{"gene":"EFTUD2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2012,"finding":"EFTUD2 (U5-116kD) encodes a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly; haploinsufficiency causes mandibulofacial dysostosis with microcephaly (MFDM), establishing its essential role in the major spliceosome.","method":"Whole-exome sequencing identifying causative mutations (null alleles, frameshifts) in patients; consistent with haploinsufficiency across 12 unrelated individuals","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mutations in 12 independent cases with defined molecular mechanism (spliceosomal GTPase haploinsufficiency), replicated across multiple unrelated individuals","pmids":["22305528"],"is_preprint":false},{"year":2005,"finding":"The C-terminus of Snu114 (EFTUD2 ortholog) is required for spliceosome activation; C-terminal truncation allele snu114-60 was synthetically lethal with ATPases Brr2 and Prp28 required for U1 and U4 snRNP release, suggesting a rearrangement between Prp8 and the C-terminus of Snu114 leads to release of U1 and U4 snRNPs to activate the spliceosome. GTP binding/hydrolysis domain mutations blocked the first step of splicing in vivo and in vitro.","method":"Random mutagenesis to create conditional lethal alleles; in vivo and in vitro splicing assays; synthetic lethality analysis with PRP8, BRR2, PRP28, SAD1, BRR1","journal":"Genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro and in vivo splicing assays combined with genetic epistasis, multiple allele classes characterized, replicated across multiple genetic interactions","pmids":["15911574"],"is_preprint":false},{"year":2006,"finding":"Assembly of Snu114 (EFTUD2 ortholog) into the U5 snRNP requires both a functional GTPase domain and Prp8. GTPase domain mutations prevent Snu114 interaction with Prp8 and with U5 snRNA, blocking U5 snRNP assembly. The C-terminal truncation mutant assembles spliceosomes but blocks U4 snRNP release.","method":"Biochemical analysis of snRNP and spliceosome assembly in SNU114 mutant yeast extracts; co-immunoprecipitation of Snu114 with Prp8 and U5 snRNA","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct biochemical reconstitution of snRNP assembly with multiple mutant alleles, reciprocal interaction assays, two orthogonal methods","pmids":["16540695"],"is_preprint":false},{"year":2008,"finding":"In the yeast tri-snRNP EM structure, Prp8 and Snu114 (EFTUD2 ortholog) are located centrally, while Brr2 occupies a separate head domain; U4/U6 snRNP forms the arm domain. The head and arm domains adopt variable relative positions, suggesting structural dynamics during catalytic activation.","method":"Electron microscopy projection structure of S. cerevisiae tri-snRNP with genetically tagged proteins visualized by EM","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct EM structural localization with genetic tagging, multiple proteins mapped, structural validation","pmids":["18953335"],"is_preprint":false},{"year":2013,"finding":"The U5 snRNA internal loop 1 (IL1), particularly its 3' side, is a platform required for Prp8, Snu114 (EFTUD2 ortholog), and Brr2 association with U5 snRNA during U5 snRNP assembly. Mutations in IL1 3' side caused the greatest reduction in association of all three proteins.","method":"Site-directed mutagenesis of U5 snRNA loop 1 and internal loop 1; in vivo functional assays; co-immunoprecipitation of Prp8, Snu114, Brr2 with U5 snRNA; synthetic lethal screening of brr2 and U5 snRNA mutants","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with RNA and genetic epistasis, single lab, two orthogonal methods","pmids":["23857713"],"is_preprint":false},{"year":2017,"finding":"Disruption of eftud2 in zebrafish leads to transcriptome-wide RNA splicing deficiency (intron retention and exon skipping), causing inadequate nonsense-mediated RNA decay and activation of the p53 pathway, resulting in increased apoptosis and mitosis of neural progenitors during brain development.","method":"Positional cloning of nonsense mutation; RNA-seq transcriptome analysis; functional analysis in zebrafish fn10a mutant; TUNEL apoptosis assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-seq plus functional validation in vivo, pathway placement via p53 activation downstream of splicing deficiency, multiple orthogonal methods","pmids":["27899647"],"is_preprint":false},{"year":2015,"finding":"EFTUD2 restricts HCV infection through an RIG-I/MDA5-dependent, JAK-STAT-independent pathway; EFTUD2 upregulates RIG-I and MDA5 expression by gene splicing, and its antiviral effect on interferon-stimulated gene induction was absent in RIG-I-knockdown or RIG-I-defective cells.","method":"siRNA knockdown; overexpression in Huh7 cells; RIG-I knockdown and RIG-I-defective cell lines as controls; measurement of ISG induction and HCV replication","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via RIG-I knockdown controls, functional splicing assay, single lab","pmids":["25878102"],"is_preprint":false},{"year":2019,"finding":"Myeloid-specific knockout of Eftud2 suppresses NF-κB signaling activation in LPS-challenged macrophages; the mechanism involves EFTUD2-mediated alternative splicing of components of the TLR4–NF-κB cascade, thereby modulating innate immune inflammatory response.","method":"Myeloid-specific conditional knockout mouse model; LPS stimulation of macrophages; cytokine measurements; NF-κB pathway analysis; alternative splicing analysis of TLR4-NF-κB cascade components","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with defined cellular phenotype (NF-κB activation), alternative splicing mechanism identified, in vivo and in vitro validation","pmids":["31278373"],"is_preprint":false},{"year":2019,"finding":"Homozygous loss of Eftud2 causes pre-implantation lethality in mice; heterozygous mutants are viable with reduced EFTUD2 mRNA and protein levels. Eftud2 expression is enriched in the developing head and craniofacial regions.","method":"CRISPR/Cas9 deletion of exon 2; Mendelian frequency analysis at E3.5 and post-implantation; in situ hybridization for expression; ex vivo embryo culture","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic knockout with defined lethal phenotype, in situ hybridization localization, single lab","pmids":["31276534"],"is_preprint":false},{"year":2020,"finding":"Only 4 of 19 MFDGA-associated EFTUD2 missense variants cause loss-of-function through altered protein function (assessed in yeast growth assays); 5 of the remaining 15 cause loss-of-function by altering EFTUD2 pre-mRNA splicing (predominantly exon skipping or cryptic splice site activation leading to a premature termination codon).","method":"Yeast functional growth assays modeling missense variants in S. cerevisiae Snu114; minigene splicing assay; bioinformatics prediction comparison","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — yeast reconstitution assay plus minigene splicing validation, single lab, two orthogonal methods","pmids":["32333448"],"is_preprint":false},{"year":2021,"finding":"Homozygous deletion of Eftud2 in neural crest cells causes craniofacial malformations via mis-splicing of Mdm2 (exon 3 skipping), leading to increased nuclear P53, upregulation of P53-target genes, and increased cell death. Overexpression of non-spliced Mdm2 attenuates P53 pathway overactivation in Eftud2 knockdown cells, and P53 inhibitor pifithrin-α improves craniofacial development in Eftud2-mutant embryos.","method":"Conditional Wnt1-Cre2 knockout mouse; RNAseq analysis; siRNA knockdown in O9-1 neural crest cells; minigene splicing assay; Mdm2 overexpression rescue; pifithrin-α treatment rescue","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — conditional KO with RNAseq, rescue by Mdm2 overexpression and P53 inhibitor, multiple orthogonal methods, mechanistic pathway established","pmids":["33601405"],"is_preprint":false},{"year":2019,"finding":"EFTUD2 deficiency inhibits proliferation, differentiation, and maturation of osteoblasts and chondrocytes via activation of the TP53 signaling