{"gene":"PRPF3","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"Human PRPF3 (hPrp3) is a component of a stable protein complex with the human Prp4 homolog and a cyclophilin, and this complex is associated with U4/U6 snRNPs purified from HeLa cells. The complex behaves as a single species throughout purification, indicating tight association independent of RNA.","method":"Biochemical purification from HeLa cells, peptide sequencing, full-length cDNA cloning, co-purification analysis","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-purification with peptide sequencing, replicated in yeast context by independent lab same year","pmids":["9404889"],"is_preprint":false},{"year":1997,"finding":"Yeast Prp3p is a component of the U4/U6 snRNP and U4/U6.U5 tri-snRNP; heat inactivation of Prp3p leads to loss of free U6 snRNPs and tri-snRNPs, accumulation of free U4 snRNA, and failure of spliceosome assembly from prespliceosomes, establishing Prp3p as required for stable U4/U6 snRNP formation and tri-snRNP assembly.","method":"Genetic heat-inactivation of prp3 mutant yeast, snRNA analysis (Northern blotting), splicing assays in vitro and in vivo","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (splicing assays, snRNA levels, snRNP fractionation) in yeast with defined functional phenotype","pmids":["9326489"],"is_preprint":false},{"year":1998,"finding":"Yeast Prp4 interacts directly with yeast Prp3 through the C-terminal WD-repeat (beta-propeller) domain of Prp4; deletion analysis and point mutations mapped the Prp3-binding surface to the C-terminal half of Prp4, and a small basic-rich N-terminal region of Prp4 is essential for cell viability.","method":"Yeast two-hybrid system, in vitro immunoprecipitation, deletion and point-mutation analysis, 3D structural modelling","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal two-hybrid and in vitro immunoprecipitation with systematic mutagenesis, single lab","pmids":["9826507"],"is_preprint":false},{"year":2002,"finding":"Two missense mutations (T494M and P493S) in the 11th exon of HPRP3 (PRPF3) co-segregate with autosomal dominant retinitis pigmentosa in multiple families; the altered residues are highly conserved across all known Prp3 orthologs, implicating this domain in the splicing function essential for photoreceptor survival.","method":"Genomic sequencing, haplotype analysis with SNPs, family linkage/co-segregation analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — genetic co-segregation in multiple independent families; no direct biochemical mechanism experiment, but replicated across labs","pmids":["11773002"],"is_preprint":false},{"year":2007,"finding":"Wild-type PRPF3 co-localizes with small nuclear ribonucleoproteins (snRNPs) and SC35-marked nuclear speckles. The RP-causing T494M mutant PRPF3 forms abnormally large nuclear aggregates specifically in photoreceptor cells, triggers apoptosis in those cells, and disrupts the distribution of other splicing factors; this aggregation is not seen in non-photoreceptor cells.","method":"Immunofluorescence/co-localization in transfected cells and human retina sections, apoptosis assays, transcriptional/translational/proteasome inhibition experiments","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional consequence (apoptosis), multiple cell types tested, single lab","pmids":["17517693"],"is_preprint":false},{"year":2008,"finding":"Heterozygous Prpf3 knockout mice do not show photoreceptor degeneration, establishing that RP18 is not caused by haploinsufficiency. Compensatory upregulation of the wild-type allele maintains near-normal Prpf3 levels. Homozygous knockout is embryonic lethal in mice and causes high cell death in zebrafish eyes, confirming Prpf3 is essential for early development.","method":"Gene-trap knockout mouse and zebrafish generation, retinal histology, ERG, Western blotting, RT-PCR splicing assay, survival analysis","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO in two species with multiple orthogonal readouts (histology, ERG, molecular), clearly distinguishing gain-of-function from haploinsufficiency","pmids":["18552388"],"is_preprint":false},{"year":2008,"finding":"SPF30 bridges a simultaneous interaction between U2AF35 (prespliceosome) and hPrp3 (tri-snRNP component) via its N-terminal domain binding U2AF35 and its C-terminus binding a middle domain of hPrp3, potentially linking 3' splice site recognition to tri-snRNP addition during spliceosome assembly.","method":"Co-immunoprecipitation, GST pulldown assays with defined domain constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct pulldown identifying simultaneous complex, domain-mapping with truncation constructs, single lab","pmids":["18211889"],"is_preprint":false},{"year":2015,"finding":"Prp3 contains a bipartite RNA-binding region: an expanded ferredoxin-like fold that recognizes the 3'-single-stranded overhang of U6 snRNA, and a