{"gene":"MBNL2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2002,"finding":"GFP-tagged MBNL2 (MBLL) co-localizes with nuclear foci of expanded CUG/CCUG repeat transcripts in DM1 and DM2 cells, indicating direct sequestration of MBNL2 in repeat RNA foci.","method":"GFP-fusion protein co-localization by fluorescence microscopy in DM1 and DM2 patient cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging with tagged protein in patient cells, single lab but replicated across two disease contexts","pmids":["11929853"],"is_preprint":false},{"year":2008,"finding":"Loss of MBNL2 in mice causes myotonia and defective mRNA splicing of the chloride channel (Clcn1) in skeletal muscle, demonstrating that MBNL2 is required for correct Clcn1 alternative splicing in vivo.","method":"Mbnl2 knockout mouse model; electromyography for myotonia; RT-PCR for Clcn1 splicing","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined cellular and splicing phenotype, single lab, two orthogonal readouts","pmids":["18213585"],"is_preprint":false},{"year":2014,"finding":"MBNL1 and MBNL2 both act as enhancers of Tau exon 2 inclusion; an intronic region 250 nt downstream of exon 2 contains cis-regulatory enhancers that directly bind MBNL1, and both MBNL1 and MBNL2 must interact together to fully reverse Tau exon 2 mis-splicing induced by long CUG repeats.","method":"Tau minigene splicing assays in cell culture; EMSAs/binding assays to identify cis-regulatory elements; overexpression and knockdown of MBNL1/MBNL2","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — minigene splicing assay combined with direct binding demonstration, single lab, multiple orthogonal methods","pmids":["24440524"],"is_preprint":false},{"year":2019,"finding":"In DM1 cells with (CTG)2600 repeat, MBNL2 exons 5 and 8 show disproportionate inclusion, causing a reduced quantity and imbalanced collection of MBNL2 splice variants that accumulate in both cytoplasm and nucleus, contributing to skeletal muscle pathology starting at the myoblast stage.","method":"Isogenic CRISPR/Cas9-edited DM1 myoblast cell lines; RT-PCR isoform analysis; subcellular fractionation; Western blotting","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic cell model, fractionation, and isoform analysis in single lab with multiple orthogonal methods","pmids":["31116797"],"is_preprint":false},{"year":2019,"finding":"MBNL2 overexpression inhibits breast and lung cancer cell migration and metastasis by suppressing the pAKT/EMT pathway; MBNL2 knockdown partially eliminates the anti-metastatic effect of neobractatin.","method":"MBNL2 overexpression and knockdown in cancer cell lines; migration/invasion assays; in vivo xenograft model; Western blotting for pAKT/EMT markers","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with defined pathway readout, in vivo confirmation, single lab","pmids":["31320607"],"is_preprint":false},{"year":2021,"finding":"MBNL2 stabilizes p21 (CDKN1A) mRNA and protein in a p53-independent manner; MBNL2 depletion increases Chk1 S345 phosphorylation and DNA damage signaling, inhibits DNA damage-induced senescence, and promotes apoptosis after DNA damage through a p21-dependent mechanism.","method":"MBNL2 knockdown in cancer cell lines; transcriptome analysis; qRT-PCR and Western blotting for p21 and pChk1; flow cytometry for senescence/apoptosis; epistasis with p21 rescue","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal readouts and epistasis experiment, single lab","pmids":["33466733"],"is_preprint":false},{"year":2021,"finding":"miR-182 directly targets and suppresses MBNL2 expression; this leads to activation of PI3K/AKT-mediated EMT and promotes cancer cell migration and invasion; re-introduction of MBNL2 reverses the pro-metastatic effect of miR-182.","method":"miR-182 overexpression and MBNL2 re-introduction in cancer cell lines; migration/invasion assays; luciferase reporter assay for miR-182 targeting of MBNL2; Western blotting for AKT/EMT markers","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment with mechanistic epistasis, reporter assay for direct targeting, single lab","pmids":["34659561"],"is_preprint":false},{"year":2022,"finding":"Neurodegenerative conditions (NMDA excitotoxicity, dysregulated calcium homeostasis) trigger nuclear translocation of calpain-2, which degrades MBNL2 in the nucleus; this degradation reverses MBNL2-regulated RNA processing to a fetal/developmental pattern; knockdown or inhibition of calpain-2 nuclear translocation prevents MBNL2 degradation and maintains adult RNA processing patterns.","method":"Neuronal culture excitotoxicity models; calpain-2 knockdown/inhibition; subcellular fractionation; Western blotting; splicing assays; DM1 and AD mouse models (EpA960/CaMKII-Cre, APP/PS1, THY-Tau22)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, KD, inhibition, multiple disease models), mechanistic epistasis, replicated across models in single rigorous study","pmids":["35606145"],"is_preprint":false},{"year":2022,"finding":"Cardiac-specific double knockout of Mbnl1 and Mbnl2 (via Myh6-Cre) in mice causes spontaneous lethal cardiac arrhythmias, recapitulates DM heart spliceopathy by RNA sequencing, and leads to ~6-fold increase in Calsequestrin 1 and 50% reduction of EGF protein in cardiomyocytes.","method":"Myh6-Cre conditional double KO mice; ECG/telemetry; RNA sequencing; immunoblotting","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cardiac phenotype and transcriptome/proteome readouts, single