pathway with increased phosphorylation of TP53 and upregulation of downstream targets (FAS, STEAP3, CASP3, P21, SESN1). P53 inhibition by morpholino reduced mortality in eftud2-null zebrafish.","method":"siRNA knockdown in human calvarial osteoblast and chondrocyte cells; zebrafish eftud2 knockout model; RNA-seq; western blot for phospho-TP53; morpholino p53 inhibition rescue","journal":"Human genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish model plus cell-based assays, pathway placement via morpholino rescue, single lab","pmids":["31806011"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of yeast Snu114 with the Snu114-binding region of Prp8 shows Snu114 in a GTP-bound conformation. The Prp8 Snu114-binding region abolishes Snu114's weak intrinsic GTPase activity. Exchange of GTP-contacting residues in Snu114 or Prp8 residues lining the Snu114 GTP-binding pocket leads to temperature-sensitive growth and affects the same set of splicing events in vivo, suggesting the Snu114-GTP-Prp8 module serves as a relay station during spliceosome activation and disassembly.","method":"Crystal structure determination of Snu114-Prp8 complex; GTPase activity assay; co-purification with endogenous GTP; yeast growth assays with GTP-contacting residue mutants; in vivo splicing analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro GTPase assay plus mutagenesis plus in vivo splicing, multiple orthogonal methods in one study","pmids":["32196113"],"is_preprint":false},{"year":2019,"finding":"Snu114 domain IVa directly interacts with protein phosphatase PP1 via a 'YGVQYK' binding motif; Cwc21 also binds this same motif in domain IVa, and these interactions are mutually exclusive. The affinity of Cwc21 and PP1 for Snu114 is influenced by the nucleotide-bound state of Snu114. A mutation in domain IVa causes a specific defect in splicing of meiotic gene transcripts (SPO22, AMA1, MER2) without affecting vegetative growth.","method":"Yeast mutagenesis; genetic and biochemical interaction assays; nucleotide-state dependent binding assays; in vivo splicing analysis of meiotic transcripts","journal":"RNA biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapping, nucleotide-state dependence, functional splicing readout, single lab","pmids":["30672374"],"is_preprint":false},{"year":2022,"finding":"Craniofacial defects in Eftud2 neural-crest-specific homozygous mutant embryos are not rescued by simultaneous deletion of Trp53, despite reduced apoptosis. Both P53-regulated (Mdm2, Foxm1) and P53-independent (Synj2bp) transcripts show increased mis-splicing in double mutants, indicating that P53-independent splicing defects also contribute to craniofacial malformations.","method":"Double homozygous conditional knockout (Eftud2;Trp53) in neural crest cells; pifithrin-α treatment; SOX10 staining; analysis of Mdm2, Foxm1, Synj2bp, and Zmat3 splicing","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — double-mutant genetic epistasis with defined molecular readouts, single lab, two orthogonal methods","pmids":["36012294"],"is_preprint":false},{"year":2022,"finding":"Knockdown of Eftud2, Snrpb, or Txnl4a in Xenopus embryos causes defects in cranial neural crest cell formation, identifying neural crest progenitor depletion through apoptosis as the likely culprit for MFD associated with EFTUD2 haploinsufficiency.","method":"Morpholino knockdown in Xenopus; neural crest cell marker analysis; apoptosis assays at multiple developmental stages","journal":"Journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with defined cellular phenotype (neural crest depletion/apoptosis), single lab","pmids":["35893124"],"is_preprint":false},{"year":2024,"finding":"Purkinje-cell-specific ablation of Eftud2 causes ferroptosis and Purkinje cell degeneration; mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity to suppress ferroptosis. Transcription factor Atf4 is a downstream target mediating anti-ferroptosis effects in a p53-independent manner. Ferroptosis inhibition rescued cerebellar deficits.","method":"Conditional Purkinje-cell-specific Eftud2 knockout mice; ferroptosis assays; lipidomic analysis; pharmacological and genetic ferroptosis inhibition rescue; Atf4 pathway analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with mechanistic pathway (Scd1/Gch1/Atf4), lipidomics, pharmacological rescue, multiple orthogonal methods in single study","pmids":["39153477"],"is_preprint":false},{"year":2023,"finding":"EFTUD2 mediates IFN anti-HBV effects through regulation of gene splicing for specific ISGs (Mx1, OAS1, PKR/EIF2AK2) without affecting Jak-STAT pathway gene expression or IFN receptors. EFTUD2 single allele knockout decreased ISG-encoded protein expression via impaired gene splicing; this was restored by EFTUD2 overexpression.","method":"CRISPR/Cas9 single allele knockout of EFTUD2 in HepG2.2.15 cells; mRNA sequencing; western blot for ISG proteins; EFTUD2 overexpression rescue experiment","journal":"Mediators of inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with mRNA-seq and rescue overexpression, single lab, two orthogonal methods","pmids":["37396299"],"is_preprint":false},{"year":2024,"finding":"EFTUD2 physically interacts with and stabilizes c-MYC protein by preventing ubiquitin-mediated proteasomal degradation; c-MYC in turn directly binds the EFTUD2 promoter to activate its transcription, forming a positive feedback loop. EFTUD2-mediated 5-FU resistance in colorectal cancer is dependent on c-MYC stabilization.","method":"Co-immunoprecipitation; ubiquitination assay; chromatin immunoprecipitation (ChIP); dual luciferase reporter assay; molecular docking; rescue experiments with c-MYC","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay plus ChIP, single lab, multiple orthogonal methods","pmids":["38163859"],"is_preprint":false},{"year":2025,"finding":"EFTUD2 directly interacts with Caspase3 and Aifm1 transcripts (shown by RNA co-immunoprecipitation) and regulates their alternative splicing to generate pro-apoptotic isoforms; NSC-specific Eftud2 knockout causes cortical disorganization and microcephaly through this apoptotic pathway.","method":"Conditional NSC-specific Eftud2 knockout mice; in utero electroporation of pathogenic EFTUD2 variants; RNA co-immunoprecipitation; full-length transcriptome sequencing; splicing assays; immunofluorescence","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA co-IP plus splicing assay plus conditional KO, single lab, multiple orthogonal methods","pmids":["40448601"],"is_preprint":false},{"year":2025,"finding":"EFTUD2 promotes efficient splicing of DDX41 mRNA and maintains oncogenic DDX41 protein expression; EFTUD2 knockdown induces DDX41 intron retention, reducing DDX41 protein and impairing malignant behavior of ovarian cancer cells. DDX41 knockdown partially phenocopied EFTUD2 knockdown.","method":"siRNA knockdown; in vitro and in vivo tumor assays; RNA-seq and alternative splicing event analysis; ASO-mediated EFTUD2 silencing","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq alternative splicing analysis plus rescue with DDX41 knockdown, single lab","pmids":["40555777"],"is_preprint":false},{"year":2025,"finding":"Eftud2 promotes exon 10-11 skipping of Kif3a (a kinesin motor for primary cilia formation) in the cerebellum; this Kif3a isoform augments medulloblastoma cell proliferation by potentiating Gli2 transcriptional activity in the SHH signaling pathway.","method":"Multi-omics sequencing; conditional Eftud2 ablation in cerebellar granule precursor cells; functional assays in human medulloblastoma cells; SHH pathway and Gli2 reporter assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus conditional KO plus pathway reporter assay, single lab","pmids":["40275081"],"is_preprint":false},{"year":2025,"finding":"EFTUD2 interacts with the NDV V protein (mapped primarily to EFTUD2 residues 116-825); EFTUD2 overexpression enhances chicken MDA5 splicing efficiency and upregulates ISGs/IFN-β to suppress NDV replication. siRNA-mediated EFTUD2 knockdown promoted viral