preceding peptide that binds the U4/U6 stem II duplex. This composite dsRNA/ssRNA binding region assembles cooperatively with Snu13 and Prp31 on U4/U6 di-snRNAs, inhibits Brr2-mediated U4/U6 unwinding in vitro, and mutations disrupting RNP contacts cause tri-snRNP assembly and splicing defects in vivo. Prp3 thus bridges U4/U6 and U5 in the tri-snRNP.","method":"X-ray crystallography, biochemical RNA-binding assays, in vitro Brr2 unwinding assay, mutational analysis in yeast with splicing and tri-snRNP assembly readouts, phylogenetic analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with in vitro reconstitution, mutagenesis, and in vivo functional validation across multiple orthogonal methods","pmids":["26161500"],"is_preprint":false},{"year":2022,"finding":"TMEM43 physically interacts with PRPF3 (identified by co-IP/mass spectrometry) and stabilizes PRPF3 protein levels; TMEM43-mediated stabilization of PRPF3 promotes pancreatic cancer progression through the RAP2B/ERK signaling axis.","method":"Co-immunoprecipitation followed by protein mass spectrometry, knockdown experiments in vitro and in vivo (xenograft), cell cycle analysis","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with MS identification, in vitro and in vivo functional validation, single lab","pmids":["35260078"],"is_preprint":false},{"year":2023,"finding":"TXNL4B interacts with PRPF3 and co-localizes with it in the nucleus after ionizing radiation. Nuclear PRPF3 promotes alternative splicing of FANCI toward variants FANCI-12 and FANCI-13, and facilitates interaction of PRP31 and PRP8 with the spliceosome core; inhibition of PRPF3 suppresses FANCI-12 production, impairs DNA damage repair, induces G2/M arrest, and increases radiosensitivity.","method":"Co-immunoprecipitation, immunofluorescence co-localization, alternative splicing assays (RT-PCR), knockdown with functional radiation-sensitivity readouts, cell cycle analysis","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional splicing and radiosensitivity assays with knockdown, single lab","pmids":["37168687"],"is_preprint":false},{"year":2026,"finding":"A novel heterozygous intronic non-canonical splice variant in PRPF3 causes dominant retinitis pigmentosa by disrupting normal splicing; antisense oligonucleotides (AONs delivered via U7 snRNA cassettes) can rescue normal splicing and restore gene function in a HEK293T dual fluorescence reporter assay, demonstrating the pathogenicity of the splice variant.","method":"Dual fluorescence reporter assay in HEK293T cells, FACS quantification of splicing rescue, co-transfection of U7snRNA-AON constructs","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay with direct splicing readout and AON rescue in cell-based system, single lab","pmids":["42211691"],"is_preprint":false}],"current_model":"PRPF3 is an essential U4/U6 di-snRNP protein that bridges U4/U6 and U5 snRNPs in the tri-snRNP via a bipartite RNA-binding region (a ferredoxin-like fold binding the U6 3'-overhang and a peptide binding U4/U6 stem II); it forms a stable complex with Prp4/PRPF4 and cyclophilin, inhibits Brr2-mediated U4/U6 unwinding, and is required for tri-snRNP integrity and spliceosome assembly; RP-associated missense mutations (notably T494M) do not cause haploinsufficiency but instead generate toxic nuclear aggregates in photoreceptor cells that trigger apoptosis, while PRPF3 protein stability is regulated by TMEM43 and its nuclear activity controls alternative splicing of FANCI after DNA damage."},"narrative":{"mechanistic_narrative":"PRPF3 is an essential pre-mRNA splicing factor that functions as a core protein of the U4/U6 di-snRNP and is required for assembly and integrity of the U4/U6.U5 tri-snRNP [PMID:9404889, PMID:9326489]. It forms a stable, RNA-independent complex with the Prp4 homolog (PRPF4) and a cyclophilin, binding the C-terminal WD-repeat β-propeller of Prp4 [PMID:9404889, PMID:9826507]. Structurally, PRPF3 uses a bipartite RNA-binding region — an expanded ferredoxin-like fold that recognizes the U6 snRNA 3' single-stranded overhang and a preceding peptide that binds the U4/U6 stem II duplex — to assemble cooperatively with Snu13 and Prp31 on U4/U6 di-snRNA, inhibit Brr2-mediated U4/U6 unwinding, and thereby bridge U4/U6 and U5 within the tri-snRNP [PMID:26161500]. During spliceosome assembly its middle domain is engaged by SPF30, which simultaneously binds U2AF35, linking 3' splice site recognition to tri-snRNP addition [PMID:18211889]. PRPF3 is essential for development, as homozygous loss is embryonic lethal in mice and lethal to zebrafish eye cells [PMID:18552388]. Dominant missense mutations (T494M, P493S) cause autosomal dominant retinitis pigmentosa not through haploinsufficiency but via a gain-of-function mechanism: the T494M mutant forms toxic nuclear aggregates specifically in photoreceptor cells, disrupts splicing-factor distribution, and triggers apoptosis [PMID:11773002, PMID:17517693, PMID:18552388]; intronic splice variants disrupting PRPF3 splicing also cause dominant RP [PMID:42211691]. Beyond constitutive splicing, nuclear PRPF3 directs alternative splicing of FANCI toward DNA-repair-competent variants after ionizing radiation, and its protein stability is regulated by the interacting partner TMEM43 [PMID:35260078, PMID:37168687].","teleology":[{"year":1997,"claim":"Established that PRPF3 is a bona fide spliceosomal protein, defining its physical context as a stable U4/U6-associated complex with the Prp4 homolog and a cyclophilin.","evidence":"Biochemical purification and peptide sequencing from HeLa cells with co-purification analysis","pmids":["9404889"],"confidence":"High","gaps":["Did not define the RNA contacts or domain architecture mediating snRNP association","Functional consequence of the cyclophilin in the complex not resolved"]},{"year":1997,"claim":"Defined PRPF3's functional role by showing the yeast ortholog is required for stable U4/U6 snRNP formation and tri-snRNP assembly, without which spliceosome assembly fails.","evidence":"Heat-inactivation of prp3 mutant yeast with snRNA Northern analysis and in vitro/in vivo splicing assays","pmids":["9326489"],"confidence":"High","gaps":["Did not establish the molecular mechanism by which Prp3 stabilizes U4/U6","Direct RNA-binding activity not shown"]},{"year":1998,"claim":"Mapped the direct PRPF3–PRPF4 interaction interface, localizing Prp3 binding to the C-terminal WD-repeat domain of Prp4.","evidence":"Yeast two-hybrid, in vitro immunoprecipitation, deletion/point mutation analysis and structural modelling","pmids":["9826507"],"confidence":"Medium","gaps":["Single-lab mapping without a co-crystal structure","Functional requirement of the interface for splicing not directly tested"]},{"year":2002,"claim":"Linked PRPF3 to human disease by identifying conserved missense mutations co-segregating with autosomal dominant retinitis pigmentosa.","evidence":"Genomic sequencing and family linkage/co-segregation analysis across multiple families","pmids":["11773002"],"confidence":"Medium","gaps":["No biochemical mechanism for how mutations cause photoreceptor disease","Did not distinguish loss-of-function from gain-of-function"]},{"year":2007,"claim":"Resolved the disease mechanism as photoreceptor-specific gain-of-function, showing T494M mutant PRPF3 forms toxic nuclear aggregates that disrupt splicing factors and trigger apoptosis.","evidence":"Immunofluorescence/co-localization in transfected cells and human retina, apoptosis and inhibitor assays","pmids":["17517693"],"confidence":"Medium","gaps":["Why aggregation is photoreceptor-restricted not explained","Aggregate composition and clearance pathway not defined"]},{"year":2008,"claim":"Genetically confirmed that RP is not caused by haploinsufficiency and demonstrated PRPF3 is essential for early development.","evidence":"Gene-trap knockout mouse and zebrafish with retinal histology, ERG, Western blotting, and survival analysis","pmids":["18552388"],"confidence":"High","gaps":["Did not model the dominant aggregate phenotype in vivo","Compensatory upregulation mechanism not detailed"]},{"year":2008,"claim":"Placed PRPF3 in the spliceosome assembly pathway by showing SPF30 bridges it to U2AF35, coupling 3' splice site recognition to tri-snRNP recruitment.","evidence":"Co-immunoprecipitation and GST pulldown with domain constructs","pmids":["18211889"],"confidence":"Medium","gaps":["Functional consequence of disrupting the bridge on splicing not tested","Stoichiometry within assembling spliceosome unknown"]},{"year":2015,"claim":"Provided the structural and mechanistic basis for PRPF3 function, defining a bipartite RNA-binding region that bridges U4/U6 and U5 and inhibits Brr2 unwinding.","evidence":"X-ray crystallography, RNA-binding and Brr2 unwinding assays, yeast mutagenesis with splicing/tri-snRNP readouts","pmids":["26161500"],"confidence":"High","gaps":["Did not connect the structural mechanism to the RP aggregation phenotype","Regulation of Brr2 inhibition timing in the catalytic cycle not addressed"]},{"year":2022,"claim":"Identified post-translational regulation of PRPF3 by TMEM43, linking PRPF3 stability to a cancer-promoting signaling axis.","evidence":"Co-IP/mass spectrometry, knockdown in vitro and in xenografts, cell cycle analysis","pmids":["35260078"],"confidence":"Medium","gaps":["Mechanism of TMEM43-mediated stabilization (e.g. degradation pathway) not defined","Whether splicing activity mediates the cancer phenotype not established"]},{"year":2023,"claim":"Extended PRPF3 function to regulated alternative splicing, showing nuclear PRPF3 drives DNA-repair-competent FANCI variants after irradiation and modulates radiosensitivity.","evidence":"Co-IP, immunofluorescence, RT-PCR splicing assays and knockdown with radiation-sensitivity and cell cycle readouts","pmids":["37168687"],"confidence":"Medium","gaps":["How