{"gene":"SNRPB","run_date":"2026-06-10T07:46:37","timeline":{"discoveries":[{"year":2014,"finding":"Mutations in a regulatory alternative exon of SNRPB cause cerebro-costo-mandibular syndrome (CCMS) by disrupting auto-regulation: the alternative exon contains a premature termination codon (PTC) that triggers nonsense-mediated mRNA decay (NMD) when included; mutations increase exon inclusion, reducing overall SNRPB expression. This establishes a conserved intragenic auto-regulatory mechanism controlling SNRPB levels.","method":"Exome sequencing, Sanger sequencing, quantitative RT-PCR measuring exon inclusion and SNRPB expression in patient leukocytes","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently by two labs (Lynch et al. 2014 and Bacrot et al. 2014) using complementary sequencing and expression methods; both confirm the same NMD-mediated auto-regulatory mechanism","pmids":["25047197","25504470"],"is_preprint":false},{"year":2014,"finding":"Heterozygous variants in SNRPB (all located in the PTC-introducing alternative exon of transcript 3) cause CCMS; qRT-PCR confirmed significant increase of the NMD-targeted transcript 3 in patient leukocytes, demonstrating haploinsufficiency via enhanced exon inclusion and reduced functional SmB/SmB' protein.","method":"Exome sequencing, Sanger sequencing in five unrelated CCMS patients, quantitative RT-PCR","journal":"Human Mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent replication of Lynch et al. 2014 findings with orthogonal sequencing and expression methods in additional patients","pmids":["25504470"],"is_preprint":false},{"year":1991,"finding":"SmB and SmB' are produced from a single gene by alternative splicing: genomic sequencing revealed that the 145-bp insertion found in SmB cDNA is flanked by splice consensus sequences, establishing that the two isoforms arise from alternative splicing of a common pre-mRNA transcript.","method":"PCR amplification and nucleotide sequencing of HeLa genomic DNA; splice site identification","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic sequencing establishing molecular mechanism; consistent with earlier cDNA work (Elkon et al. 1990) and replicated in multiple subsequent studies","pmids":["1825643"],"is_preprint":false},{"year":1999,"finding":"The human SNRPB/B' locus is alternatively spliced to produce SmB or SmB' isoforms; Western analysis demonstrated that SmB'/B levels are dramatically upregulated in Prader-Willi syndrome brain tissue (which lacks SmN), establishing a compensatory feedback/dosage-compensation loop that regulates spliceosomal component stoichiometry.","method":"Genomic, cDNA and protein analyses across multiple vertebrate species; Western blotting of Prader-Willi syndrome brain tissue","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Western blot in disease tissue plus multi-species genomic analysis in a single study; compensatory upregulation mechanistically established but not further validated by functional rescue","pmids":["10556313"],"is_preprint":false},{"year":1989,"finding":"SmB' protein expression is restricted to a subset of rodent cell types and is correlated with the ability to utilize an alternative RNA splicing pathway, providing the first evidence of tissue-specific expression of a spliceosome protein component and suggesting a role for SmB' in regulating alternative splicing.","method":"Immunoblotting of SmB and SmB' across multiple cell types and tissues; correlation with alternative splicing activity","journal":"FEBS Letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, immunoblot-based protein detection correlated with splicing activity; foundational but no direct functional manipulation","pmids":["2783916"],"is_preprint":false},{"year":1993,"finding":"SmN and SmB show differential association with snRNP particles: SmN is present in U2 but excluded from U1 snRNPs at low expression levels, whereas SmB is present in both U1 and U2 snRNPs. At high SmN expression levels, SmN incorporates into both U1 and U2 and replaces SmB, indicating lower affinity of the pre-U1 snRNP for SmN versus SmB.","method":"Immunoprecipitation with anti-snRNP monoclonal antibodies in ND7 and F9 cell lines and SmN-transfected 3T3 fibroblasts; adult rat brain analysis","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal immunoprecipitation in multiple cell lines plus transfected overexpression system; single lab with multiple orthogonal conditions","pmids":["8371979"],"is_preprint":false},{"year":2009,"finding":"Coilin phosphorylation differentially regulates its interactions with SmB' and SMN in Cajal bodies: in vitro binding studies showed SmB' preferentially binds phosphomimetic coilin C-terminal constructs, whereas SMN preferentially binds dephosphorylated coilin. Co-immunoprecipitation and phosphatase experiments confirmed that SMN binds dephosphorylated coilin in vivo, demonstrating phosphorylation-dependent control of snRNP biogenesis interactions.","method":"In vitro binding assays with phosphomimetic coilin constructs, co-immunoprecipitation with phosphatase treatment","journal":"Chromosoma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus in vivo Co-IP with phosphatase validation; single lab, two orthogonal methods","pmids":["19997741"],"is_preprint":false},{"year":2010,"finding":"In Drosophila, SmB accumulates at the posterior pole of the oocyte in polar granules; this localization requires arginine methylation of RG repeats in SmB's C-terminus by the Capsuléen-Valois methylosome complex. Methylation of SmB arginine residues is essential for germ cell formation, migration, and differentiation, and for anchoring polar granules at the posterior cortex.","method":"Immunofluorescence localization during oogenesis; genetic analysis of methylosome mutants; functional studies of germ cell development in Drosophila","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization with functional consequence plus genetic epistasis (methylosome mutants) with specific developmental phenotypes; multiple orthogonal assays in single study","pmids":["20659974"],"is_preprint":false},{"year":2010,"finding":"In planarian Schmidtea mediterranea, Smed-SmB localizes to both the nucleus and the chromatoid body of stem cells. dsRNA-mediated knockdown of Smed-SmB causes rapid loss of chromatoid body organization, impaired post-transcriptional processing of Smed-CycB transcripts, and severe proliferative failure of neoblasts, leading to depletion of the stem cell pool and lethality.","method":"RNAi knockdown, immunofluorescence localization, RT-PCR for CycB processing, stem cell proliferation assays","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi loss-of-function with specific molecular (chromatoid body, mRNA processing) and cellular (proliferation) phenotypes; multiple orthogonal readouts in single study","pmids":["20215344"],"is_preprint":false},{"year":2013,"finding":"SmB protein forms highly mobile trafficking vesicles in neural cells; the morphology and mobility of these