replication.","method":"Immunoprecipitation-mass spectrometry (IP-MS); co-immunoprecipitation; confocal microscopy; siRNA knockdown; overexpression assays; splicing efficiency measurement","journal":"Poultry science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/IP-MS with functional follow-up, single lab, interaction domain mapping but limited orthogonal validation","pmids":["40580566"],"is_preprint":false},{"year":2020,"finding":"EFTUD2 overexpression promotes HCC cell proliferation, migration, and EMT-like phenotype through enhanced STAT3 activation; stable knockdown of EFTUD2 via lentivirus was lethal for HCC cells, suggesting EFTUD2 is essential for HCC cell survival. STAT3 inhibitor partially blocked pro-malignant effects of EFTUD2 overexpression.","method":"siRNA and lentiviral knockdown; overexpression; in vitro proliferation/migration assays; xenograft mouse model; RNA sequencing with GSEA; STAT3 inhibitor (S3I-201) treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq pathway analysis plus pharmacological rescue plus in vivo xenograft, single lab","pmids":["33024090"],"is_preprint":false},{"year":2025,"finding":"lncRNA DGUOK-AS1 directly binds EFTUD2 and the deubiquitinating protein VCP-interacting protein 1, shielding EFTUD2 from ubiquitination and proteasomal degradation. EFTUD2, stabilized by this interaction, promotes exclusion of cassette exon 11 from MST1R (RON), producing the RON∆165 isoform that activates Akt/PKB signaling.","method":"RNA pull-down; RNA immunoprecipitation; co-immunoprecipitation; ubiquitination assay; western blot; RNA-seq for alternative splicing","journal":"Cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down plus Co-IP plus ubiquitination assay, single lab, multiple orthogonal methods","pmids":["40968608"],"is_preprint":false},{"year":2023,"finding":"Eftud2 deficiency in microglia results in abnormal proliferation and promotes anti-inflammatory phenotype activation; Eftud2-mediated regulation of microglial pro-inflammatory/anti-inflammatory polarization in response to LPS is dependent on the NF-κB signaling pathway.","method":"Inducible microglia-specific conditional Eftud2 knockout (CX3CR1-CreER;Eftud2f/f); siRNA knockdown in BV2 microglia; immunofluorescence; western blot; NF-κB pathway analysis","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype plus siRNA in cell line, NF-κB pathway placement, single lab","pmids":["36204854"],"is_preprint":false}],"current_model":"EFTUD2 (Snu114/U5-116kD) is a highly conserved GTPase component of the U5 snRNP that assembles with Prp8 and Brr2 on U5 snRNA to form the tri-snRNP; its GTP-bound complex with Prp8 serves as a relay station during spliceosome activation, facilitating U4 snRNP release and catalytic activation through conformational rearrangements in the C-terminal domain, while also regulating alternative splicing of diverse downstream targets including Mdm2, Kif3a, Caspase3, Aifm1, and immune sensors (RIG-I, MDA5), with haploinsufficiency triggering p53-pathway hyperactivation via splicing errors that underlie the craniofacial and neurodevelopmental defects of mandibulofacial dysostosis with microcephaly."},"narrative":{"mechanistic_narrative":"EFTUD2 (Snu114/U5-116kD) is a highly conserved spliceosomal GTPase that acts as a central regulatory node in catalytic splicing and post-splicing-complex disassembly within the major spliceosome [PMID:22305528]. It assembles into the U5 snRNP through its GTPase domain and direct interaction with Prp8, docking onto the 3' side of U5 snRNA internal loop 1 together with Brr2 [PMID:16540695, PMID:23857713]. The crystal structure of the Snu114-Prp8 complex captures EFTUD2 in a GTP-bound conformation in which Prp8 binding abolishes its weak intrinsic GTPase activity, defining a Snu114-GTP-Prp8 module that serves as a relay station governing the same set of splicing events during spliceosome activation and disassembly [PMID:32196113]; its C-terminus drives the conformational rearrangement with Prp8 that triggers U1 and U4 snRNP release to activate the spliceosome [PMID:15911574, PMID:16540695]. Beyond catalytic core function, EFTUD2 directs alternative splicing of specific transcripts: it controls Mdm2 (exon 3) and pro-apoptotic Caspase3/Aifm1 isoforms, with loss causing intron retention and exon skipping transcriptome-wide [PMID:27899647, PMID:33601405, PMID:40448601]. Haploinsufficiency depletes neural crest and neural progenitor pools through splicing errors that stabilize nuclear P53 and hyperactivate the p53 pathway, driving the craniofacial and neurodevelopmental defects of mandibulofacial dysostosis with microcephaly [PMID:22305528, PMID:27899647, PMID:33601405]; P53-independent mis-splicing and lineage-specific outputs such as ferroptosis suppression in Purkinje cells also contribute to tissue phenotypes [PMID:36012294, PMID:39153477]. EFTUD2 additionally tunes innate immunity by splicing-dependent regulation of RIG-I/MDA5, interferon-stimulated genes, and the TLR4-NF-κB cascade [PMID:25878102, PMID:31278373, PMID:37396299], and acts oncogenically in several cancers by regulating splicing of targets including Kif3a, MST1R/RON, and DDX41 and by stabilizing c-MYC against proteasomal degradation [PMID:38163859, PMID:40555777, PMID:40275081, PMID:40968608].","teleology":[{"year":2005,"claim":"Established that the Snu114/EFTUD2 C-terminus and GTPase activity are functionally required for spliceosome activation rather than being passive structural features.","evidence":"Conditional lethal alleles, in vivo/in vitro splicing assays, and synthetic lethality with Brr2/Prp28 in yeast","pmids":["15911574"],"confidence":"High","gaps":["Did not resolve the structural basis of the Prp8-Snu114 rearrangement","GTP hydrolysis cycle timing during catalysis not defined"]},{"year":2006,"claim":"Defined how EFTUD2 assembles into the U5 snRNP, showing the GTPase domain and Prp8 are both required for stable incorporation and that C-terminal function maps specifically to U4 release.","evidence":"Biochemical snRNP/spliceosome assembly in SNU114 mutant yeast extracts with Co-IP of Prp8 and U5 snRNA","pmids":["16540695"],"confidence":"High","gaps":["Atomic-resolution view of the assembly interfaces lacking at this stage","Order of Prp8 vs U5 snRNA engagement not established"]},{"year":2008,"claim":"Placed Prp8/Snu114 centrally and Brr2 peripherally in the tri-snRNP, revealing structural dynamics consistent with conformational activation.","evidence":"Electron microscopy projection structure of genetically tagged S. cerevisiae tri-snRNP","pmids":["18953335"],"confidence":"High","gaps":["Projection resolution insufficient for atomic contacts","Functional state of the captured conformers undefined"]},{"year":2012,"claim":"Linked EFTUD2 to human disease, establishing that haploinsufficiency of this spliceosomal GTPase causes mandibulofacial dysostosis with microcephaly.","evidence":"Whole-exome sequencing of 12 unrelated MFDM patients identifying null/frameshift alleles","pmids":["22305528"],"confidence":"High","gaps":["Did not define which mis-splicing events drive the phenotype","Tissue-specific vulnerability of neural crest unexplained"]},{"year":2013,"claim":"Identified the U5 snRNA internal loop 1 3' side as the platform required for co-recruitment of Prp8, Snu114, and Brr2.","evidence":"Site-directed mutagenesis of U5 snRNA with Co-IP and synthetic lethal screening in yeast","pmids":["23857713"],"confidence":"Medium","gaps":["Single-lab finding","Whether IL1 binding is direct or bridged by protein partners not resolved"]},{"year":2017,"claim":"Connected EFTUD2 loss to a transcriptome-wide splicing defect that activates the p53 pathway, providing the first mechanistic bridge between splicing failure and the developmental phenotype.","evidence":"Positional cloning, RNA-seq, and TUNEL in zebrafish eftud2 mutant","pmids":["27899647"],"confidence":"High","gaps":["Specific causative mis-spliced transcripts not yet identified","Mechanism linking NMD failure to p53 activation undefined"]},{"year":2019,"claim":"Resolved