TXNL4B directs PRPF3 toward FANCI splicing is unclear","Single-lab finding without independent confirmation"]},{"year":2026,"claim":"Demonstrated that intronic non-canonical splice variants in PRPF3 cause dominant RP and are amenable to antisense correction.","evidence":"Dual fluorescence reporter assay in HEK293T with FACS quantification and U7snRNA-AON rescue","pmids":["42211691"],"confidence":"Medium","gaps":["Rescue shown only in a cell-based reporter, not in patient tissue or animal models","Cell-type specificity of the pathogenic mechanism not addressed"]},{"year":null,"claim":"How PRPF3's defined splicing functions mechanistically connect to the photoreceptor-specific toxicity of RP mutants and to its non-canonical roles in cancer and DNA damage remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural explanation for why T494M aggregates only in photoreceptors","Whether non-spliceosomal PRPF3 roles share its RNA-binding mechanism is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,9]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[9]}],"complexes":["U4/U6 di-snRNP","U4/U6.U5 tri-snRNP"],"partners":["PRPF4","SNU13","PRPF31","SPF30","U2AF35","TMEM43","TXNL4B","PRPF8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43395","full_name":"U4/U6 small nuclear ribonucleoprotein Prp3","aliases":["Pre-mRNA-splicing factor 3","hPrp3","U4/U6 snRNP 90 kDa protein"],"length_aa":683,"mass_kda":77.5,"function":"Plays a role in pre-mRNA splicing as component of the U4/U6-U5 tri-snRNP complex that is involved in spliceosome assembly, and as component of the precatalytic spliceosome (spliceosome B complex)","subcellular_location":"Nucleus; Nucleus speckle","url":"https://www.uniprot.org/uniprotkb/O43395/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PRPF3","classification":"Common Essential","n_dependent_lines":1183,"n_total_lines":1208,"dependency_fraction":0.9793046357615894},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRPF4B","stoichiometry":10.0},{"gene":"PRPF8","stoichiometry":4.0},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CD2BP2","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DDX39B","stoichiometry":0.2},{"gene":"EFTUD2","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RBM17","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PRPF3","total_profiled":1310},"omim":[{"mim_id":"621494","title":"RNA, U6 SMALL NUCLEAR 9; RNU6-9","url":"https://www.omim.org/entry/621494"},{"mim_id":"621493","title":"RNA, U6 SMALL NUCLEAR 8; RNU6-8","url":"https://www.omim.org/entry/621493"},{"mim_id":"621491","title":"RNA, U6 SMALL NUCLEAR 2; RNU6-2","url":"https://www.omim.org/entry/621491"},{"mim_id":"620823","title":"RNA, U4 SMALL NUCLEAR 2; RNU4-2","url":"https://www.omim.org/entry/620823"},{"mim_id":"620415","title":"WOOLLY HAIR-SKIN FRAGILITY SYNDROME; WHSF","url":"https://www.omim.org/entry/620415"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRPF3"},"hgnc":{"alias_symbol":["Prp3","hPrp3","SNRNP90"],"prev_symbol":["RP18"]},"alphafold":{"accession":"O43395","domains":[{"cath_id":"1.20.1390.10","chopping":"4-78","consensus_level":"high","plddt":83.8972,"start":4,"end":78},{"cath_id":"-","chopping":"442-523","consensus_level":"medium","plddt":91.7355,"start":442,"end":523},{"cath_id":"3.30.70.100","chopping":"540-605_626-679","consensus_level":"medium","plddt":91.4303,"start":540,"end":679}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43395","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43395-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43395-F1-predicted_aligned_error_v6.png","plddt_mean":73.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRPF3","jax_strain_url":"https://www.jax.org/strain/search?query=PRPF3"},"sequence":{"accession":"O43395","fasta_url":"https://rest.uniprot.org/uniprotkb/O43395.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43395/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43395"}},"corpus_meta":[{"pmid":"11773002","id":"PMC_11773002","title":"Mutations in HPRP3, a third member of pre-mRNA splicing factor genes, implicated in autosomal dominant retinitis pigmentosa.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11773002","citation_count":194,"is_preprint":false},{"pmid":"3196309","id":"PMC_3196309","title":"The primary structures of six human salivary acidic proline-rich proteins (PRP-1, PRP-2, PRP-3, PRP-4, PIF-s and PIF-f).","date":"1988","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/3196309","citation_count":97,"is_preprint":false},{"pmid":"12714658","id":"PMC_12714658","title":"Mutations in the pre-mRNA splicing-factor genes PRPF3, PRPF8, and PRPF31 in Spanish families with autosomal dominant retinitis pigmentosa.","date":"2003","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/12714658","citation_count":82,"is_preprint":false},{"pmid":"9404889","id":"PMC_9404889","title":"A new cyclophilin and the human homologues of yeast Prp3 and Prp4 form a complex associated with U4/U6 snRNPs.","date":"1997","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9404889","citation_count":76,"is_preprint":false},{"pmid":"12199583","id":"PMC_12199583","title":"Tandem mass spectrometry for structural characterization of proline-rich proteins: application to salivary PRP-3.","date":"2002","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12199583","citation_count":49,"is_preprint":false},{"pmid":"21283520","id":"PMC_21283520","title":"Temporal and tissue specific regulation of RP-associated splicing factor genes PRPF3, PRPF31 and PRPC8--implications in the pathogenesis of RP.