vesicles depend on cellular levels of both SMN and SmB, implicating SmB in cytoplasmic snRNP biogenesis trafficking in neural cells.","method":"Time-resolved quantitative proteomics, live imaging of SmB-positive vesicles in neural cells, SMN/SmB knockdown effects on vesicle behavior","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics combined with live imaging and knockdown; single lab, two orthogonal methods","pmids":["24357717"],"is_preprint":false},{"year":2015,"finding":"In yeast, simultaneous mutations of the RNA-binding Asn or Arg residues in SmD3 and SmB are lethal, demonstrating built-in redundancy in the Sm ring's RNA-binding triad (His/Ser-Asn-Arg); individual mutations are tolerated but combined SmD3+SmB mutations are not, placing SmB as a functionally redundant RNA-contact subunit within the Sm ring of U1 snRNP.","method":"Mutational analysis guided by crystal structure of human U1 snRNP; yeast growth assays; genetic interaction (synthetic lethality) screens","journal":"RNA","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-guided mutagenesis with in vivo functional validation; single lab but multiple orthogonal mutant combinations tested","pmids":["25897024"],"is_preprint":false},{"year":2016,"finding":"SNRPB knockdown in a GBM cell line followed by RNA sequencing revealed that SNRPB regulates splicing and gene expression of genes involved in RNA processing, DNA repair, and chromatin remodeling, as well as gliomagenesis-associated pathways, establishing SNRPB as a functional regulator of alternative splicing in cancer cells.","method":"SNRPB knockdown in GBM cell lines, RNA sequencing, cell viability/proliferation/apoptosis assays","journal":"Genome Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with transcriptome-wide splicing readout (RNA-seq) plus functional cellular assays; single lab","pmids":["27287018"],"is_preprint":false},{"year":2019,"finding":"SNRPB promotes NSCLC tumorigenesis via regulation of RAB26: suppression of SNRPB causes intron 7 retention in RAB26 mRNA, activating NMD and reducing RAB26 protein; forced expression of RAB26 partially rescues the decreased tumorigenicity caused by SNRPB depletion, establishing a SNRPB→RAB26 splicing axis in lung cancer.","method":"SNRPB knockdown/overexpression in NSCLC cell lines and xenograft models, RNA-seq identifying intron retention, NMD validation, RAB26 rescue experiment","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific splicing molecular mechanism identified, plus rescue experiment; single lab with multiple orthogonal approaches","pmids":["31511502"],"is_preprint":false},{"year":2020,"finding":"SNRPB directly interacts with p53 in cervical cancer cells; Co-immunoprecipitation demonstrated SNRPB-p53 interaction, and this interaction modulates cervical cancer cell proliferation, migration, invasion, and apoptosis.","method":"Co-immunoprecipitation (SNRPB-p53 interaction), shRNA knockdown, xenograft model","journal":"Biomedicine & Pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP pulldown result from a single lab; mechanistic follow-up is limited and the functional link between the interaction and phenotype is not deeply characterized","pmids":["32106364"],"is_preprint":false},{"year":2020,"finding":"SNRPB promotes AKT3-204 and LDHA-220 splice variant formation in HCC cells; SNRPB overexpression activates these variants to drive Akt pathway activation and aerobic glycolysis (Warburg effect), while SNRPB knockdown reverses these effects, establishing a mechanistic link between SNRPB-driven alternative splicing and metabolic reprogramming.","method":"RNA sequencing for alternative splicing analysis, SNRPB overexpression/knockdown in HCC cell lines, Akt pathway and glycolysis functional assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq identification of specific splice variants combined with functional pathway validation; single lab","pmids":["33289700"],"is_preprint":false},{"year":2020,"finding":"c-Myc transcriptionally upregulates SNRPB in HCC; luciferase reporter and chromatin immunoprecipitation (ChIP) assays demonstrated direct c-Myc binding and transactivation of the SNRPB promoter, establishing c-Myc as a transcriptional driver of SNRPB overexpression in hepatocellular carcinoma.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), correlation in clinical samples","journal":"Cell Biology International","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and ChIP provide two orthogonal methods establishing transcriptional regulation; single lab","pmids":["31930637"],"is_preprint":false},{"year":2022,"finding":"Snrpb haploinsufficiency in neural crest cells of mice causes increased exon skipping (including in negative regulators of the p53 pathway) and intron retention, elevated nuclear p53 and p53 target gene expression, and mis-splicing of craniofacial transcripts (Smad2, Rere); ectopic/missing Fgf8 and Shh expression is also detected, establishing that SNRPB regulates splicing fidelity and p53 pathway activity during craniofacial development.","method":"Conditional Snrpb heterozygous knockout in mouse neural crest cells, RNAseq splicing analysis, p53 immunostaining, Trp53 double-mutant epistasis experiment, in situ hybridization for Fgf8/Shh","journal":"Disease Models & Mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional mouse KO with transcriptome-wide splicing analysis, protein-level validation, and genetic epistasis (Trp53 rescue attempt); multiple orthogonal approaches in single rigorous study","pmids":["35593225"],"is_preprint":false},{"year":2022,"finding":"Knockdown of Snrpb in Xenopus embryos causes defects in cranial neural crest cell formation, establishing that SNRPB is required for neural crest specification and craniofacial development; this parallels EFTUD2 and TXNL4A knockdown phenotypes, suggesting a common spliceosomal mechanism underlying mandibulofacial dysostosis syndromes.","method":"Morpholino knockdown of Snrpb, Eftud2, and Txnl4a in Xenopus embryos; neural crest marker analysis at multiple developmental stages","journal":"Journal of Developmental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO/KD with defined neural crest phenotypic readout in Xenopus model; single lab","pmids":["35893124"],"is_preprint":false},{"year":2023,"finding":"SNRPB promotes ovarian cancer progression by suppressing exon 3 skipping of POLA1 and BRCA2: SNRPB knockdown induces exon 3 skipping of POLA1 (leading to NMD) and of BRCA2 (causing loss of the PALB2-binding domain required for homologous recombination, increasing cisplatin sensitivity); POLA1 or BRCA2 knockdown partially phenocopies the effect of SNRPB overexpression, and miR-654-5p reduces SNRPB by binding its 3'-UTR.","method":"SNRPB knockdown/overexpression, RNA-seq for alternative splicing, NMD validation, BRCA2 domain functional analysis, POLA1/BRCA2 rescue/knockdown experiments, miRNA 3'-UTR reporter assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, NMD validation, rescue experiments, miRNA functional assay) establishing specific splicing mechanism with downstream functional consequences; single lab but highly rigorous","pmids":["37391593"],"is_preprint":false}],"current_model":"SNRPB encodes the core spliceosomal Sm proteins SmB and SmB' (produced by alternative splicing of a single gene) that form part of the Sm ring in U1 and U2 snRNPs; SNRPB levels are auto-regulated by a conserved NMD-coupled alternative exon mechanism, its arginine residues are methylated by the methylosome complex to direct subcellular localization (including to germ granules and Cajal body-associated vesicles), its interaction with coilin is phosphorylation-dependent, and it drives alternative splicing of cancer-relevant targets (RAB26, AKT3, LDHA, POLA1, BRCA2) and craniofacial developmental genes, with haploinsufficiency causing p53 pathway activation and neural crest defects underlying cerebro-costo-mandibular syndrome."