the in vivo requirement for EFTUD2 in mammalian development, showing homozygous loss is pre-implantation lethal while heterozygotes model the dosage-sensitive disease.","evidence":"CRISPR/Cas9 exon 2 deletion mouse with Mendelian analysis and in situ hybridization","pmids":["31276534"],"confidence":"Medium","gaps":["Molecular cause of pre-implantation lethality not dissected","Single-lab study"]},{"year":2019,"claim":"Demonstrated EFTUD2's role in innate immunity, showing it modulates the TLR4-NF-κB inflammatory response through alternative splicing of cascade components.","evidence":"Myeloid-specific conditional knockout mice with LPS challenge and splicing analysis","pmids":["31278373"],"confidence":"High","gaps":["Exact NF-κB cascade transcripts mis-spliced not fully enumerated","Relationship to spliceosome core function unclear"]},{"year":2019,"claim":"Mapped a substrate-discriminating surface on Snu114 domain IVa where PP1 and Cwc21 bind competitively in a nucleotide-state-dependent manner, controlling splicing of a specific transcript subset.","evidence":"Yeast mutagenesis, nucleotide-state binding assays, and meiotic transcript splicing readout","pmids":["30672374"],"confidence":"Medium","gaps":["Functional consequence of PP1 recruitment to the spliceosome not defined","Single-lab finding"]},{"year":2019,"claim":"Extended the p53-mediated mechanism to skeletal lineages, showing EFTUD2 deficiency impairs osteoblast/chondrocyte differentiation via TP53 activation.","evidence":"siRNA in human calvarial cells, zebrafish knockout, RNA-seq, and morpholino p53 rescue","pmids":["31806011"],"confidence":"Medium","gaps":["Causative mis-spliced transcripts upstream of p53 not identified here","Single-lab study"]},{"year":2020,"claim":"Delivered the atomic basis of the relay-station model, showing Prp8 locks Snu114 in a GTP-bound state and that perturbing the shared GTP pocket alters a defined set of splicing events.","evidence":"Crystal structure of Snu114-Prp8, GTPase assays, and in vivo splicing with pocket mutants in yeast","pmids":["32196113"],"confidence":"High","gaps":["Whether GTP exchange ever occurs during the cycle unresolved","Trigger for the conformational relay not defined"]},{"year":2020,"claim":"Pinpointed Mdm2 exon 3 skipping as a direct driver of P53 overactivation in neural crest, validated by Mdm2 and pifithrin-α rescue of craniofacial defects.","evidence":"Wnt1-Cre2 conditional knockout mice, RNA-seq, minigene assay, and dual rescue","pmids":["33601405"],"confidence":"High","gaps":["Did not exclude additional contributing mis-splicing events","Extent of P53-independent contribution unaddressed"]},{"year":2020,"claim":"Resolved the molecular consequence of disease missense variants, partitioning them into protein-function-altering versus splicing-altering loss-of-function classes.","evidence":"Yeast Snu114 growth assays and minigene splicing assays for 19 MFDGA variants","pmids":["32333448"],"confidence":"Medium","gaps":["Mechanism for variants without detectable defect unclear","Single-lab functional surrogate"]},{"year":2022,"claim":"Showed that p53 loss alone does not rescue craniofacial malformation, establishing that P53-independent mis-splicing also contributes to disease.","evidence":"Eftud2;Trp53 double conditional knockout with splicing analysis of P53-dependent and -independent transcripts","pmids":["36012294"],"confidence":"Medium","gaps":["Functional impact of P53-independent targets (Synj2bp) not established","Single-lab study"]},{"year":2022,"claim":"Generalized neural crest progenitor depletion via apoptosis as the cellular basis of spliceosomopathy-associated MFD across multiple splicing factors.","evidence":"Morpholino knockdown of Eftud2/Snrpb/Txnl4a in Xenopus with neural crest marker and apoptosis assays","pmids":["35893124"],"confidence":"Medium","gaps":["Did not identify EFTUD2-specific splicing targets in this system","Morpholino-based knockdown"]},{"year":2024,"claim":"Uncovered a p53-independent, lineage-specific role in which EFTUD2 suppresses ferroptosis to protect cerebellar Purkinje cells.","evidence":"Purkinje-cell-specific knockout mice, lipidomics, and pharmacological/genetic ferroptosis rescue with Atf4 pathway analysis","pmids":["39153477"],"confidence":"High","gaps":["Whether Scd1/Gch1/Atf4 regulation is splicing-dependent not fully resolved","Generality beyond Purkinje cells unknown"]},{"year":2025,"claim":"Identified direct EFTUD2 binding to Caspase3 and Aifm1 transcripts to generate pro-apoptotic isoforms underlying cortical microcephaly.","evidence":"NSC-specific knockout mice, in utero electroporation, RNA co-IP, and full-length transcriptome sequencing","pmids":["40448601"],"confidence":"Medium","gaps":["Direct vs spliceosome-mediated transcript binding not distinguished","Single-lab finding"]},{"year":2025,"claim":"Expanded the oncogenic splicing repertoire, linking EFTUD2 to Kif3a, MST1R/RON, and DDX41 isoform regulation across cancers.","evidence":"Conditional knockouts, siRNA/ASO knockdown, RNA-seq splicing analysis, and pathway reporter assays in medulloblastoma, ovarian, and other cancer models","pmids":["40275081","40555777","40968608"],"confidence":"Medium","gaps":["Whether these reflect direct splicing regulation or core spliceosome function unclear","Each finding from a single lab"]},{"year":2024,"claim":"Revealed a non-splicing function in which EFTUD2 stabilizes c-MYC protein against ubiquitin-mediated degradation within a positive feedback loop driving chemoresistance.","evidence":"Reciprocal Co-IP, ubiquitination assay, ChIP, and luciferase reporter in colorectal cancer","pmids":["38163859"],"confidence":"Medium","gaps":["Mechanism by which EFTUD2 blocks c-MYC ubiquitination not defined","Single-lab study"]},{"year":2023,"claim":"Extended splicing-dependent immune regulation to antiviral defense and microglial polarization, showing EFTUD2 controls ISG and inflammatory outputs independent of JAK-STAT.","evidence":"CRISPR knockout in hepatocytes, microglia-specific conditional knockout, and RIG-I-dependent ISG induction assays","pmids":["37396299","25878102","36204854"],"confidence":"Medium","gaps":["Which ISG transcripts are direct splicing substrates not fully mapped","Mechanism of NF-κB cascade splicing regulation incomplete"]},{"year":null,"claim":"It remains unresolved how EFTUD2 selects specific transcripts (Mdm2, Kif3a, Caspase3, ISGs) for regulated alternative splicing distinct from its constitutive core spliceosome role, and how its non-canonical c-MYC-stabilizing and ferroptosis-suppressing activities mechanistically arise.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No model distinguishing core spliceosome function from substrate-specific regulation","Structural basis of non-splicing protein-stabilization activity unknown","Human structural data for EFTUD2-containing tri-snRNP not in corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[1,2,12]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[4,19,24]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5,10,19]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,7,17,25]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell 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Component of the U5 snRNP and the U4/U6-U5 tri-snRNP complex, a building block of the spliceosome (PubMed:16723661). 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\"Whole-exome sequencing identifying causative mutations (null alleles, frameshifts) in patients; consistent with haploinsufficiency across 12 unrelated individuals\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mutations in 12 independent cases with defined molecular mechanism (spliceosomal GTPase haploinsufficiency), replicated across multiple unrelated individuals\",\n      \"pmids\": [\"22305528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The C-terminus of Snu114 (EFTUD2 ortholog) is required for spliceosome activation; C-terminal truncation allele snu114-60 was synthetically lethal with ATPases Brr2 and Prp28 required for U1 and U4 snRNP release, suggesting a rearrangement between Prp8 and the C-terminus of Snu114 leads to release of U1 and U4 snRNPs to activate the spliceosome. GTP binding/hydrolysis domain mutations blocked the first step of splicing in vivo and in vitro.