lab","pmids":["35567413"],"is_preprint":false},{"year":2023,"finding":"Loss of MBNL1 increases inclusion of Mbnl2 exon 6 and exon 9; exon 6 inclusion promotes MBNL2 nuclear translocation; exon 9 inclusion shifts the reading frame to an alternative C-terminus lacking a PEST domain that otherwise targets MBNL2 for proteasomal degradation, resulting in compensatory upregulation of MBNL2 protein.","method":"Mbnl1 KO mice; RT-PCR for exon inclusion; nuclear/cytoplasmic fractionation; proteasome inhibitor experiments; protein stability assays; DM1 mouse model validation","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (splicing assays, fractionation, proteasome inhibition, in vivo model validation), mechanistic epistasis, replicated in DM1 model","pmids":["36617982"],"is_preprint":false},{"year":2024,"finding":"MBNL2 is required for nuclear envelope MTOC (NE-MTOC) formation in skeletal muscle cells; Mbnl2 depletion reduces expression of AKAP6β and affects Pericentrin (Pcnt) isoform expression, thereby impairing the developmental switch from centrosomal to NE-localized MTOC.","method":"siRNA knockdown of Mbnl2 in differentiating C2C12 myoblasts; longitudinal co-immunofluorescence staining; Western blotting for AKAP6β and Pcnt isoforms","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA depletion with defined functional phenotype and molecular mechanism, single lab, two orthogonal readouts","pmids":["39996710"],"is_preprint":false},{"year":2024,"finding":"MBNL2 interacts with p21 (CDKN1A) and the piRNA CFAPIR competitively binds MBNL2 to modulate the TGF-β1/SMAD3 signaling pathway and cardiac fibrosis.","method":"Arraystar PiRNA profiling; RNA-protein immunoprecipitation; pulldown assays; Western blotting for TGF-β1/SMAD3 pathway markers; in vivo and in vitro cardiac fibrosis models","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pulldown and Co-IP without detailed mechanistic follow-up; competitive binding proposed but mechanistic detail limited in abstract","pmids":["39122223"],"is_preprint":false},{"year":2024,"finding":"MBNL2 promotes aging-related cardiac fibrosis by orchestrating SUMOylation of KLF4; MBNL2 inhibition increases SUMO1 binding to KLF4 by reducing SENP1-mediated deSUMOylation, and the TGF-β1/SMAD3 pathway mediates the pro-fibrotic effect of MBNL2 overexpression.","method":"MBNL2 overexpression and inhibition in senescent cardiac fibroblasts and aged mouse hearts; SUMO1-KLF4 co-IP; SENP1 expression analysis; Western blotting for TGF-β1/SMAD3","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, Co-IP for SUMOylation, pathway inference, limited mechanistic resolution in abstract","pmids":["38974966"],"is_preprint":false},{"year":2026,"finding":"MBNL2 binds the 3'-UTR of Ccr2 mRNA in dorsal root ganglion (DRG) neurons; paclitaxel-induced downregulation of MBNL2 reduces this binding, enhancing Ccr2 mRNA stability and increasing CCR2 protein expression, thereby contributing to chemotherapy-induced neuropathic pain.","method":"DRG neuron MBNL2 knockdown and rescue; RNA immunoprecipitation for MBNL2-Ccr2 3'UTR binding; mRNA stability assay; behavioral pain assays in mice","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP for direct binding, mRNA stability assay, in vivo rescue, single lab with multiple orthogonal methods","pmids":["41967179"],"is_preprint":false},{"year":2026,"finding":"MBNL2 is expressed in outer radial glial (oRG) cells during corticogenesis; dysfunction of MBNL2 (due to CTG-expanded DMPK transcript sequestration) in these progenitors impairs neuronal migration and differentiation of late-born cortical neurons, as demonstrated in CDM patient hiPSC-derived forebrain organoids with CRISPR-corrected controls.","method":"CDM patient hiPSC-derived forebrain organoids; CRISPR/Cas9 excision of CTG repeats as isogenic control; immunostaining for oRG markers and cortical neuron markers; MBNL2 expression analysis","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isogenic hiPSC organoid model with CRISPR correction, direct MBNL2 expression and functional analysis, single lab","pmids":["41644016"],"is_preprint":false}],"current_model":"MBNL2 is a nuclear/cytoplasmic RNA-binding protein that regulates alternative splicing of multiple targets (including Clcn1, Tau exon 2, and developmental RNA processing programs) and controls mRNA stability (e.g., Ccr2 3'-UTR, p21); its subcellular localization and protein levels are regulated post-translationally by calpain-2-mediated nuclear degradation and by alternative splicing of its own exons 6 and 9 (which control nuclear translocation and PEST-domain-dependent proteasomal degradation, respectively); in myotonic dystrophy, MBNL2 is sequestered in nuclear CUG/CCUG repeat RNA foci, causing widespread spliceopathy in muscle, brain, and heart; and it also modulates cell migration/invasion via the PI3K/AKT-EMT axis, DNA damage response via p21 stabilization, NE-MTOC formation via AKAP6β expression, and cortical progenitor differentiation during brain development."