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21283520","citation_count":44,"is_preprint":false},{"pmid":"26161500","id":"PMC_26161500","title":"A composite double-/single-stranded RNA-binding region in protein Prp3 supports tri-snRNP stability and 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FANCI.","date":"2023","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/37168687","citation_count":6,"is_preprint":false},{"pmid":"19757174","id":"PMC_19757174","title":"Differential display reveals a novel pig gene, PRPF3, which is differentially expressed in Large White versus Wujin skeletal muscle tissues.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19757174","citation_count":2,"is_preprint":false},{"pmid":"28848678","id":"PMC_28848678","title":"PRPF3-Associated Autosomal Dominant Retinitis Pigmentosa and CYP4V2-Associated Bietti's Crystalline Corneoretinal Dystrophy Coexist in a Multigenerational Chinese Family.","date":"2017","source":"Journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/28848678","citation_count":1,"is_preprint":false},{"pmid":"6370789","id":"PMC_6370789","title":"[Deletions of plasmid pRP3.1ts12 derived from RP1 leading to the suppression of the thermosensitive ts12 mutation and mucoid phenotype induction in Escherichia coli K-12].","date":"1984","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/6370789","citation_count":0,"is_preprint":false},{"pmid":"42211691","id":"PMC_42211691","title":"FACS-based dual fluorescence reporter assay demonstrates efficacy of antisense oligonucleotide therapy of novel PRPF3 intronic splice variant.","date":"2026","source":"Molecular therapy. Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/42211691","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.06.24317169","title":"De novo and inherited dominant variants in U4 and U6 snRNAs cause retinitis pigmentosa","date":"2025-01-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.06.24317169","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14963,"output_tokens":3005,"usd":0.044982,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10311,"output_tokens":3677,"usd":0.07174,"stage2_stop_reason":"end_turn"},"total_usd":0.116722,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Human PRPF3 (hPrp3) is a component of a stable protein complex with the human Prp4 homolog and a cyclophilin, and this complex is associated with U4/U6 snRNPs purified from HeLa cells. The complex behaves as a single species throughout purification, indicating tight association independent of RNA.\",\n      \"method\": \"Biochemical purification from HeLa cells, peptide sequencing, full-length cDNA cloning, co-purification analysis\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-purification with peptide sequencing, replicated in yeast context by independent lab same year\",\n      \"pmids\": [\"9404889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Prp3p is a component of the U4/U6 snRNP and U4/U6.U5 tri-snRNP; heat inactivation of Prp3p leads to loss of free U6 snRNPs and tri-snRNPs, accumulation of free U4 snRNA, and failure of spliceosome assembly from prespliceosomes, establishing Prp3p as required for stable U4/U6 snRNP formation and tri-snRNP assembly.\",\n      \"method\": \"Genetic heat-inactivation of prp3 mutant yeast, snRNA analysis (Northern blotting), splicing assays in vitro and in vivo\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (splicing assays, snRNA levels, snRNP fractionation) in yeast with defined functional phenotype\",\n      \"pmids\": [\"9326489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Prp4 interacts directly with yeast Prp3 through the C-terminal WD-repeat (beta-propeller) domain of Prp4; deletion analysis and point mutations mapped the Prp3-binding surface to the C-terminal half of Prp4, and a small basic-rich N-terminal region of Prp4 is essential for cell viability.\",\n      \"method\": \"Yeast two-hybrid system, in vitro immunoprecipitation, deletion and point-mutation analysis, 3D structural modelling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal two-hybrid and in vitro immunoprecipitation with systematic mutagenesis, single lab\",\n      \"pmids\": [\"9826507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Two missense mutations (T494M and P493S) in the 11th exon of HPRP3 (PRPF3) co-segregate with autosomal dominant retinitis pigmentosa in multiple families; the altered residues are highly conserved across all known Prp3 orthologs, implicating this domain in the splicing function essential for photoreceptor survival.