\",\n      \"method\": \"Random mutagenesis to create conditional lethal alleles; in vivo and in vitro splicing assays; synthetic lethality analysis with PRP8, BRR2, PRP28, SAD1, BRR1\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro and in vivo splicing assays combined with genetic epistasis, multiple allele classes characterized, replicated across multiple genetic interactions\",\n      \"pmids\": [\"15911574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Assembly of Snu114 (EFTUD2 ortholog) into the U5 snRNP requires both a functional GTPase domain and Prp8. GTPase domain mutations prevent Snu114 interaction with Prp8 and with U5 snRNA, blocking U5 snRNP assembly. The C-terminal truncation mutant assembles spliceosomes but blocks U4 snRNP release.\",\n      \"method\": \"Biochemical analysis of snRNP and spliceosome assembly in SNU114 mutant yeast extracts; co-immunoprecipitation of Snu114 with Prp8 and U5 snRNA\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct biochemical reconstitution of snRNP assembly with multiple mutant alleles, reciprocal interaction assays, two orthogonal methods\",\n      \"pmids\": [\"16540695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In the yeast tri-snRNP EM structure, Prp8 and Snu114 (EFTUD2 ortholog) are located centrally, while Brr2 occupies a separate head domain; U4/U6 snRNP forms the arm domain. The head and arm domains adopt variable relative positions, suggesting structural dynamics during catalytic activation.\",\n      \"method\": \"Electron microscopy projection structure of S. cerevisiae tri-snRNP with genetically tagged proteins visualized by EM\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct EM structural localization with genetic tagging, multiple proteins mapped, structural validation\",\n      \"pmids\": [\"18953335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The U5 snRNA internal loop 1 (IL1), particularly its 3' side, is a platform required for Prp8, Snu114 (EFTUD2 ortholog), and Brr2 association with U5 snRNA during U5 snRNP assembly. Mutations in IL1 3' side caused the greatest reduction in association of all three proteins.\",\n      \"method\": \"Site-directed mutagenesis of U5 snRNA loop 1 and internal loop 1; in vivo functional assays; co-immunoprecipitation of Prp8, Snu114, Brr2 with U5 snRNA; synthetic lethal screening of brr2 and U5 snRNA mutants\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with RNA and genetic epistasis, single lab, two orthogonal methods\",\n      \"pmids\": [\"23857713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disruption of eftud2 in zebrafish leads to transcriptome-wide RNA splicing deficiency (intron retention and exon skipping), causing inadequate nonsense-mediated RNA decay and activation of the p53 pathway, resulting in increased apoptosis and mitosis of neural progenitors during brain development.\",\n      \"method\": \"Positional cloning of nonsense mutation; RNA-seq transcriptome analysis; functional analysis in zebrafish fn10a mutant; TUNEL apoptosis assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-seq plus functional validation in vivo, pathway placement via p53 activation downstream of splicing deficiency, multiple orthogonal methods\",\n      \"pmids\": [\"27899647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"EFTUD2 restricts HCV infection through an RIG-I/MDA5-dependent, JAK-STAT-independent pathway; EFTUD2 upregulates RIG-I and MDA5 expression by gene splicing, and its antiviral effect on interferon-stimulated gene induction was absent in RIG-I-knockdown or RIG-I-defective cells.\",\n      \"method\": \"siRNA knockdown; overexpression in Huh7 cells; RIG-I knockdown and RIG-I-defective cell lines as controls; measurement of ISG induction and HCV replication\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via RIG-I knockdown controls, functional splicing assay, single lab\",\n      \"pmids\": [\"25878102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myeloid-specific knockout of Eftud2 suppresses NF-κB signaling activation in LPS-challenged macrophages; the mechanism involves EFTUD2-mediated alternative splicing of components of the TLR4–NF-κB cascade, thereby modulating innate immune inflammatory response.\",\n      \"method\": \"Myeloid-specific conditional knockout mouse model; LPS stimulation of macrophages; cytokine measurements; NF-κB pathway analysis; alternative splicing analysis of TLR4-NF-κB cascade components\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with defined cellular phenotype (NF-κB activation), alternative splicing mechanism identified, in vivo and in vitro validation\",\n      \"pmids\": [\"31278373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Homozygous loss of Eftud2 causes pre-implantation lethality in mice; heterozygous mutants are viable with reduced EFTUD2 mRNA and protein levels. Eftud2 expression is enriched in the developing head and craniofacial regions.\",\n      \"method\": \"CRISPR/Cas9 deletion of exon 2; Mendelian frequency analysis at E3.5 and post-implantation; in situ hybridization for expression; ex vivo embryo culture\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic knockout with defined lethal phenotype, in situ hybridization localization, single lab\",\n      \"pmids\": [\"31276534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Only 4 of 19 MFDGA-associated EFTUD2 missense variants cause loss-of-function through altered protein function (assessed in yeast growth assays); 5 of the remaining 15 cause loss-of-function by altering EFTUD2 pre-mRNA splicing (predominantly exon skipping or cryptic splice site activation leading to a premature termination codon).\",\n      \"method\": \"Yeast functional growth assays modeling missense variants in S. cerevisiae Snu114; minigene splicing assay; bioinformatics prediction comparison\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — yeast reconstitution assay plus minigene splicing validation, single lab, two orthogonal methods\",\n      \"pmids\": [\"32333448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Homozygous deletion of Eftud2 in neural crest cells causes craniofacial malformations via mis-splicing of Mdm2 (exon 3 skipping), leading to increased nuclear P53, upregulation of P53-target genes, and increased cell death. Overexpression of non-spliced Mdm2 attenuates P53 pathway overactivation in Eftud2 knockdown cells, and P53 inhibitor pifithrin-α improves craniofacial development in Eftud2-mutant embryos.\",\n      \"method\": \"Conditional Wnt1-Cre2 knockout mouse; RNAseq analysis; siRNA knockdown in O9-1 neural crest cells; minigene splicing assay; Mdm2 overexpression rescue; pifithrin-α treatment rescue\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — conditional KO with RNAseq, rescue by Mdm2 overexpression and P53 inhibitor, multiple orthogonal methods, mechanistic pathway established\",\n      \"pmids\": [\"33601405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"EFTUD2 deficiency inhibits proliferation, differentiation, and maturation of osteoblasts and chondrocytes via activation of the TP53 signaling pathway with increased phosphorylation of TP53 and upregulation of downstream targets (FAS, STEAP3, CASP3, P21, SESN1). P53 inhibition by morpholino reduced mortality in eftud2-null zebrafish.