},"narrative":{"mechanistic_narrative":"SNRPB encodes the core spliceosomal Sm proteins SmB and SmB', which arise from alternative splicing of a single locus and function as RNA-binding subunits of the Sm ring of U1 and U2 snRNPs [PMID:1825643, PMID:25897024]. Within the Sm ring, SmB contributes a functionally redundant RNA-contact role: combined mutation of its RNA-binding residues with those of SmD3 is lethal in yeast, whereas single mutations are tolerated [PMID:25897024]. SNRPB expression is auto-regulated through a conserved intragenic mechanism in which inclusion of an alternative exon bearing a premature termination codon triggers nonsense-mediated decay, tuning overall SmB/B' levels [PMID:25047197, PMID:25504470]; heterozygous mutations that increase inclusion of this exon reduce functional protein and cause cerebro-costo-mandibular syndrome [PMID:25047197, PMID:25504470]. Beyond its constitutive splicing role, SNRPB acts as a regulator of alternative splicing whose dosage shapes development and disease: Snrpb haploinsufficiency in neural crest cells causes mis-splicing of craniofacial transcripts and nuclear p53 accumulation, and is required for cranial neural crest formation across mouse and Xenopus models [PMID:35593225, PMID:35893124]. In cancer, SNRPB drives oncogenic splicing programs, controlling intron retention and exon-skipping events in targets including RAB26, AKT3, LDHA, POLA1 and BRCA2 to promote tumorigenesis, metabolic reprogramming, and altered DNA-repair capacity [PMID:31511502, PMID:33289700, PMID:37391593]. SmB localization and trafficking are governed by arginine methylation of its C-terminal RG repeats by the methylosome and by phosphorylation-dependent interaction with coilin at Cajal bodies [PMID:19997741, PMID:20659974].","teleology":[{"year":1989,"claim":"Established that SmB' is not ubiquitous but tissue-restricted and correlated with alternative splicing capacity, first hinting that a core Sm protein could have regulatory rather than purely structural roles.","evidence":"Immunoblotting of SmB/SmB' across rodent cell types correlated with splicing activity","pmids":["2783916"],"confidence":"Medium","gaps":["Correlation only, no direct functional manipulation","Mechanism linking SmB' to alternative splicing not defined"]},{"year":1991,"claim":"Resolved the origin of the two protein isoforms by showing SmB and SmB' are generated from a single gene via alternative splicing, defining the genetic architecture of the locus.","evidence":"PCR and genomic sequencing of HeLa DNA identifying splice consensus sequences flanking a 145-bp insertion","pmids":["1825643"],"confidence":"High","gaps":["Does not address functional distinction between isoforms","Regulation of the alternative splicing choice not characterized"]},{"year":1993,"claim":"Characterized differential incorporation of Sm variants into snRNP particles, showing SmB occupies both U1 and U2 snRNPs and can be displaced by SmN, establishing affinity-based assembly stoichiometry.","evidence":"Anti-snRNP immunoprecipitation in cell lines, rat brain, and SmN-transfected fibroblasts","pmids":["8371979"],"confidence":"Medium","gaps":["Functional consequence of variant swapping on splicing output unresolved","Single-lab observation"]},{"year":1999,"claim":"Demonstrated dosage compensation among Sm variants, with SmB'/B upregulated when SmN is absent, indicating regulated stoichiometry of spliceosomal components.","evidence":"Western blotting of Prader-Willi brain tissue plus multi-species genomic/cDNA analysis","pmids":["10556313"],"confidence":"Medium","gaps":["No functional rescue confirming compensation","Mechanism of cross-regulation not defined"]},{"year":2009,"claim":"Showed that coilin phosphorylation state selects between SmB' and SMN binding at Cajal bodies, linking post-translational control to snRNP biogenesis interactions.","evidence":"In vitro binding to phosphomimetic coilin constructs and Co-IP with phosphatase treatment","pmids":["19997741"],"confidence":"Medium","gaps":["Kinase/phosphatase regulating coilin in this context not identified","Single lab, two methods"]},{"year":2010,"claim":"Established that arginine methylation of SmB's RG repeats by the methylosome directs its localization to germ-granule structures and is required for germ cell development, defining a methylation-controlled localization mechanism.","evidence":"Immunofluorescence and methylosome-mutant genetic analysis in Drosophila oogenesis","pmids":["20659974"],"confidence":"High","gaps":["Conservation of the methylation-localization link to human SmB not tested here","Direct methyltransferase contact residues inferred genetically"]},{"year":2010,"claim":"Demonstrated that SmB is essential for stem cell maintenance via chromatoid body organization and post-transcriptional processing, showing a loss-of-function requirement for proliferation in vivo.","evidence":"RNAi knockdown, localization, CycB processing RT-PCR, and proliferation assays in planarian neoblasts","pmids":["20215344"],"confidence":"High","gaps":["Direct splicing targets in stem cells not enumerated","Relationship to human disease phenotypes indirect"]},{"year":2013,"claim":"Identified SmB in highly mobile cytoplasmic vesicles whose behavior depends on SMN and SmB levels, implicating SmB in cytoplasmic snRNP biogenesis trafficking.","evidence":"Quantitative proteomics and live imaging with SMN/SmB knockdown in neural cells","pmids":["24357717"],"confidence":"Medium","gaps":["Cargo and destination of vesicles not fully defined","Single lab"]},{"year":2014,"claim":"Defined the disease mechanism and the auto-regulatory logic of the locus: a PTC-containing alternative exon couples its own inclusion to NMD, and CCMS mutations increase inclusion to reduce functional SmB/B' (haploinsufficiency).","evidence":"Exome/Sanger sequencing and qRT-PCR of exon inclusion in CCMS patient leukocytes, replicated across two studies","pmids":["25047197","25504470"],"confidence":"High","gaps":["Tissue-specific consequences of reduced SmB/B' not resolved by leukocyte data","Trans-acting factors