\",\n      \"method\": \"Genomic sequencing, haplotype analysis with SNPs, family linkage/co-segregation analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — genetic co-segregation in multiple independent families; no direct biochemical mechanism experiment, but replicated across labs\",\n      \"pmids\": [\"11773002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Wild-type PRPF3 co-localizes with small nuclear ribonucleoproteins (snRNPs) and SC35-marked nuclear speckles. The RP-causing T494M mutant PRPF3 forms abnormally large nuclear aggregates specifically in photoreceptor cells, triggers apoptosis in those cells, and disrupts the distribution of other splicing factors; this aggregation is not seen in non-photoreceptor cells.\",\n      \"method\": \"Immunofluorescence/co-localization in transfected cells and human retina sections, apoptosis assays, transcriptional/translational/proteasome inhibition experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional consequence (apoptosis), multiple cell types tested, single lab\",\n      \"pmids\": [\"17517693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Heterozygous Prpf3 knockout mice do not show photoreceptor degeneration, establishing that RP18 is not caused by haploinsufficiency. Compensatory upregulation of the wild-type allele maintains near-normal Prpf3 levels. Homozygous knockout is embryonic lethal in mice and causes high cell death in zebrafish eyes, confirming Prpf3 is essential for early development.\",\n      \"method\": \"Gene-trap knockout mouse and zebrafish generation, retinal histology, ERG, Western blotting, RT-PCR splicing assay, survival analysis\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO in two species with multiple orthogonal readouts (histology, ERG, molecular), clearly distinguishing gain-of-function from haploinsufficiency\",\n      \"pmids\": [\"18552388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SPF30 bridges a simultaneous interaction between U2AF35 (prespliceosome) and hPrp3 (tri-snRNP component) via its N-terminal domain binding U2AF35 and its C-terminus binding a middle domain of hPrp3, potentially linking 3' splice site recognition to tri-snRNP addition during spliceosome assembly.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown assays with defined domain constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct pulldown identifying simultaneous complex, domain-mapping with truncation constructs, single lab\",\n      \"pmids\": [\"18211889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Prp3 contains a bipartite RNA-binding region: an expanded ferredoxin-like fold that recognizes the 3'-single-stranded overhang of U6 snRNA, and a preceding peptide that binds the U4/U6 stem II duplex. This composite dsRNA/ssRNA binding region assembles cooperatively with Snu13 and Prp31 on U4/U6 di-snRNAs, inhibits Brr2-mediated U4/U6 unwinding in vitro, and mutations disrupting RNP contacts cause tri-snRNP assembly and splicing defects in vivo. Prp3 thus bridges U4/U6 and U5 in the tri-snRNP.\",\n      \"method\": \"X-ray crystallography, biochemical RNA-binding assays, in vitro Brr2 unwinding assay, mutational analysis in yeast with splicing and tri-snRNP assembly readouts, phylogenetic analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with in vitro reconstitution, mutagenesis, and in vivo functional validation across multiple orthogonal methods\",\n      \"pmids\": [\"26161500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM43 physically interacts with PRPF3 (identified by co-IP/mass spectrometry) and stabilizes PRPF3 protein levels; TMEM43-mediated stabilization of PRPF3 promotes pancreatic cancer progression through the RAP2B/ERK signaling axis.\",\n      \"method\": \"Co-immunoprecipitation followed by protein mass spectrometry, knockdown experiments in vitro and in vivo (xenograft), cell cycle analysis\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with MS identification, in vitro and in vivo functional validation, single lab\",\n      \"pmids\": [\"35260078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TXNL4B interacts with PRPF3 and co-localizes with it in the nucleus after ionizing radiation. Nuclear PRPF3 promotes alternative splicing of FANCI toward variants FANCI-12 and FANCI-13, and facilitates interaction of PRP31 and PRP8 with the spliceosome core; inhibition of PRPF3 suppresses FANCI-12 production, impairs DNA damage repair, induces G2/M arrest, and increases radiosensitivity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, alternative splicing assays (RT-PCR), knockdown with functional radiation-sensitivity readouts, cell cycle analysis\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional splicing and radiosensitivity assays with knockdown, single lab\",\n      \"pmids\": [\"37168687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"A novel heterozygous intronic non-canonical splice variant in PRPF3 causes dominant retinitis pigmentosa by disrupting normal splicing; antisense oligonucleotides (AONs delivered via U7 snRNA cassettes) can rescue normal splicing and restore gene function in a HEK293T dual fluorescence reporter assay, demonstrating the pathogenicity of the splice variant.