\",\n      \"method\": \"siRNA knockdown in human calvarial osteoblast and chondrocyte cells; zebrafish eftud2 knockout model; RNA-seq; western blot for phospho-TP53; morpholino p53 inhibition rescue\",\n      \"journal\": \"Human genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish model plus cell-based assays, pathway placement via morpholino rescue, single lab\",\n      \"pmids\": [\"31806011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of yeast Snu114 with the Snu114-binding region of Prp8 shows Snu114 in a GTP-bound conformation. The Prp8 Snu114-binding region abolishes Snu114's weak intrinsic GTPase activity. Exchange of GTP-contacting residues in Snu114 or Prp8 residues lining the Snu114 GTP-binding pocket leads to temperature-sensitive growth and affects the same set of splicing events in vivo, suggesting the Snu114-GTP-Prp8 module serves as a relay station during spliceosome activation and disassembly.\",\n      \"method\": \"Crystal structure determination of Snu114-Prp8 complex; GTPase activity assay; co-purification with endogenous GTP; yeast growth assays with GTP-contacting residue mutants; in vivo splicing analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro GTPase assay plus mutagenesis plus in vivo splicing, multiple orthogonal methods in one study\",\n      \"pmids\": [\"32196113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Snu114 domain IVa directly interacts with protein phosphatase PP1 via a 'YGVQYK' binding motif; Cwc21 also binds this same motif in domain IVa, and these interactions are mutually exclusive. The affinity of Cwc21 and PP1 for Snu114 is influenced by the nucleotide-bound state of Snu114. A mutation in domain IVa causes a specific defect in splicing of meiotic gene transcripts (SPO22, AMA1, MER2) without affecting vegetative growth.\",\n      \"method\": \"Yeast mutagenesis; genetic and biochemical interaction assays; nucleotide-state dependent binding assays; in vivo splicing analysis of meiotic transcripts\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapping, nucleotide-state dependence, functional splicing readout, single lab\",\n      \"pmids\": [\"30672374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Craniofacial defects in Eftud2 neural-crest-specific homozygous mutant embryos are not rescued by simultaneous deletion of Trp53, despite reduced apoptosis. Both P53-regulated (Mdm2, Foxm1) and P53-independent (Synj2bp) transcripts show increased mis-splicing in double mutants, indicating that P53-independent splicing defects also contribute to craniofacial malformations.\",\n      \"method\": \"Double homozygous conditional knockout (Eftud2;Trp53) in neural crest cells; pifithrin-α treatment; SOX10 staining; analysis of Mdm2, Foxm1, Synj2bp, and Zmat3 splicing\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — double-mutant genetic epistasis with defined molecular readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"36012294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of Eftud2, Snrpb, or Txnl4a in Xenopus embryos causes defects in cranial neural crest cell formation, identifying neural crest progenitor depletion through apoptosis as the likely culprit for MFD associated with EFTUD2 haploinsufficiency.\",\n      \"method\": \"Morpholino knockdown in Xenopus; neural crest cell marker analysis; apoptosis assays at multiple developmental stages\",\n      \"journal\": \"Journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with defined cellular phenotype (neural crest depletion/apoptosis), single lab\",\n      \"pmids\": [\"35893124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Purkinje-cell-specific ablation of Eftud2 causes ferroptosis and Purkinje cell degeneration; mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity to suppress ferroptosis. Transcription factor Atf4 is a downstream target mediating anti-ferroptosis effects in a p53-independent manner. Ferroptosis inhibition rescued cerebellar deficits.\",\n      \"method\": \"Conditional Purkinje-cell-specific Eftud2 knockout mice; ferroptosis assays; lipidomic analysis; pharmacological and genetic ferroptosis inhibition rescue; Atf4 pathway analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with mechanistic pathway (Scd1/Gch1/Atf4), lipidomics, pharmacological rescue, multiple orthogonal methods in single study\",\n      \"pmids\": [\"39153477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EFTUD2 mediates IFN anti-HBV effects through regulation of gene splicing for specific ISGs (Mx1, OAS1, PKR/EIF2AK2) without affecting Jak-STAT pathway gene expression or IFN receptors. EFTUD2 single allele knockout decreased ISG-encoded protein expression via impaired gene splicing; this was restored by EFTUD2 overexpression.\",\n      \"method\": \"CRISPR/Cas9 single allele knockout of EFTUD2 in HepG2.2.15 cells; mRNA sequencing; western blot for ISG proteins; EFTUD2 overexpression rescue experiment\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with mRNA-seq and rescue overexpression, single lab, two orthogonal methods\",\n      \"pmids\": [\"37396299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EFTUD2 physically interacts with and stabilizes c-MYC protein by preventing ubiquitin-mediated proteasomal degradation; c-MYC in turn directly binds the EFTUD2 promoter to activate its transcription, forming a positive feedback loop. EFTUD2-mediated 5-FU resistance in colorectal cancer is dependent on c-MYC stabilization.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; chromatin immunoprecipitation (ChIP); dual luciferase reporter assay; molecular docking; rescue experiments with c-MYC\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ubiquitination assay plus ChIP, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38163859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EFTUD2 directly interacts with Caspase3 and Aifm1 transcripts (shown by RNA co-immunoprecipitation) and regulates their alternative splicing to generate pro-apoptotic isoforms; NSC-specific Eftud2 knockout causes cortical disorganization and microcephaly through this apoptotic pathway.\",\n      \"method\": \"Conditional NSC-specific Eftud2 knockout mice; in utero electroporation of pathogenic EFTUD2 variants; RNA co-immunoprecipitation; full-length transcriptome sequencing; splicing assays; immunofluorescence\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA co-IP plus splicing assay plus conditional KO, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40448601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EFTUD2 promotes efficient splicing of DDX41 mRNA and maintains oncogenic DDX41 protein expression; EFTUD2 knockdown induces DDX41 intron retention, reducing DDX41 protein and impairing malignant behavior of ovarian cancer cells. DDX41 knockdown partially phenocopied EFTUD2 knockdown.\",\n      \"method\": \"siRNA knockdown; in vitro and in vivo tumor assays; RNA-seq and alternative splicing event analysis; ASO-mediated EFTUD2 silencing\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq alternative splicing analysis plus rescue with DDX41 knockdown, single lab\",\n      \"pmids\": [\"40555777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Eftud2 promotes exon 10-11 skipping of Kif3a (a kinesin motor for primary cilia formation) in the cerebellum; this Kif3a isoform augments medulloblastoma cell proliferation by potentiating Gli2 transcriptional activity in the SHH signaling pathway.\",\n      \"method\": \"Multi-omics sequencing; conditional Eftud2 ablation in cerebellar granule precursor cells; functional assays in human medulloblastoma cells; SHH pathway and Gli2 reporter assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus conditional KO plus pathway reporter assay, single lab\",\n      \"pmids\": [\"40275081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EFTUD2 interacts with the NDV V protein (mapped primarily to EFTUD2 residues 116-825); EFTUD2 overexpression enhances chicken MDA5 splicing efficiency and upregulates ISGs/IFN-β to suppress NDV replication. siRNA-mediated EFTUD2 knockdown promoted viral replication.