},"narrative":{"mechanistic_narrative":"MBNL2 is an RNA-binding protein that controls developmental RNA processing programs by regulating alternative splicing and mRNA stability across muscle, heart, and brain [PMID:18213585, PMID:35567413, PMID:35606145]. As a splicing regulator it is required for correct alternative splicing of the muscle chloride channel Clcn1 in vivo, and loss of MBNL2 produces myotonia [PMID:18213585]; together with MBNL1 it acts as an enhancer of Tau exon 2 inclusion through intronic cis-regulatory elements, and the two paralogs cooperate to reverse repeat-induced mis-splicing [PMID:24440524]. Beyond splicing, MBNL2 directly binds target transcripts to control their stability, stabilizing p21 (CDKN1A) mRNA in a p53-independent manner to drive DNA-damage-induced senescence [PMID:33466733] and binding the Ccr2 3'-UTR in sensory neurons to limit Ccr2 transcript stability [PMID:41967179]. MBNL2 abundance and nuclear localization are set post-translationally: calpain-2 translocates to the nucleus under excitotoxic/calcium-dysregulated conditions and degrades nuclear MBNL2, reverting RNA processing to a fetal pattern [PMID:35606145], while alternative splicing of MBNL2's own exon 6 (controlling nuclear translocation) and exon 9 (which removes a PEST degron and stabilizes the protein) is governed by MBNL1, providing a compensatory autoregulatory circuit [PMID:36617982]. In myotonic dystrophy, expanded CUG/CCUG repeat transcripts sequester MBNL2 into nuclear RNA foci, producing widespread spliceopathy [PMID:11929853, PMID:35567413] and, in the developing cortex, impairing migration and differentiation of late-born neurons through MBNL2 dysfunction in outer radial glial progenitors [PMID:41644016]. MBNL2 also restrains cancer cell migration and invasion by suppressing the PI3K/AKT-driven EMT program [PMID:31320607, PMID:34659561].","teleology":[{"year":2002,"claim":"Established that MBNL2 is physically captured by pathogenic repeat RNA, providing the first molecular link between MBNL2 and myotonic dystrophy.","evidence":"GFP-fusion co-localization with CUG/CCUG foci in DM1 and DM2 patient cells","pmids":["11929853"],"confidence":"Medium","gaps":["Did not define downstream splicing targets affected by sequestration","Tagged overexpression rather than endogenous protein"]},{"year":2008,"claim":"Showed MBNL2 has a non-redundant in vivo splicing function, connecting its loss to a concrete muscle phenotype.","evidence":"Mbnl2 knockout mice with EMG myotonia and RT-PCR of Clcn1 splicing","pmids":["18213585"],"confidence":"Medium","gaps":["Single splicing target characterized","Did not address brain or cardiac roles"]},{"year":2014,"claim":"Defined how MBNL1 and MBNL2 cooperate on a neuronal splicing target, clarifying the basis of repeat-induced Tau mis-splicing.","evidence":"Tau minigene splicing assays, EMSA binding, MBNL1/2 over/knockdown","pmids":["24440524"],"confidence":"Medium","gaps":["Direct binding shown for MBNL1; MBNL2 contribution inferred from functional cooperation","Cell-line minigene context only"]},{"year":2019,"claim":"Linked MBNL2's own isoform balance and subcellular distribution to disease, and revealed a splicing-independent anti-metastatic role.","evidence":"Isogenic CRISPR DM1 myoblasts with fractionation and isoform analysis; cancer cell over/knockdown with migration and xenograft assays","pmids":["31116797","31320607"],"confidence":"Medium","gaps":["Mechanism linking MBNL2 to AKT/EMT not resolved at molecular level","Whether mis-spliced MBNL2 isoforms are functionally distinct untested"]},{"year":2021,"claim":"Identified MBNL2 as a stabilizer of p21 mRNA and a node in the DNA damage response, and showed miR-182 suppresses MBNL2 to engage PI3K/AKT-EMT.","evidence":"MBNL2 knockdown with transcriptomics, p21/pChk1 readouts and p21 epistasis; miR-182 luciferase targeting and MBNL2 rescue","pmids":["33466733","34659561"],"confidence":"Medium","gaps":["Direct MBNL2 binding to p21 mRNA not shown","Connection between p21 stabilization and EMT roles unintegrated"]},{"year":2022,"claim":"Defined a post-translational switch — nuclear calpain-2 degradation of MBNL2 — that converts adult to fetal RNA processing, and extended MBNL2 loss to lethal cardiac phenotypes.","evidence":"Neuronal excitotoxicity models with calpain-2 KD/inhibition, fractionation and splicing assays across DM1/AD mouse models; Myh6-Cre Mbnl1/2 double KO with ECG and RNA-seq","pmids":["35606145","35567413"],"confidence":"High","gaps":["Calpain-2 cleavage site on MBNL2 not mapped","Cardiac phenotype requires combined Mbnl1/Mbnl2 loss, isolating MBNL2 contribution unresolved"]},{"year":2023,"claim":"Revealed an MBNL1-controlled autoregulatory circuit in which MBNL2 exon 6 and exon 9 splicing tune nuclear localization and PEST-dependent proteasomal stability.","evidence":"Mbnl1 KO mice with RT-PCR, fractionation, proteasome inhibition and stability assays, validated in DM1 model","pmids":["36617982"],"confidence":"High","gaps":["Functional consequences of compensatory MBNL2 upregulation in disease not quantified","Direct MBNL1 binding to Mbnl2 pre-mRNA not detailed"]},{"year":2024,"claim":"Expanded MBNL2 function to muscle MTOC reprogramming and to cardiac fibrosis regulation through protein interaction and SUMOylation pathways.","evidence":"Mbnl2 siRNA in differentiating C2C12 with AKAP6β/Pcnt readouts; piRNA profiling with RIP/pulldown; MBNL2 over/inhibition in fibroblasts with SUMO1-KLF4 co-IP","pmids":["39996710","39122223","38974966"],"confidence":"Low","gaps":["Cardiac fibrosis mechanisms rest on Co-IP/pulldown without reconstitution","Whether MBNL2 directly regulates AKAP6β transcript vs splicing not resolved","SUMOylation effect inferred from pathway markers"]},{"year":2026,"claim":"Demonstrated direct MBNL2 control of Ccr2 mRNA stability in sensory neurons and a progenitor-stage role in cortical development under repeat-expansion conditions.","evidence":"DRG neuron MBNL2 knockdown/rescue with RIP and mRNA stability assays and