controlling the exon choice unknown"]},{"year":2015,"claim":"Placed SmB structurally within the Sm ring as a functionally redundant RNA-contacting subunit, showing combined SmB+SmD3 RNA-binding mutations are lethal while singles are tolerated.","evidence":"Structure-guided mutagenesis and synthetic-lethality assays in yeast","pmids":["25897024"],"confidence":"High","gaps":["Redundancy mapping in human cells not directly tested","Effect on specific splicing events not measured"]},{"year":2016,"claim":"Showed SNRPB acts as a transcriptome-wide regulator of alternative splicing and gene expression in cancer cells, including RNA-processing, DNA-repair and chromatin genes.","evidence":"SNRPB knockdown plus RNA-seq and proliferation/apoptosis assays in GBM cells","pmids":["27287018"],"confidence":"Medium","gaps":["Individual functional targets not validated mechanistically","Single lab"]},{"year":2019,"claim":"Established a specific oncogenic splicing axis in which SNRPB suppresses RAB26 intron retention to maintain RAB26 protein and promote lung tumorigenesis.","evidence":"SNRPB knockdown/overexpression, RNA-seq, NMD validation, and RAB26 rescue in NSCLC cells and xenografts","pmids":["31511502"],"confidence":"Medium","gaps":["Direct binding of SNRPB to RAB26 pre-mRNA not shown","Single lab"]},{"year":2020,"claim":"Connected SNRPB to upstream transcriptional control and downstream metabolic/signaling reprogramming, with c-Myc driving SNRPB and SNRPB-driven AKT3/LDHA variants activating Akt signaling and glycolysis, plus a Co-IP-based SNRPB–p53 interaction.","evidence":"ChIP/luciferase for c-Myc; RNA-seq and pathway assays for AKT3-204/LDHA-220 in HCC; Co-IP in cervical cancer","pmids":["31930637","33289700","32106364"],"confidence":"Medium","gaps":["SNRPB–p53 interaction rests on a single Co-IP without reciprocal validation","Direct splicing mechanism for AKT3/LDHA variants not mapped to SNRPB binding"]},{"year":2022,"claim":"Established the developmental mechanism of CCMS-related phenotypes: Snrpb dosage controls splicing fidelity in neural crest, and its reduction activates the p53 pathway and mis-splices craniofacial regulators, with neural crest formation requiring Snrpb across species.","evidence":"Conditional Snrpb mouse KO with RNA-seq, p53 immunostaining, Trp53 epistasis, and Snrpb morpholino knockdown in Xenopus","pmids":["35593225","35893124"],"confidence":"High","gaps":["Direct splicing targets that trigger p53 activation not fully resolved","Link between specific mis-splicing events and Fgf8/Shh changes indirect"]},{"year":2023,"claim":"Demonstrated that SNRPB suppresses exon-3 skipping of POLA1 and BRCA2 to drive ovarian cancer, controlling DNA-replication and homologous-recombination capacity and chemosensitivity, with miR-654-5p as an upstream regulator.","evidence":"SNRPB knockdown/overexpression, RNA-seq, NMD and BRCA2 domain analysis, POLA1/BRCA2 rescue, and miRNA 3'-UTR reporter","pmids":["37391593"],"confidence":"High","gaps":["Direct SNRPB binding to POLA1/BRCA2 pre-mRNA not demonstrated","Generalizability beyond ovarian cancer untested"]},{"year":null,"claim":"How SNRPB achieves target selectivity — whether its splicing outputs reflect direct sequence-specific pre-mRNA contacts versus dosage-dependent effects on global snRNP assembly — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct RNA-binding map of SNRPB to its reported target transcripts","Mechanism distinguishing structural Sm-ring role from regulatory splicing role not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[10,5]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,17]}],"complexes":["Sm core ring (U1 snRNP)","U2 snRNP"],"partners":["SMN1","COIL","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14678","full_name":"Small nuclear ribonucleoprotein-associated proteins B and B'","aliases":["Sm protein B/B'","Sm-B/B'","SmB/B'"],"length_aa":240,"mass_kda":24.6,"function":"Plays a role in pre-mRNA splicing as a core component of the spliceosomal U1, U2, U4 and U5 small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome (PubMed:11991638, PubMed:18984161, PubMed:19325628, PubMed:25555158, PubMed:26912367, PubMed:28076346, PubMed:28502770, PubMed:28781166, PubMed:32494006). Component of both the pre-catalytic spliceosome B complex and activated spliceosome C complexes (PubMed:11991638, PubMed:28076346, PubMed:28502770, PubMed:28781166). As a component of the minor spliceosome, involved in the splicing of U12-type introns in pre-mRNAs (PubMed:15146077). As part of the U7 snRNP it is involved in histone pre-mRNA 3'-end processing (PubMed:12975319)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/P14678/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SNRPB","classification":"Common Essential","n_dependent_lines":1206,"n_total_lines":1208,"dependency_fraction":0.9983443708609272},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000125835","cell_line_id":"CID001904","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"SNRPB;SNRPN","stoichiometry":10.0},{"gene":"SNRNP70","stoichiometry":10.0},{"gene":"SNRPC","stoichiometry":10.0},{"gene":"SNRPF","stoichiometry":10.0},{"gene":"WDR77","stoichiometry":10.0},{"gene":"HNRNPA1;HNRNPA1L2","stoichiometry":10.0},{"gene":"SF3A1","stoichiometry":10.0},{"gene":"SNRPD3","stoichiometry":10.0},{"gene":"SNRPD2","stoichiometry":10.0},{"gene":"SNRPD1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001904","total_profiled":1310},"omim":[{"mim_id":"617910","title":"LSM11, U7 SMALL NUCLEAR RNA-ASSOCIATED PROTEIN; LSM11","url":"https://www.omim.org/entry/617910"},{"mim_id":"617909","title":"LSM10, U7 SMALL NUCLEAR RNA-ASSOCIATED PROTEIN; LSM10","url":"https://www.omim.org/entry/617909"},{"mim_id":"617876","title":"RNA, U7 SMALL NUCLEAR 1; RNU7-1","url":"https://www.omim.org/entry/617876"},{"mim_id":"616587","title":"SIR2 ANTIPHAGE-LIKE PROTEIN 1; SIRAL1","url":"https://www.omim.org/entry/616587"},{"mim_id":"611734","title":"WD REPEAT-CONTAINING PROTEIN 77; WDR77","url":"https://www.omim.org/entry/611734"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SNRPB"},"hgnc":{"alias_symbol":["COD","SmB/SmB'","Sm-B/B'","snRNP-B"],"prev_symbol":["SNRPB1"]},"alphafold":{"accession":"P14678","domains":[{"cath_id":"2.30.30.100","chopping":"1-85","consensus_level":"medium","plddt":90.2665,"start":1,"end":85}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14678","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14678-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14678-F1-predicted_aligned_error_v6.png","plddt_mean":69.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SNRPB","jax_strain_url":"https://www.jax.org/strain/search?query=SNRPB"},"sequence":{"accession":"P14678","fasta_url":"https://rest.uniprot.org/uniprotkb/P14678.