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry (IP-MS); co-immunoprecipitation; confocal microscopy; siRNA knockdown; overexpression assays; splicing efficiency measurement\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/IP-MS with functional follow-up, single lab, interaction domain mapping but limited orthogonal validation\",\n      \"pmids\": [\"40580566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EFTUD2 overexpression promotes HCC cell proliferation, migration, and EMT-like phenotype through enhanced STAT3 activation; stable knockdown of EFTUD2 via lentivirus was lethal for HCC cells, suggesting EFTUD2 is essential for HCC cell survival. STAT3 inhibitor partially blocked pro-malignant effects of EFTUD2 overexpression.\",\n      \"method\": \"siRNA and lentiviral knockdown; overexpression; in vitro proliferation/migration assays; xenograft mouse model; RNA sequencing with GSEA; STAT3 inhibitor (S3I-201) treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq pathway analysis plus pharmacological rescue plus in vivo xenograft, single lab\",\n      \"pmids\": [\"33024090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"lncRNA DGUOK-AS1 directly binds EFTUD2 and the deubiquitinating protein VCP-interacting protein 1, shielding EFTUD2 from ubiquitination and proteasomal degradation. EFTUD2, stabilized by this interaction, promotes exclusion of cassette exon 11 from MST1R (RON), producing the RON∆165 isoform that activates Akt/PKB signaling.\",\n      \"method\": \"RNA pull-down; RNA immunoprecipitation; co-immunoprecipitation; ubiquitination assay; western blot; RNA-seq for alternative splicing\",\n      \"journal\": \"Cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down plus Co-IP plus ubiquitination assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40968608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Eftud2 deficiency in microglia results in abnormal proliferation and promotes anti-inflammatory phenotype activation; Eftud2-mediated regulation of microglial pro-inflammatory/anti-inflammatory polarization in response to LPS is dependent on the NF-κB signaling pathway.\",\n      \"method\": \"Inducible microglia-specific conditional Eftud2 knockout (CX3CR1-CreER;Eftud2f/f); siRNA knockdown in BV2 microglia; immunofluorescence; western blot; NF-κB pathway analysis\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype plus siRNA in cell line, NF-κB pathway placement, single lab\",\n      \"pmids\": [\"36204854\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFTUD2 (Snu114/U5-116kD) is a highly conserved GTPase component of the U5 snRNP that assembles with Prp8 and Brr2 on U5 snRNA to form the tri-snRNP; its GTP-bound complex with Prp8 serves as a relay station during spliceosome activation, facilitating U4 snRNP release and catalytic activation through conformational rearrangements in the C-terminal domain, while also regulating alternative splicing of diverse downstream targets including Mdm2, Kif3a, Caspase3, Aifm1, and immune sensors (RIG-I, MDA5), with haploinsufficiency triggering p53-pathway hyperactivation via splicing errors that underlie the craniofacial and neurodevelopmental defects of mandibulofacial dysostosis with microcephaly.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EFTUD2 (Snu114/U5-116kD) is a highly conserved spliceosomal GTPase that acts as a central regulatory node in catalytic splicing and post-splicing-complex disassembly within the major spliceosome [#0]. It assembles into the U5 snRNP through its GTPase domain and direct interaction with Prp8, docking onto the 3' side of U5 snRNA internal loop 1 together with Brr2 [#2, #4]. The crystal structure of the Snu114-Prp8 complex captures EFTUD2 in a GTP-bound conformation in which Prp8 binding abolishes its weak intrinsic GTPase activity, defining a Snu114-GTP-Prp8 module that serves as a relay station governing the same set of splicing events during spliceosome activation and disassembly [#12]; its C-terminus drives the conformational rearrangement with Prp8 that triggers U1 and U4 snRNP release to activate the spliceosome [#1, #2]. Beyond catalytic core function, EFTUD2 directs alternative splicing of specific transcripts: it controls Mdm2 (exon 3) and pro-apoptotic Caspase3/Aifm1 isoforms, with loss causing intron retention and exon skipping transcriptome-wide [#5, #10, #19]. Haploinsufficiency depletes neural crest and neural progenitor pools through splicing errors that stabilize nuclear P53 and hyperactivate the p53 pathway, driving the craniofacial and neurodevelopmental defects of mandibulofacial dysostosis with microcephaly [#0, #5, #10]; P53-independent mis-splicing and lineage-specific outputs such as ferroptosis suppression in Purkinje cells also contribute to tissue phenotypes [#14, #16]. EFTUD2 additionally tunes innate immunity by splicing-dependent regulation of RIG-I/MDA5, interferon-stimulated genes, and the TLR4-NF-\\u03baB cascade [#6, #7, #17], and acts oncogenically in several cancers by regulating splicing of targets including Kif3a, MST1R/RON, and DDX41 and by stabilizing c-MYC against proteasomal degradation [#18, #20, #21, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that the Snu114/EFTUD2 C-terminus and GTPase activity are functionally required for spliceosome activation rather than being passive structural features.\",\n      \"evidence\": \"Conditional lethal alleles, in vivo/in vitro splicing assays, and synthetic lethality with Brr2/Prp28 in yeast\",\n      \"pmids\": [\"15911574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the Prp8-Snu114 rearrangement\", \"GTP hydrolysis cycle timing during catalysis not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined how EFTUD2 assembles into the U5 snRNP, showing the GTPase domain and Prp8 are both required for stable incorporation and that C-terminal function maps specifically to U4 release.\",\n      \"evidence\": \"Biochemical snRNP/spliceosome assembly in SNU114 mutant yeast extracts with Co-IP of Prp8 and U5 snRNA\",\n      \"pmids\": [\"16540695\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution view of the assembly interfaces lacking at this stage\", \"Order of Prp8 vs U5 snRNA engagement not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed Prp8/Snu114 centrally and Brr2 peripherally in the tri-snRNP, revealing structural dynamics consistent with conformational activation.\",\n      \"evidence\": \"Electron microscopy projection structure of genetically tagged S. cerevisiae tri-snRNP\",\n      \"pmids\": [\"18953335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Projection resolution insufficient for atomic contacts\", \"Functional state of the captured conformers undefined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked EFTUD2 to human disease, establishing that haploinsufficiency of this spliceosomal GTPase causes mandibulofacial dysostosis with microcephaly.\",\n      \"evidence\": \"Whole-exome sequencing of 12 unrelated MFDM patients identifying null/frameshift alleles\",\n      \"pmids\": [\"22305528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which mis-splicing events drive the phenotype\", \"Tissue-specific vulnerability of neural crest unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the U5 snRNA internal loop 1 3' side as the platform required for co-recruitment of Prp8, Snu114, and Brr2.\",\n      \"evidence\": \"Site-directed mutagenesis of U5 snRNA with Co-IP and synthetic lethal screening in yeast\",\n      \"pmids\": [\"23857713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Whether IL1 binding is direct or bridged by protein partners not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected EFTUD2 loss to a transcriptome-wide splicing defect that activates the p53 pathway, providing the first mechanistic bridge between splicing failure and the developmental phenotype.\",\n      \"evidence\": \"Positional cloning, RNA-seq, and TUNEL in zebrafish eftud2 mutant\",\n      \"pmids\": [\"27899647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific causative mis-spliced transcripts not yet identified\", \"Mechanism linking NMD failure to p53 activation undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the in vivo requirement for EFTUD2 in mammalian development, showing homozygous loss is pre-implantation lethal while heterozygotes model the dosage-sensitive disease.