behavioral pain models; CDM hiPSC forebrain organoids with CRISPR-corrected isogenic controls","pmids":["41967179","41644016"],"confidence":"Medium","gaps":["Whether MBNL2 acts on Ccr2 via the same RNA-binding mode used for splicing untested","oRG-specific MBNL2 targets driving migration defects not identified"]},{"year":null,"claim":"The full target set MBNL2 regulates and how its distinct splicing versus mRNA-stability activities are partitioned across tissues remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No transcriptome-wide MBNL2 binding map integrating splicing and stability roles","Structural basis of MBNL2 RNA recognition not addressed in this corpus","Causal MBNL2-specific contribution to human DM phenotypes vs MBNL1 not isolated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,5,13]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,7,9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,9]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,8,14]}],"complexes":[],"partners":["MBNL1","CDKN1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VZF2","full_name":"Muscleblind-like protein 2","aliases":["Muscleblind-like protein 1","Muscleblind-like protein-like","Muscleblind-like protein-like 39"],"length_aa":373,"mass_kda":40.5,"function":"Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. RNA-binding protein that binds to 5'ACACCC-3' core sequence, termed zipcode, within the 3'UTR of ITGA3. Binds to CUG triplet repeat expansion in myotonic dystrophy muscle cells by sequestering the target RNAs. Together with RNA binding proteins RBPMS and RBFOX2, activates vascular smooth muscle cells alternative splicing events (By similarity). Regulates NCOR2 alternative splicing (By similarity). Seems to regulate expression and localization of ITGA3 by transporting it from the nucleus to cytoplasm at adhesion plaques. May play a role in myotonic dystrophy pathophysiology (DM)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5VZF2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBNL2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MBNL2","total_profiled":1310},"omim":[{"mim_id":"607327","title":"MUSCLEBLIND-LIKE SPLICING REGULATOR 2; MBNL2","url":"https://www.omim.org/entry/607327"},{"mim_id":"606516","title":"MUSCLEBLIND-LIKE SPLICING REGULATOR 1; MBNL1","url":"https://www.omim.org/entry/606516"},{"mim_id":"300413","title":"MUSCLEBLIND-LIKE SPLICING REGULATOR 3; MBNL3","url":"https://www.omim.org/entry/300413"}],"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/MBNL2"},"hgnc":{"alias_symbol":["MBLL","MBLL39"],"prev_symbol":[]},"alphafold":{"accession":"Q5VZF2","domains":[{"cath_id":"3.30.1370.210","chopping":"11-102","consensus_level":"high","plddt":89.0297,"start":11,"end":102},{"cath_id":"3.30.1370.210","chopping":"177-251","consensus_level":"high","plddt":87.7091,"start":177,"end":251}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VZF2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VZF2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VZF2-F1-predicted_aligned_error_v6.png","plddt_mean":64.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBNL2","jax_strain_url":"https://www.jax.org/strain/search?query=MBNL2"},"sequence":{"accession":"Q5VZF2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VZF2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VZF2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VZF2"}},"corpus_meta":[{"pmid":"11929853","id":"PMC_11929853","title":"Three proteins, MBNL, MBLL and MBXL, co-localize in vivo with nuclear foci of expanded-repeat transcripts in DM1 and DM2 cells.","date":"2002","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11929853","citation_count":375,"is_preprint":false},{"pmid":"12915312","id":"PMC_12915312","title":"Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2 and Mbnl3.","date":"2003","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/12915312","citation_count":107,"is_preprint":false},{"pmid":"18213585","id":"PMC_18213585","title":"Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy.","date":"2008","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/18213585","citation_count":51,"is_preprint":false},{"pmid":"31320607","id":"PMC_31320607","title":"The natural compound neobractatin inhibits tumor metastasis by upregulating the RNA-binding-protein MBNL2.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31320607","citation_count":36,"is_preprint":false},{"pmid":"24440524","id":"PMC_24440524","title":"Tau exon 2 responsive elements deregulated in myotonic dystrophy type I are proximal to exon 2 and synergistically regulated by MBNL1 and MBNL2.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24440524","citation_count":27,"is_preprint":false},{"pmid":"30060068","id":"PMC_30060068","title":"Methylphenidate Attenuates the Cognitive and Mood Alterations Observed in Mbnl2 Knockout Mice and Reduces Microglia Overexpression.","date":"2019","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/30060068","citation_count":26,"is_preprint":false},{"pmid":"33466733","id":"PMC_33466733","title":"MBNL2 Regulates DNA Damage Response via Stabilizing p21.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33466733","citation_count":21,"is_preprint":false},{"pmid":"31116797","id":"PMC_31116797","title":"(CTG)n repeat-mediated dysregulation of MBNL1 and MBNL2 expression during myogenesis in DM1 occurs already at the myoblast stage.