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14678/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14678"}},"corpus_meta":[{"pmid":"21832995","id":"PMC_21832995","title":"The genome sequence of Atlantic cod reveals a unique immune system.","date":"2011","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/21832995","citation_count":560,"is_preprint":false},{"pmid":"7530756","id":"PMC_7530756","title":"Immunoglobulin epitope spreading and autoimmune disease after peptide immunization: Sm B/B'-derived PPPGMRPP and PPPGIRGP induce spliceosome autoimmunity.","date":"1995","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7530756","citation_count":294,"is_preprint":false},{"pmid":"10710504","id":"PMC_10710504","title":"Cod and soy proteins compared with casein improve glucose tolerance and insulin sensitivity in rats.","date":"2000","source":"American journal of physiology. 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Part A, Chemistry, analysis, control, exposure & risk assessment","url":"https://pubmed.ncbi.nlm.nih.gov/30633651","citation_count":14,"is_preprint":false},{"pmid":"31895939","id":"PMC_31895939","title":"Severe thiamine deficiency in eastern Baltic cod (Gadus morhua).","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31895939","citation_count":14,"is_preprint":false},{"pmid":"28780570","id":"PMC_28780570","title":"Sex steroids differentially regulate fshb, lhb and gnrhr expression in Atlantic cod (Gadus morhua).","date":"2017","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28780570","citation_count":14,"is_preprint":false},{"pmid":"36275630","id":"PMC_36275630","title":"The oncogenic role of SNRPB in human tumors: A pan-cancer analysis.","date":"2022","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36275630","citation_count":13,"is_preprint":false},{"pmid":"33835288","id":"PMC_33835288","title":"SNRPB is a mediator for cellular response to cisplatin in non-small-cell lung cancer.","date":"2021","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33835288","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50137,"output_tokens":4890,"usd":0.11188,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13166,"output_tokens":4513,"usd":0.089328,"stage2_stop_reason":"end_turn"},"total_usd":0.201208,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Mutations in a regulatory alternative exon of SNRPB cause cerebro-costo-mandibular syndrome (CCMS) by disrupting auto-regulation: the alternative exon contains a premature termination codon (PTC) that triggers nonsense-mediated mRNA decay (NMD) when included; mutations increase exon inclusion, reducing overall SNRPB expression. This establishes a conserved intragenic auto-regulatory mechanism controlling SNRPB levels.\",\n      \"method\": \"Exome sequencing, Sanger sequencing, quantitative RT-PCR measuring exon inclusion and SNRPB expression in patient leukocytes\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently by two labs (Lynch et al. 2014 and Bacrot et al. 2014) using complementary sequencing and expression methods; both confirm the same NMD-mediated auto-regulatory mechanism\",\n      \"pmids\": [\"25047197\", \"25504470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Heterozygous variants in SNRPB (all located in the PTC-introducing alternative exon of transcript 3) cause CCMS; qRT-PCR confirmed significant increase of the NMD-targeted transcript 3 in patient leukocytes, demonstrating haploinsufficiency via enhanced exon inclusion and reduced functional SmB/SmB' protein.\",\n      \"method\": \"Exome sequencing, Sanger sequencing in five unrelated CCMS patients, quantitative RT-PCR\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent replication of Lynch et al. 2014 findings with orthogonal sequencing and expression methods in additional patients\",\n      \"pmids\": [\"25504470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"SmB and SmB' are produced from a single gene by alternative splicing: genomic sequencing revealed that the 145-bp insertion found in SmB cDNA is flanked by splice consensus sequences, establishing that the two isoforms arise from alternative splicing of a common pre-mRNA transcript.\",\n      \"method\": \"PCR amplification and nucleotide sequencing of HeLa genomic DNA; splice site identification\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic sequencing establishing molecular mechanism; consistent with earlier cDNA work (Elkon et al. 1990) and replicated in multiple subsequent studies\",\n      \"pmids\": [\"1825643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The human SNRPB/B' locus is alternatively spliced to produce SmB or SmB' isoforms; Western analysis demonstrated that SmB'/B levels are dramatically upregulated in Prader-Willi syndrome brain tissue (which lacks SmN), establishing a compensatory feedback/dosage-compensation loop that regulates spliceosomal component stoichiometry.\",\n      \"method\": \"Genomic, cDNA and protein analyses across multiple vertebrate species; Western blotting of Prader-Willi syndrome brain tissue\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Western blot in disease tissue plus multi-species genomic analysis in a single study; compensatory upregulation mechanistically established but not further validated by functional rescue\",\n      \"pmids\": [\"10556313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"SmB' protein expression is restricted to a subset of rodent cell types and is correlated with the ability to utilize an alternative RNA splicing pathway, providing the first evidence of tissue-specific expression of a spliceosome protein component and suggesting a role for SmB' in regulating alternative splicing.\",\n      \"method\": \"Immunoblotting of SmB and SmB' across multiple cell types and tissues; correlation with alternative splicing activity\",\n      \"journal\": \"FEBS Letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, immunoblot-based protein detection correlated with splicing activity; foundational but no direct functional manipulation\",\n      \"pmids\": [\"2783916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"SmN and SmB show differential association with snRNP particles: SmN is present in U2 but excluded from U1 snRNPs at low expression levels, whereas SmB is present in both U1 and U2 snRNPs. At high SmN expression levels, SmN incorporates into both U1 and U2 and replaces SmB, indicating lower affinity of the pre-U1 snRNP for SmN versus SmB.\",\n      \"method\": \"Immunoprecipitation with anti-snRNP monoclonal antibodies in ND7 and F9 cell lines and SmN-transfected 3T3 fibroblasts; adult rat brain analysis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal immunoprecipitation in multiple cell lines plus transfected overexpression system; single lab with multiple orthogonal conditions\",\n      \"pmids\": [\"8371979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Coilin phosphorylation differentially regulates its interactions with SmB' and SMN in Cajal bodies: in vitro binding studies showed SmB' preferentially binds phosphomimetic coilin C-terminal constructs, whereas SMN preferentially binds dephosphorylated coilin. Co-immunoprecipitation and phosphatase experiments confirmed that SMN binds dephosphorylated coilin in vivo, demonstrating phosphorylation-dependent control of snRNP biogenesis interactions.