\",\n      \"method\": \"Dual fluorescence reporter assay in HEK293T cells, FACS quantification of splicing rescue, co-transfection of U7snRNA-AON constructs\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay with direct splicing readout and AON rescue in cell-based system, single lab\",\n      \"pmids\": [\"42211691\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRPF3 is an essential U4/U6 di-snRNP protein that bridges U4/U6 and U5 snRNPs in the tri-snRNP via a bipartite RNA-binding region (a ferredoxin-like fold binding the U6 3'-overhang and a peptide binding U4/U6 stem II); it forms a stable complex with Prp4/PRPF4 and cyclophilin, inhibits Brr2-mediated U4/U6 unwinding, and is required for tri-snRNP integrity and spliceosome assembly; RP-associated missense mutations (notably T494M) do not cause haploinsufficiency but instead generate toxic nuclear aggregates in photoreceptor cells that trigger apoptosis, while PRPF3 protein stability is regulated by TMEM43 and its nuclear activity controls alternative splicing of FANCI after DNA damage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRPF3 is an essential pre-mRNA splicing factor that functions as a core protein of the U4/U6 di-snRNP and is required for assembly and integrity of the U4/U6.U5 tri-snRNP [#0, #1]. It forms a stable, RNA-independent complex with the Prp4 homolog (PRPF4) and a cyclophilin, binding the C-terminal WD-repeat β-propeller of Prp4 [#0, #2]. Structurally, PRPF3 uses a bipartite RNA-binding region — an expanded ferredoxin-like fold that recognizes the U6 snRNA 3' single-stranded overhang and a preceding peptide that binds the U4/U6 stem II duplex — to assemble cooperatively with Snu13 and Prp31 on U4/U6 di-snRNA, inhibit Brr2-mediated U4/U6 unwinding, and thereby bridge U4/U6 and U5 within the tri-snRNP [#7]. During spliceosome assembly its middle domain is engaged by SPF30, which simultaneously binds U2AF35, linking 3' splice site recognition to tri-snRNP addition [#6]. PRPF3 is essential for development, as homozygous loss is embryonic lethal in mice and lethal to zebrafish eye cells [#5]. Dominant missense mutations (T494M, P493S) cause autosomal dominant retinitis pigmentosa not through haploinsufficiency but via a gain-of-function mechanism: the T494M mutant forms toxic nuclear aggregates specifically in photoreceptor cells, disrupts splicing-factor distribution, and triggers apoptosis [#3, #4, #5]; intronic splice variants disrupting PRPF3 splicing also cause dominant RP [#10]. Beyond constitutive splicing, nuclear PRPF3 directs alternative splicing of FANCI toward DNA-repair-competent variants after ionizing radiation, and its protein stability is regulated by the interacting partner TMEM43 [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that PRPF3 is a bona fide spliceosomal protein, defining its physical context as a stable U4/U6-associated complex with the Prp4 homolog and a cyclophilin.\",\n      \"evidence\": \"Biochemical purification and peptide sequencing from HeLa cells with co-purification analysis\",\n      \"pmids\": [\"9404889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the RNA contacts or domain architecture mediating snRNP association\", \"Functional consequence of the cyclophilin in the complex not resolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined PRPF3's functional role by showing the yeast ortholog is required for stable U4/U6 snRNP formation and tri-snRNP assembly, without which spliceosome assembly fails.\",\n      \"evidence\": \"Heat-inactivation of prp3 mutant yeast with snRNA Northern analysis and in vitro/in vivo splicing assays\",\n      \"pmids\": [\"9326489\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the molecular mechanism by which Prp3 stabilizes U4/U6\", \"Direct RNA-binding activity not shown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapped the direct PRPF3–PRPF4 interaction interface, localizing Prp3 binding to the C-terminal WD-repeat domain of Prp4.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro immunoprecipitation, deletion/point mutation analysis and structural modelling\",\n      \"pmids\": [\"9826507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab mapping without a co-crystal structure\", \"Functional requirement of the interface for splicing not directly tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked PRPF3 to human disease by identifying conserved missense mutations co-segregating with autosomal dominant retinitis pigmentosa.