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/31116797","citation_count":20,"is_preprint":false},{"pmid":"36617982","id":"PMC_36617982","title":"Alternative splicing mediates the compensatory upregulation of MBNL2 upon MBNL1 loss-of-function.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36617982","citation_count":19,"is_preprint":false},{"pmid":"27564110","id":"PMC_27564110","title":"Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27564110","citation_count":19,"is_preprint":false},{"pmid":"34659561","id":"PMC_34659561","title":"RNA-binding Protein MBNL2 regulates Cancer Cell Metastasis through MiR-182-MBNL2-AKT Pathway.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34659561","citation_count":18,"is_preprint":false},{"pmid":"34848815","id":"PMC_34848815","title":"Mbnl1 and Mbnl2 regulate brain structural integrity in mice.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/34848815","citation_count":16,"is_preprint":false},{"pmid":"35567413","id":"PMC_35567413","title":"Mice lacking MBNL1 and MBNL2 exhibit sudden cardiac death and molecular signatures recapitulating myotonic dystrophy.","date":"2022","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35567413","citation_count":16,"is_preprint":false},{"pmid":"32652860","id":"PMC_32652860","title":"SNPs in SNCA, MCCC1, DLG2, GBF1 and MBNL2 are associated with Parkinson's disease in southern Chinese population.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32652860","citation_count":15,"is_preprint":false},{"pmid":"35606145","id":"PMC_35606145","title":"Calpain-2 Mediates MBNL2 Degradation and a Developmental RNA Processing Program in Neurodegeneration.","date":"2022","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35606145","citation_count":13,"is_preprint":false},{"pmid":"32171677","id":"PMC_32171677","title":"Protective effects of mirtazapine in mice lacking the Mbnl2 gene in forebrain glutamatergic neurons: Relevance for myotonic dystrophy 1.","date":"2020","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32171677","citation_count":11,"is_preprint":false},{"pmid":"39122223","id":"PMC_39122223","title":"PiRNA CFAPIR inhibits cardiac fibrosis by regulating the muscleblind-like protein MBNL2.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39122223","citation_count":7,"is_preprint":false},{"pmid":"38473933","id":"PMC_38473933","title":"Studying the Effect of MBNL1 and MBNL2 Loss in Skeletal Muscle Regeneration.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38473933","citation_count":6,"is_preprint":false},{"pmid":"38974966","id":"PMC_38974966","title":"MBNL2 promotes aging-related cardiac fibrosis via inhibited SUMOylation of Krüppel-like factor4.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/38974966","citation_count":6,"is_preprint":false},{"pmid":"37216102","id":"PMC_37216102","title":"Mbnl2 loss alters novel context processing and impairs object recognition memory.","date":"2023","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/37216102","citation_count":5,"is_preprint":false},{"pmid":"40176605","id":"PMC_40176605","title":"MBNL2 enhances cisplatin resistance by regulating apoptosis in ovarian cancer cells.","date":"2025","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/40176605","citation_count":1,"is_preprint":false},{"pmid":"39996710","id":"PMC_39996710","title":"NE-MTOC Formation in Skeletal Muscle Is Mbnl2-Dependent and Occurs in a Sequential and Gradual Manner.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39996710","citation_count":1,"is_preprint":false},{"pmid":"40819508","id":"PMC_40819508","title":"Primary pulmonary spindle cell sarcoma with novel MBNL2::NUTM1 fusion and associated langerhans cell hyperplasia.","date":"2025","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/40819508","citation_count":0,"is_preprint":false},{"pmid":"41967179","id":"PMC_41967179","title":"RNA-binding protein MBNL2 mitigates neuropathic pain after chemotherapy through destabilizing CCR2 expression in primary sensory neurons.","date":"2026","source":"Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/41967179","citation_count":0,"is_preprint":false},{"pmid":"41644016","id":"PMC_41644016","title":"MBNL2 dysfunction in outer radial glial cells is associated with disrupted corticogenesis in congenital myotonic dystrophy.","date":"2026","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/41644016","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.06.641895","title":"ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.06.641895","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14966,"output_tokens":3937,"usd":0.051977,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11677,"output_tokens":3423,"usd":0.07198,"stage2_stop_reason":"end_turn"},"total_usd":0.123957,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"GFP-tagged MBNL2 (MBLL) co-localizes with nuclear foci of expanded CUG/CCUG repeat transcripts in DM1 and DM2 cells, indicating direct sequestration of MBNL2 in repeat RNA foci.\",\n      \"method\": \"GFP-fusion protein co-localization by fluorescence microscopy in DM1 and DM2 patient cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging with tagged protein in patient cells, single lab but replicated across two disease contexts\",\n      \"pmids\": [\"11929853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of MBNL2 in mice causes myotonia and defective mRNA splicing of the chloride channel (Clcn1) in skeletal muscle, demonstrating that MBNL2 is required for correct Clcn1 alternative splicing in vivo.