\",\n      \"method\": \"In vitro binding assays with phosphomimetic coilin constructs, co-immunoprecipitation with phosphatase treatment\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus in vivo Co-IP with phosphatase validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"19997741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In Drosophila, SmB accumulates at the posterior pole of the oocyte in polar granules; this localization requires arginine methylation of RG repeats in SmB's C-terminus by the Capsuléen-Valois methylosome complex. Methylation of SmB arginine residues is essential for germ cell formation, migration, and differentiation, and for anchoring polar granules at the posterior cortex.\",\n      \"method\": \"Immunofluorescence localization during oogenesis; genetic analysis of methylosome mutants; functional studies of germ cell development in Drosophila\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization with functional consequence plus genetic epistasis (methylosome mutants) with specific developmental phenotypes; multiple orthogonal assays in single study\",\n      \"pmids\": [\"20659974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In planarian Schmidtea mediterranea, Smed-SmB localizes to both the nucleus and the chromatoid body of stem cells. dsRNA-mediated knockdown of Smed-SmB causes rapid loss of chromatoid body organization, impaired post-transcriptional processing of Smed-CycB transcripts, and severe proliferative failure of neoblasts, leading to depletion of the stem cell pool and lethality.\",\n      \"method\": \"RNAi knockdown, immunofluorescence localization, RT-PCR for CycB processing, stem cell proliferation assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi loss-of-function with specific molecular (chromatoid body, mRNA processing) and cellular (proliferation) phenotypes; multiple orthogonal readouts in single study\",\n      \"pmids\": [\"20215344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SmB protein forms highly mobile trafficking vesicles in neural cells; the morphology and mobility of these vesicles depend on cellular levels of both SMN and SmB, implicating SmB in cytoplasmic snRNP biogenesis trafficking in neural cells.\",\n      \"method\": \"Time-resolved quantitative proteomics, live imaging of SmB-positive vesicles in neural cells, SMN/SmB knockdown effects on vesicle behavior\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics combined with live imaging and knockdown; single lab, two orthogonal methods\",\n      \"pmids\": [\"24357717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In yeast, simultaneous mutations of the RNA-binding Asn or Arg residues in SmD3 and SmB are lethal, demonstrating built-in redundancy in the Sm ring's RNA-binding triad (His/Ser-Asn-Arg); individual mutations are tolerated but combined SmD3+SmB mutations are not, placing SmB as a functionally redundant RNA-contact subunit within the Sm ring of U1 snRNP.\",\n      \"method\": \"Mutational analysis guided by crystal structure of human U1 snRNP; yeast growth assays; genetic interaction (synthetic lethality) screens\",\n      \"journal\": \"RNA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-guided mutagenesis with in vivo functional validation; single lab but multiple orthogonal mutant combinations tested\",\n      \"pmids\": [\"25897024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SNRPB knockdown in a GBM cell line followed by RNA sequencing revealed that SNRPB regulates splicing and gene expression of genes involved in RNA processing, DNA repair, and chromatin remodeling, as well as gliomagenesis-associated pathways, establishing SNRPB as a functional regulator of alternative splicing in cancer cells.\",\n      \"method\": \"SNRPB knockdown in GBM cell lines, RNA sequencing, cell viability/proliferation/apoptosis assays\",\n      \"journal\": \"Genome Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with transcriptome-wide splicing readout (RNA-seq) plus functional cellular assays; single lab\",\n      \"pmids\": [\"27287018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNRPB promotes NSCLC tumorigenesis via regulation of RAB26: suppression of SNRPB causes intron 7 retention in RAB26 mRNA, activating NMD and reducing RAB26 protein; forced expression of RAB26 partially rescues the decreased tumorigenicity caused by SNRPB depletion, establishing a SNRPB→RAB26 splicing axis in lung cancer.\",\n      \"method\": \"SNRPB knockdown/overexpression in NSCLC cell lines and xenograft models, RNA-seq identifying intron retention, NMD validation, RAB26 rescue experiment\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific splicing molecular mechanism identified, plus rescue experiment; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"31511502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SNRPB directly interacts with p53 in cervical cancer cells; Co-immunoprecipitation demonstrated SNRPB-p53 interaction, and this interaction modulates cervical cancer cell proliferation, migration, invasion, and apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (SNRPB-p53 interaction), shRNA knockdown, xenograft model\",\n      \"journal\": \"Biomedicine & Pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP pulldown result from a single lab; mechanistic follow-up is limited and the functional link between the interaction and phenotype is not deeply characterized\",\n      \"pmids\": [\"32106364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SNRPB promotes AKT3-204 and LDHA-220 splice variant formation in HCC cells; SNRPB overexpression activates these variants to drive Akt pathway activation and aerobic glycolysis (Warburg effect), while SNRPB knockdown reverses these effects, establishing a mechanistic link between SNRPB-driven alternative splicing and metabolic reprogramming.\",\n      \"method\": \"RNA sequencing for alternative splicing analysis, SNRPB overexpression/knockdown in HCC cell lines, Akt pathway and glycolysis functional assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq identification of specific splice variants combined with functional pathway validation; single lab\",\n      \"pmids\": [\"33289700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"c-Myc transcriptionally upregulates SNRPB in HCC; luciferase reporter and chromatin immunoprecipitation (ChIP) assays demonstrated direct c-Myc binding and transactivation of the SNRPB promoter, establishing c-Myc as a transcriptional driver of SNRPB overexpression in hepatocellular carcinoma.