing induced by oncogenic SF3B1 mutations, functionally antagonizing SUGP1, such that its silencing corrects a substantial fraction of mutant SF3B1-dependent mis-splicing events and rescues hematopoietic dysfunction.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPATCH8 is a G-patch domain-containing splicing factor that participates in the quality control of branchpoint selection during pre-mRNA splicing [#3]. It physically interacts with the RNA helicase DHX15, consistent with the canonical role of G-patch proteins in activating RNA helicases [#1]. Within the branchpoint quality-control pathway, GPATCH8 functionally antagonizes SUGP1, the two proteins acting in the same pathway with opposing roles during SF3B1-mutant mis-splicing [#2]. GPATCH8 is required for the aberrant splicing driven by oncogenic SF3B1 mutations: its silencing corrects roughly one-third of mutant SF3B1-dependent splicing defects and improves dysfunctional hematopoiesis in SF3B1-mutant mouse models and primary human hematopoietic progenitors, identifying it as a tractable node in mutant SF3B1 disease biology [#0]. Beyond these splicing functions, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Before any functional role was known, the question was simply where GPATCH8 (KIAA0553) is expressed; this established a tissue context but no mechanism.\",\n      \"evidence\": \"EST frequency analysis of cardiac libraries confirmed by Northern blot\",\n      \"pmids\": [\"15498521\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Expression-only observation with no functional follow-up\",\n        \"No molecular activity or interaction partner identified\",\n        \"Differential cardiac expression not linked to any phenotype\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A reporter screen and in vivo genetics addressed whether any trans factor is required for oncogenic SF3B1-driven mis-splicing, showing GPATCH8 is necessary and that its loss reverses both splicing defects and hematopoietic dysfunction.\",\n      \"evidence\": \"Synthetic intron reporter screen, genetic silencing in SF3B1-mutant mouse models and primary human hematopoietic progenitors, splicing analysis\",\n      \"pmids\": [\"38688280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Only ~one-third of mis-splicing events corrected, leaving other contributing factors undefined\",\n        \"Direct biochemical mechanism of how GPATCH8 acts on the spliceosome not reconstituted\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"To place GPATCH8 mechanistically, its interaction with the RNA helicase DHX15 was examined, linking it to helicase activation during splicing.\",\n      \"evidence\": \"Protein interaction studies in the context of splicing function characterization\",\n      \"pmids\": [\"38688280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Interaction reported without specified Co-IP or pulldown detail and no reciprocal validation\",\n        \"Helicase-activating activity inferred from G-patch context rather than directly assayed\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Epistasis experiments addressed how GPATCH8 relates to other branchpoint factors, establishing it as a functional antagonist of SUGP1 within the same quality-control pathway.\",\n      \"evidence\": \"Genetic epistasis and functional splicing assays in SF3B1-mutant cellular models\",\n      \"pmids\": [\"38688280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab cellular epistasis without in vitro reconstitution\",\n        \"Molecular basis of the antagonism with SUGP1 not defined\",\n        \"Whether antagonism operates in wild-type SF3B1 contexts unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical mechanism by which GPATCH8, via DHX15, enforces branchpoint selection quality control and counteracts SUGP1 remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No in vitro reconstitution of GPATCH8/DHX15 activity on the spliceosome\",\n        \"No structural model of GPATCH8 within the branchpoint recognition machinery\",\n        \"Mechanism of antagonism with SUGP1 at the molecular level undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DHX15\", \"SUGP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":4,"faith_pct":75.0}}