\",\n      \"method\": \"Mbnl2 knockout mouse model; electromyography for myotonia; RT-PCR for Clcn1 splicing\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined cellular and splicing phenotype, single lab, two orthogonal readouts\",\n      \"pmids\": [\"18213585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MBNL1 and MBNL2 both act as enhancers of Tau exon 2 inclusion; an intronic region 250 nt downstream of exon 2 contains cis-regulatory enhancers that directly bind MBNL1, and both MBNL1 and MBNL2 must interact together to fully reverse Tau exon 2 mis-splicing induced by long CUG repeats.\",\n      \"method\": \"Tau minigene splicing assays in cell culture; EMSAs/binding assays to identify cis-regulatory elements; overexpression and knockdown of MBNL1/MBNL2\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — minigene splicing assay combined with direct binding demonstration, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24440524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In DM1 cells with (CTG)2600 repeat, MBNL2 exons 5 and 8 show disproportionate inclusion, causing a reduced quantity and imbalanced collection of MBNL2 splice variants that accumulate in both cytoplasm and nucleus, contributing to skeletal muscle pathology starting at the myoblast stage.\",\n      \"method\": \"Isogenic CRISPR/Cas9-edited DM1 myoblast cell lines; RT-PCR isoform analysis; subcellular fractionation; Western blotting\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic cell model, fractionation, and isoform analysis in single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31116797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MBNL2 overexpression inhibits breast and lung cancer cell migration and metastasis by suppressing the pAKT/EMT pathway; MBNL2 knockdown partially eliminates the anti-metastatic effect of neobractatin.\",\n      \"method\": \"MBNL2 overexpression and knockdown in cancer cell lines; migration/invasion assays; in vivo xenograft model; Western blotting for pAKT/EMT markers\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with defined pathway readout, in vivo confirmation, single lab\",\n      \"pmids\": [\"31320607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBNL2 stabilizes p21 (CDKN1A) mRNA and protein in a p53-independent manner; MBNL2 depletion increases Chk1 S345 phosphorylation and DNA damage signaling, inhibits DNA damage-induced senescence, and promotes apoptosis after DNA damage through a p21-dependent mechanism.\",\n      \"method\": \"MBNL2 knockdown in cancer cell lines; transcriptome analysis; qRT-PCR and Western blotting for p21 and pChk1; flow cytometry for senescence/apoptosis; epistasis with p21 rescue\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal readouts and epistasis experiment, single lab\",\n      \"pmids\": [\"33466733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"miR-182 directly targets and suppresses MBNL2 expression; this leads to activation of PI3K/AKT-mediated EMT and promotes cancer cell migration and invasion; re-introduction of MBNL2 reverses the pro-metastatic effect of miR-182.\",\n      \"method\": \"miR-182 overexpression and MBNL2 re-introduction in cancer cell lines; migration/invasion assays; luciferase reporter assay for miR-182 targeting of MBNL2; Western blotting for AKT/EMT markers\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment with mechanistic epistasis, reporter assay for direct targeting, single lab\",\n      \"pmids\": [\"34659561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Neurodegenerative conditions (NMDA excitotoxicity, dysregulated calcium homeostasis) trigger nuclear translocation of calpain-2, which degrades MBNL2 in the nucleus; this degradation reverses MBNL2-regulated RNA processing to a fetal/developmental pattern; knockdown or inhibition of calpain-2 nuclear translocation prevents MBNL2 degradation and maintains adult RNA processing patterns.\",\n      \"method\": \"Neuronal culture excitotoxicity models; calpain-2 knockdown/inhibition; subcellular fractionation; Western blotting; splicing assays; DM1 and AD mouse models (EpA960/CaMKII-Cre, APP/PS1, THY-Tau22)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, KD, inhibition, multiple disease models), mechanistic epistasis, replicated across models in single rigorous study\",\n      \"pmids\": [\"35606145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cardiac-specific double knockout of Mbnl1 and Mbnl2 (via Myh6-Cre) in mice causes spontaneous lethal cardiac arrhythmias, recapitulates DM heart spliceopathy by RNA sequencing, and leads to ~6-fold increase in Calsequestrin 1 and 50% reduction of EGF protein in cardiomyocytes.\",\n      \"method\": \"Myh6-Cre conditional double KO mice; ECG/telemetry; RNA sequencing; immunoblotting\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cardiac phenotype and transcriptome/proteome readouts, single lab\",\n      \"pmids\": [\"35567413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Loss of MBNL1 increases inclusion of Mbnl2 exon 6 and exon 9; exon 6 inclusion promotes MBNL2 nuclear translocation; exon 9 inclusion shifts the reading frame to an alternative C-terminus lacking a PEST domain that otherwise targets MBNL2 for proteasomal degradation, resulting in compensatory upregulation of MBNL2 protein.