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), correlation in clinical samples\",\n      \"journal\": \"Cell Biology International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and ChIP provide two orthogonal methods establishing transcriptional regulation; single lab\",\n      \"pmids\": [\"31930637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Snrpb haploinsufficiency in neural crest cells of mice causes increased exon skipping (including in negative regulators of the p53 pathway) and intron retention, elevated nuclear p53 and p53 target gene expression, and mis-splicing of craniofacial transcripts (Smad2, Rere); ectopic/missing Fgf8 and Shh expression is also detected, establishing that SNRPB regulates splicing fidelity and p53 pathway activity during craniofacial development.\",\n      \"method\": \"Conditional Snrpb heterozygous knockout in mouse neural crest cells, RNAseq splicing analysis, p53 immunostaining, Trp53 double-mutant epistasis experiment, in situ hybridization for Fgf8/Shh\",\n      \"journal\": \"Disease Models & Mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional mouse KO with transcriptome-wide splicing analysis, protein-level validation, and genetic epistasis (Trp53 rescue attempt); multiple orthogonal approaches in single rigorous study\",\n      \"pmids\": [\"35593225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of Snrpb in Xenopus embryos causes defects in cranial neural crest cell formation, establishing that SNRPB is required for neural crest specification and craniofacial development; this parallels EFTUD2 and TXNL4A knockdown phenotypes, suggesting a common spliceosomal mechanism underlying mandibulofacial dysostosis syndromes.\",\n      \"method\": \"Morpholino knockdown of Snrpb, Eftud2, and Txnl4a in Xenopus embryos; neural crest marker analysis at multiple developmental stages\",\n      \"journal\": \"Journal of Developmental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO/KD with defined neural crest phenotypic readout in Xenopus model; single lab\",\n      \"pmids\": [\"35893124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SNRPB promotes ovarian cancer progression by suppressing exon 3 skipping of POLA1 and BRCA2: SNRPB knockdown induces exon 3 skipping of POLA1 (leading to NMD) and of BRCA2 (causing loss of the PALB2-binding domain required for homologous recombination, increasing cisplatin sensitivity); POLA1 or BRCA2 knockdown partially phenocopies the effect of SNRPB overexpression, and miR-654-5p reduces SNRPB by binding its 3'-UTR.\",\n      \"method\": \"SNRPB knockdown/overexpression, RNA-seq for alternative splicing, NMD validation, BRCA2 domain functional analysis, POLA1/BRCA2 rescue/knockdown experiments, miRNA 3'-UTR reporter assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNA-seq, NMD validation, rescue experiments, miRNA functional assay) establishing specific splicing mechanism with downstream functional consequences; single lab but highly rigorous\",\n      \"pmids\": [\"37391593\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SNRPB encodes the core spliceosomal Sm proteins SmB and SmB' (produced by alternative splicing of a single gene) that form part of the Sm ring in U1 and U2 snRNPs; SNRPB levels are auto-regulated by a conserved NMD-coupled alternative exon mechanism, its arginine residues are methylated by the methylosome complex to direct subcellular localization (including to germ granules and Cajal body-associated vesicles), its interaction with coilin is phosphorylation-dependent, and it drives alternative splicing of cancer-relevant targets (RAB26, AKT3, LDHA, POLA1, BRCA2) and craniofacial developmental genes, with haploinsufficiency causing p53 pathway activation and neural crest defects underlying cerebro-costo-mandibular syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SNRPB encodes the core spliceosomal Sm proteins SmB and SmB', which arise from alternative splicing of a single locus and function as RNA-binding subunits of the Sm ring of U1 and U2 snRNPs [#2, #10]. Within the Sm ring, SmB contributes a functionally redundant RNA-contact role: combined mutation of its RNA-binding residues with those of SmD3 is lethal in yeast, whereas single mutations are tolerated [#10]. SNRPB expression is auto-regulated through a conserved intragenic mechanism in which inclusion of an alternative exon bearing a premature termination codon triggers nonsense-mediated decay, tuning overall SmB/B' levels [#0]; heterozygous mutations that increase inclusion of this exon reduce functional protein and cause cerebro-costo-mandibular syndrome [#0, #1]. Beyond its constitutive splicing role, SNRPB acts as a regulator of alternative splicing whose dosage shapes development and disease: Snrpb haploinsufficiency in neural crest cells causes mis-splicing of craniofacial transcripts and nuclear p53 accumulation, and is required for cranial neural crest formation across mouse and Xenopus models [#16, #17]. In cancer, SNRPB drives oncogenic splicing programs, controlling intron retention and exon-skipping events in targets including RAB26, AKT3, LDHA, POLA1 and BRCA2 to promote tumorigenesis, metabolic reprogramming, and altered DNA-repair capacity [#12, #14, #18]. SmB localization and trafficking are governed by arginine methylation of its C-terminal RG repeats by the methylosome and by phosphorylation-dependent interaction with coilin at Cajal bodies [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Established that SmB' is not ubiquitous but tissue-restricted and correlated with alternative splicing capacity, first hinting that a core Sm protein could have regulatory rather than purely structural roles.\",\n      \"evidence\": \"Immunoblotting of SmB/SmB' across rodent cell types correlated with splicing activity\",\n      \"pmids\": [\"2783916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlation only, no direct functional manipulation\", \"Mechanism linking SmB' to alternative splicing not defined\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Resolved the origin of the two protein isoforms by showing SmB and SmB' are generated from a single gene via alternative splicing, defining the genetic architecture of the locus.\",\n      \"evidence\": \"PCR and genomic sequencing of HeLa DNA identifying splice consensus sequences flanking a 145-bp insertion\",\n      \"pmids\": [\"1825643\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address functional distinction between isoforms\", \"Regulation of the alternative splicing choice not characterized\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Characterized differential incorporation of Sm variants into snRNP particles, showing SmB occupies both U1 and U2 snRNPs and can be displaced by SmN, establishing affinity-based assembly stoichiometry.\",\n      \"evidence\": \"Anti-snRNP immunoprecipitation in cell lines, rat brain, and SmN-transfected fibroblasts\",\n      \"pmids\": [\"8371979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of variant swapping on splicing output unresolved\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated dosage compensation among Sm variants, with SmB'/B upregulated when SmN is absent, indicating regulated stoichiometry of spliceosomal components.