\",\n      \"evidence\": \"CRISPR/Cas9 exon 2 deletion mouse with Mendelian analysis and in situ hybridization\",\n      \"pmids\": [\"31276534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cause of pre-implantation lethality not dissected\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated EFTUD2's role in innate immunity, showing it modulates the TLR4-NF-\\u03baB inflammatory response through alternative splicing of cascade components.\",\n      \"evidence\": \"Myeloid-specific conditional knockout mice with LPS challenge and splicing analysis\",\n      \"pmids\": [\"31278373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact NF-\\u03baB cascade transcripts mis-spliced not fully enumerated\", \"Relationship to spliceosome core function unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped a substrate-discriminating surface on Snu114 domain IVa where PP1 and Cwc21 bind competitively in a nucleotide-state-dependent manner, controlling splicing of a specific transcript subset.\",\n      \"evidence\": \"Yeast mutagenesis, nucleotide-state binding assays, and meiotic transcript splicing readout\",\n      \"pmids\": [\"30672374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PP1 recruitment to the spliceosome not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the p53-mediated mechanism to skeletal lineages, showing EFTUD2 deficiency impairs osteoblast/chondrocyte differentiation via TP53 activation.\",\n      \"evidence\": \"siRNA in human calvarial cells, zebrafish knockout, RNA-seq, and morpholino p53 rescue\",\n      \"pmids\": [\"31806011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causative mis-spliced transcripts upstream of p53 not identified here\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Delivered the atomic basis of the relay-station model, showing Prp8 locks Snu114 in a GTP-bound state and that perturbing the shared GTP pocket alters a defined set of splicing events.\",\n      \"evidence\": \"Crystal structure of Snu114-Prp8, GTPase assays, and in vivo splicing with pocket mutants in yeast\",\n      \"pmids\": [\"32196113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether GTP exchange ever occurs during the cycle unresolved\", \"Trigger for the conformational relay not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pinpointed Mdm2 exon 3 skipping as a direct driver of P53 overactivation in neural crest, validated by Mdm2 and pifithrin-\\u03b1 rescue of craniofacial defects.\",\n      \"evidence\": \"Wnt1-Cre2 conditional knockout mice, RNA-seq, minigene assay, and dual rescue\",\n      \"pmids\": [\"33601405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not exclude additional contributing mis-splicing events\", \"Extent of P53-independent contribution unaddressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the molecular consequence of disease missense variants, partitioning them into protein-function-altering versus splicing-altering loss-of-function classes.\",\n      \"evidence\": \"Yeast Snu114 growth assays and minigene splicing assays for 19 MFDGA variants\",\n      \"pmids\": [\"32333448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism for variants without detectable defect unclear\", \"Single-lab functional surrogate\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed that p53 loss alone does not rescue craniofacial malformation, establishing that P53-independent mis-splicing also contributes to disease.\",\n      \"evidence\": \"Eftud2;Trp53 double conditional knockout with splicing analysis of P53-dependent and -independent transcripts\",\n      \"pmids\": [\"36012294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional impact of P53-independent targets (Synj2bp) not established\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Generalized neural crest progenitor depletion via apoptosis as the cellular basis of spliceosomopathy-associated MFD across multiple splicing factors.\",\n      \"evidence\": \"Morpholino knockdown of Eftud2/Snrpb/Txnl4a in Xenopus with neural crest marker and apoptosis assays\",\n      \"pmids\": [\"35893124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify EFTUD2-specific splicing targets in this system\", \"Morpholino-based knockdown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a p53-independent, lineage-specific role in which EFTUD2 suppresses ferroptosis to protect cerebellar Purkinje cells.\",\n      \"evidence\": \"Purkinje-cell-specific knockout mice, lipidomics, and pharmacological/genetic ferroptosis rescue with Atf4 pathway analysis\",\n      \"pmids\": [\"39153477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Scd1/Gch1/Atf4 regulation is splicing-dependent not fully resolved\", \"Generality beyond Purkinje cells unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified direct EFTUD2 binding to Caspase3 and Aifm1 transcripts to generate pro-apoptotic isoforms underlying cortical microcephaly.\",\n      \"evidence\": \"NSC-specific knockout mice, in utero electroporation, RNA co-IP, and full-length transcriptome sequencing\",\n      \"pmids\": [\"40448601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs spliceosome-mediated transcript binding not distinguished\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the oncogenic splicing repertoire, linking EFTUD2 to Kif3a, MST1R/RON, and DDX41 isoform regulation across cancers.\",\n      \"evidence\": \"Conditional knockouts, siRNA/ASO knockdown, RNA-seq splicing analysis, and pathway reporter assays in medulloblastoma, ovarian, and other cancer models\",\n      \"pmids\": [\"40275081\", \"40555777\", \"40968608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these reflect direct splicing regulation or core spliceosome function unclear\", \"Each finding from a single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-splicing function in which EFTUD2 stabilizes c-MYC protein against ubiquitin-mediated degradation within a positive feedback loop driving chemoresistance.\",\n      \"evidence\": \"Reciprocal Co-IP, ubiquitination assay, ChIP, and luciferase reporter in colorectal cancer\",\n      \"pmids\": [\"38163859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EFTUD2 blocks c-MYC ubiquitination not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended splicing-dependent immune regulation to antiviral defense and microglial polarization, showing EFTUD2 controls ISG and inflammatory outputs independent of JAK-STAT.\",\n      \"evidence\": \"CRISPR knockout in hepatocytes, microglia-specific conditional knockout, and RIG-I-dependent ISG induction assays\",\n      \"pmids\": [\"37396299\", \"25878102\", \"36204854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which ISG transcripts are direct splicing substrates not fully mapped\", \"Mechanism of NF-\\u03baB cascade splicing regulation incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how EFTUD2 selects specific transcripts (Mdm2, Kif3a, Caspase3, ISGs) for regulated alternative splicing distinct from its constitutive core spliceosome role, and how its non-canonical c-MYC-stabilizing and ferroptosis-suppressing activities mechanistically arise.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No model distinguishing core spliceosome function from substrate-specific regulation\", \"Structural basis of non-splicing protein-stabilization activity unknown\", \"Human structural data for EFTUD2-containing tri-snRNP not in corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [1, 2, 12]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [4, 19, 24]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5, 10, 19]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 7, 17, 25]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 16, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 8, 10, 15]}\n    ],\n    \"complexes\": [\n      \"U5 snRNP\",\n      \"spliceosomal tri-snRNP\"\n    ],\n    \"partners\": [\n      \"PRP8\",\n      \"BRR2\",\n      \"PP1\",\n      \"CWC21\",\n      \"MYC\",\n      \"DGUOK-AS1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}