\",\n      \"method\": \"Mbnl1 KO mice; RT-PCR for exon inclusion; nuclear/cytoplasmic fractionation; proteasome inhibitor experiments; protein stability assays; DM1 mouse model validation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (splicing assays, fractionation, proteasome inhibition, in vivo model validation), mechanistic epistasis, replicated in DM1 model\",\n      \"pmids\": [\"36617982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MBNL2 is required for nuclear envelope MTOC (NE-MTOC) formation in skeletal muscle cells; Mbnl2 depletion reduces expression of AKAP6β and affects Pericentrin (Pcnt) isoform expression, thereby impairing the developmental switch from centrosomal to NE-localized MTOC.\",\n      \"method\": \"siRNA knockdown of Mbnl2 in differentiating C2C12 myoblasts; longitudinal co-immunofluorescence staining; Western blotting for AKAP6β and Pcnt isoforms\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA depletion with defined functional phenotype and molecular mechanism, single lab, two orthogonal readouts\",\n      \"pmids\": [\"39996710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MBNL2 interacts with p21 (CDKN1A) and the piRNA CFAPIR competitively binds MBNL2 to modulate the TGF-β1/SMAD3 signaling pathway and cardiac fibrosis.\",\n      \"method\": \"Arraystar PiRNA profiling; RNA-protein immunoprecipitation; pulldown assays; Western blotting for TGF-β1/SMAD3 pathway markers; in vivo and in vitro cardiac fibrosis models\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pulldown and Co-IP without detailed mechanistic follow-up; competitive binding proposed but mechanistic detail limited in abstract\",\n      \"pmids\": [\"39122223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MBNL2 promotes aging-related cardiac fibrosis by orchestrating SUMOylation of KLF4; MBNL2 inhibition increases SUMO1 binding to KLF4 by reducing SENP1-mediated deSUMOylation, and the TGF-β1/SMAD3 pathway mediates the pro-fibrotic effect of MBNL2 overexpression.\",\n      \"method\": \"MBNL2 overexpression and inhibition in senescent cardiac fibroblasts and aged mouse hearts; SUMO1-KLF4 co-IP; SENP1 expression analysis; Western blotting for TGF-β1/SMAD3\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, Co-IP for SUMOylation, pathway inference, limited mechanistic resolution in abstract\",\n      \"pmids\": [\"38974966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MBNL2 binds the 3'-UTR of Ccr2 mRNA in dorsal root ganglion (DRG) neurons; paclitaxel-induced downregulation of MBNL2 reduces this binding, enhancing Ccr2 mRNA stability and increasing CCR2 protein expression, thereby contributing to chemotherapy-induced neuropathic pain.\",\n      \"method\": \"DRG neuron MBNL2 knockdown and rescue; RNA immunoprecipitation for MBNL2-Ccr2 3'UTR binding; mRNA stability assay; behavioral pain assays in mice\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP for direct binding, mRNA stability assay, in vivo rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"41967179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MBNL2 is expressed in outer radial glial (oRG) cells during corticogenesis; dysfunction of MBNL2 (due to CTG-expanded DMPK transcript sequestration) in these progenitors impairs neuronal migration and differentiation of late-born cortical neurons, as demonstrated in CDM patient hiPSC-derived forebrain organoids with CRISPR-corrected controls.\",\n      \"method\": \"CDM patient hiPSC-derived forebrain organoids; CRISPR/Cas9 excision of CTG repeats as isogenic control; immunostaining for oRG markers and cortical neuron markers; MBNL2 expression analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isogenic hiPSC organoid model with CRISPR correction, direct MBNL2 expression and functional analysis, single lab\",\n      \"pmids\": [\"41644016\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBNL2 is a nuclear/cytoplasmic RNA-binding protein that regulates alternative splicing of multiple targets (including Clcn1, Tau exon 2, and developmental RNA processing programs) and controls mRNA stability (e.g., Ccr2 3'-UTR, p21); its subcellular localization and protein levels are regulated post-translationally by calpain-2-mediated nuclear degradation and by alternative splicing of its own exons 6 and 9 (which control nuclear translocation and PEST-domain-dependent proteasomal degradation, respectively); in myotonic dystrophy, MBNL2 is sequestered in nuclear CUG/CCUG repeat RNA foci, causing widespread spliceopathy in muscle, brain, and heart; and it also modulates cell migration/invasion via the PI3K/AKT-EMT axis, DNA damage response via p21 stabilization, NE-MTOC formation via AKAP6β expression, and cortical progenitor differentiation during brain development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MBNL2 is an RNA-binding protein that controls developmental RNA processing programs by regulating alternative splicing and mRNA stability across muscle, heart, and brain [#1, #8, #7]. As a splicing regulator it is required for correct alternative splicing of the muscle chloride channel Clcn1 in vivo, and loss of MBNL2 produces myotonia [#1]; together with MBNL1 it acts as an enhancer of Tau exon 2 inclusion through intronic cis-regulatory elements, and the two paralogs cooperate to reverse repeat-induced mis-splicing [#2]. Beyond splicing, MBNL2 directly binds target transcripts to control their stability, stabilizing p21 (CDKN1A) mRNA in a p53-independent manner to drive DNA-damage-induced senescence [#5] and binding the Ccr2 3'-UTR in sensory neurons to limit Ccr2 transcript stability [#13]. MBNL2 abundance and nuclear localization are set post-translationally: calpain-2 translocates to the nucleus under