\",\n      \"evidence\": \"Western blotting of Prader-Willi brain tissue plus multi-species genomic/cDNA analysis\",\n      \"pmids\": [\"10556313\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional rescue confirming compensation\", \"Mechanism of cross-regulation not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that coilin phosphorylation state selects between SmB' and SMN binding at Cajal bodies, linking post-translational control to snRNP biogenesis interactions.\",\n      \"evidence\": \"In vitro binding to phosphomimetic coilin constructs and Co-IP with phosphatase treatment\",\n      \"pmids\": [\"19997741\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase/phosphatase regulating coilin in this context not identified\", \"Single lab, two methods\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that arginine methylation of SmB's RG repeats by the methylosome directs its localization to germ-granule structures and is required for germ cell development, defining a methylation-controlled localization mechanism.\",\n      \"evidence\": \"Immunofluorescence and methylosome-mutant genetic analysis in Drosophila oogenesis\",\n      \"pmids\": [\"20659974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the methylation-localization link to human SmB not tested here\", \"Direct methyltransferase contact residues inferred genetically\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that SmB is essential for stem cell maintenance via chromatoid body organization and post-transcriptional processing, showing a loss-of-function requirement for proliferation in vivo.\",\n      \"evidence\": \"RNAi knockdown, localization, CycB processing RT-PCR, and proliferation assays in planarian neoblasts\",\n      \"pmids\": [\"20215344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing targets in stem cells not enumerated\", \"Relationship to human disease phenotypes indirect\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified SmB in highly mobile cytoplasmic vesicles whose behavior depends on SMN and SmB levels, implicating SmB in cytoplasmic snRNP biogenesis trafficking.\",\n      \"evidence\": \"Quantitative proteomics and live imaging with SMN/SmB knockdown in neural cells\",\n      \"pmids\": [\"24357717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo and destination of vesicles not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the disease mechanism and the auto-regulatory logic of the locus: a PTC-containing alternative exon couples its own inclusion to NMD, and CCMS mutations increase inclusion to reduce functional SmB/B' (haploinsufficiency).\",\n      \"evidence\": \"Exome/Sanger sequencing and qRT-PCR of exon inclusion in CCMS patient leukocytes, replicated across two studies\",\n      \"pmids\": [\"25047197\", \"25504470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific consequences of reduced SmB/B' not resolved by leukocyte data\", \"Trans-acting factors controlling the exon choice unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SmB structurally within the Sm ring as a functionally redundant RNA-contacting subunit, showing combined SmB+SmD3 RNA-binding mutations are lethal while singles are tolerated.\",\n      \"evidence\": \"Structure-guided mutagenesis and synthetic-lethality assays in yeast\",\n      \"pmids\": [\"25897024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy mapping in human cells not directly tested\", \"Effect on specific splicing events not measured\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed SNRPB acts as a transcriptome-wide regulator of alternative splicing and gene expression in cancer cells, including RNA-processing, DNA-repair and chromatin genes.\",\n      \"evidence\": \"SNRPB knockdown plus RNA-seq and proliferation/apoptosis assays in GBM cells\",\n      \"pmids\": [\"27287018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Individual functional targets not validated mechanistically\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a specific oncogenic splicing axis in which SNRPB suppresses RAB26 intron retention to maintain RAB26 protein and promote lung tumorigenesis.\",\n      \"evidence\": \"SNRPB knockdown/overexpression, RNA-seq, NMD validation, and RAB26 rescue in NSCLC cells and xenografts\",\n      \"pmids\": [\"31511502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of SNRPB to RAB26 pre-mRNA not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected SNRPB to upstream transcriptional control and downstream metabolic/signaling reprogramming, with c-Myc driving SNRPB and SNRPB-driven AKT3/LDHA variants activating Akt signaling and glycolysis, plus a Co-IP-based SNRPB–p53 interaction.\",\n      \"evidence\": \"ChIP/luciferase for c-Myc; RNA-seq and pathway assays for AKT3-204/LDHA-220 in HCC; Co-IP in cervical cancer\",\n      \"pmids\": [\"31930637\", \"33289700\", \"32106364\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SNRPB–p53 interaction rests on a single Co-IP without reciprocal validation\", \"Direct splicing mechanism for AKT3/LDHA variants not mapped to SNRPB binding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established the developmental mechanism of CCMS-related phenotypes: Snrpb dosage controls splicing fidelity in neural crest, and its reduction activates the p53 pathway and mis-splices craniofacial regulators, with neural crest formation requiring Snrpb across species.\",\n      \"evidence\": \"Conditional Snrpb mouse KO with RNA-seq, p53 immunostaining, Trp53 epistasis, and Snrpb morpholino knockdown in Xenopus\",\n      \"pmids\": [\"35593225\", \"35893124\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing targets that trigger p53 activation not fully resolved\", \"Link between specific mis-splicing events and Fgf8/Shh changes indirect\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that SNRPB suppresses exon-3 skipping of POLA1 and BRCA2 to drive ovarian cancer, controlling DNA-replication and homologous-recombination capacity and chemosensitivity, with miR-654-5p as an upstream regulator.\",\n      \"evidence\": \"SNRPB knockdown/overexpression, RNA-seq, NMD and BRCA2 domain analysis, POLA1/BRCA2 rescue, and miRNA 3'-UTR reporter\",\n      \"pmids\": [\"37391593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SNRPB binding to POLA1/BRCA2 pre-mRNA not demonstrated\", \"Generalizability beyond ovarian cancer untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SNRPB achieves target selectivity — whether its splicing outputs reflect direct sequence-specific pre-mRNA contacts versus dosage-dependent effects on global snRNP assembly — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct RNA-binding map of SNRPB to its reported target transcripts\", \"Mechanism distinguishing structural Sm-ring role from regulatory splicing role not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [10, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"complexes\": [\"Sm core ring (U1 snRNP)\", \"U2 snRNP\"],\n    \"partners\": [\"SMN1\", \"COIL\", \"TP53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}