\",\n      \"evidence\": \"Genomic sequencing and family linkage/co-segregation analysis across multiple families\",\n      \"pmids\": [\"11773002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No biochemical mechanism for how mutations cause photoreceptor disease\", \"Did not distinguish loss-of-function from gain-of-function\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved the disease mechanism as photoreceptor-specific gain-of-function, showing T494M mutant PRPF3 forms toxic nuclear aggregates that disrupt splicing factors and trigger apoptosis.\",\n      \"evidence\": \"Immunofluorescence/co-localization in transfected cells and human retina, apoptosis and inhibitor assays\",\n      \"pmids\": [\"17517693\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why aggregation is photoreceptor-restricted not explained\", \"Aggregate composition and clearance pathway not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetically confirmed that RP is not caused by haploinsufficiency and demonstrated PRPF3 is essential for early development.\",\n      \"evidence\": \"Gene-trap knockout mouse and zebrafish with retinal histology, ERG, Western blotting, and survival analysis\",\n      \"pmids\": [\"18552388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not model the dominant aggregate phenotype in vivo\", \"Compensatory upregulation mechanism not detailed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed PRPF3 in the spliceosome assembly pathway by showing SPF30 bridges it to U2AF35, coupling 3' splice site recognition to tri-snRNP recruitment.\",\n      \"evidence\": \"Co-immunoprecipitation and GST pulldown with domain constructs\",\n      \"pmids\": [\"18211889\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of disrupting the bridge on splicing not tested\", \"Stoichiometry within assembling spliceosome unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural and mechanistic basis for PRPF3 function, defining a bipartite RNA-binding region that bridges U4/U6 and U5 and inhibits Brr2 unwinding.\",\n      \"evidence\": \"X-ray crystallography, RNA-binding and Brr2 unwinding assays, yeast mutagenesis with splicing/tri-snRNP readouts\",\n      \"pmids\": [\"26161500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect the structural mechanism to the RP aggregation phenotype\", \"Regulation of Brr2 inhibition timing in the catalytic cycle not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-translational regulation of PRPF3 by TMEM43, linking PRPF3 stability to a cancer-promoting signaling axis.\",\n      \"evidence\": \"Co-IP/mass spectrometry, knockdown in vitro and in xenografts, cell cycle analysis\",\n      \"pmids\": [\"35260078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TMEM43-mediated stabilization (e.g. degradation pathway) not defined\", \"Whether splicing activity mediates the cancer phenotype not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended PRPF3 function to regulated alternative splicing, showing nuclear PRPF3 drives DNA-repair-competent FANCI variants after irradiation and modulates radiosensitivity.\",\n      \"evidence\": \"Co-IP, immunofluorescence, RT-PCR splicing assays and knockdown with radiation-sensitivity and cell cycle readouts\",\n      \"pmids\": [\"37168687\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TXNL4B directs PRPF3 toward FANCI splicing is unclear\", \"Single-lab finding without independent confirmation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that intronic non-canonical splice variants in PRPF3 cause dominant RP and are amenable to antisense correction.\",\n      \"evidence\": \"Dual fluorescence reporter assay in HEK293T with FACS quantification and U7snRNA-AON rescue\",\n      \"pmids\": [\"42211691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Rescue shown only in a cell-based reporter, not in patient tissue or animal models\", \"Cell-type specificity of the pathogenic mechanism not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRPF3's defined splicing functions mechanistically connect to the photoreceptor-specific toxicity of RP mutants and to its non-canonical roles in cancer and DNA damage remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural explanation for why T494M aggregates only in photoreceptors\", \"Whether non-spliceosomal PRPF3 roles share its RNA-binding mechanism is unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"U4/U6 di-snRNP\",\n      \"U4/U6.U5 tri-snRNP\"\n    ],\n    \"partners\": [\n      \"PRPF4\",\n      \"SNU13\",\n      \"PRPF31\",\n      \"SPF30\",\n      \"U2AF35\",\n      \"TMEM43\",\n      \"TXNL4B\",\n      \"PRPF8\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}