excitotoxic/calcium-dysregulated conditions and degrades nuclear MBNL2, reverting RNA processing to a fetal pattern [#7], while alternative splicing of MBNL2's own exon 6 (controlling nuclear translocation) and exon 9 (which removes a PEST degron and stabilizes the protein) is governed by MBNL1, providing a compensatory autoregulatory circuit [#9]. In myotonic dystrophy, expanded CUG/CCUG repeat transcripts sequester MBNL2 into nuclear RNA foci, producing widespread spliceopathy [#0, #8] and, in the developing cortex, impairing migration and differentiation of late-born neurons through MBNL2 dysfunction in outer radial glial progenitors [#14]. MBNL2 also restrains cancer cell migration and invasion by suppressing the PI3K/AKT-driven EMT program [#4, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that MBNL2 is physically captured by pathogenic repeat RNA, providing the first molecular link between MBNL2 and myotonic dystrophy.\",\n      \"evidence\": \"GFP-fusion co-localization with CUG/CCUG foci in DM1 and DM2 patient cells\",\n      \"pmids\": [\"11929853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define downstream splicing targets affected by sequestration\", \"Tagged overexpression rather than endogenous protein\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed MBNL2 has a non-redundant in vivo splicing function, connecting its loss to a concrete muscle phenotype.\",\n      \"evidence\": \"Mbnl2 knockout mice with EMG myotonia and RT-PCR of Clcn1 splicing\",\n      \"pmids\": [\"18213585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single splicing target characterized\", \"Did not address brain or cardiac roles\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined how MBNL1 and MBNL2 cooperate on a neuronal splicing target, clarifying the basis of repeat-induced Tau mis-splicing.\",\n      \"evidence\": \"Tau minigene splicing assays, EMSA binding, MBNL1/2 over/knockdown\",\n      \"pmids\": [\"24440524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding shown for MBNL1; MBNL2 contribution inferred from functional cooperation\", \"Cell-line minigene context only\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked MBNL2's own isoform balance and subcellular distribution to disease, and revealed a splicing-independent anti-metastatic role.\",\n      \"evidence\": \"Isogenic CRISPR DM1 myoblasts with fractionation and isoform analysis; cancer cell over/knockdown with migration and xenograft assays\",\n      \"pmids\": [\"31116797\", \"31320607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking MBNL2 to AKT/EMT not resolved at molecular level\", \"Whether mis-spliced MBNL2 isoforms are functionally distinct untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified MBNL2 as a stabilizer of p21 mRNA and a node in the DNA damage response, and showed miR-182 suppresses MBNL2 to engage PI3K/AKT-EMT.\",\n      \"evidence\": \"MBNL2 knockdown with transcriptomics, p21/pChk1 readouts and p21 epistasis; miR-182 luciferase targeting and MBNL2 rescue\",\n      \"pmids\": [\"33466733\", \"34659561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct MBNL2 binding to p21 mRNA not shown\", \"Connection between p21 stabilization and EMT roles unintegrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a post-translational switch — nuclear calpain-2 degradation of MBNL2 — that converts adult to fetal RNA processing, and extended MBNL2 loss to lethal cardiac phenotypes.\",\n      \"evidence\": \"Neuronal excitotoxicity models with calpain-2 KD/inhibition, fractionation and splicing assays across DM1/AD mouse models; Myh6-Cre Mbnl1/2 double KO with ECG and RNA-seq\",\n      \"pmids\": [\"35606145\", \"35567413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calpain-2 cleavage site on MBNL2 not mapped\", \"Cardiac phenotype requires combined Mbnl1/Mbnl2 loss, isolating MBNL2 contribution unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed an MBNL1-controlled autoregulatory circuit in which MBNL2 exon 6 and exon 9 splicing tune nuclear localization and PEST-dependent proteasomal stability.\",\n      \"evidence\": \"Mbnl1 KO mice with RT-PCR, fractionation, proteasome inhibition and stability assays, validated in DM1 model\",\n      \"pmids\": [\"36617982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of compensatory MBNL2 upregulation in disease not quantified\", \"Direct MBNL1 binding to Mbnl2 pre-mRNA not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded MBNL2 function to muscle MTOC reprogramming and to cardiac fibrosis regulation through protein interaction and SUMOylation pathways.\",\n      \"evidence\": \"Mbnl2 siRNA in differentiating C2C12 with AKAP6β/Pcnt readouts; piRNA profiling with RIP/pulldown; MBNL2 over/inhibition in fibroblasts with SUMO1-KLF4 co-IP\",\n      \"pmids\": [\"39996710\", \"39122223\", \"38974966\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Cardiac fibrosis mechanisms rest on Co-IP/pulldown without reconstitution\", \"Whether MBNL2 directly regulates AKAP6β transcript vs splicing not resolved\", \"SUMOylation effect inferred from pathway markers\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated direct MBNL2 control of Ccr2 mRNA stability in sensory neurons and a progenitor-stage role in cortical development under repeat-expansion conditions.\",\n      \"evidence\": \"DRG neuron MBNL2 knockdown/rescue with RIP and mRNA stability assays and behavioral pain models; CDM hiPSC forebrain organoids with CRISPR-corrected isogenic controls\",\n      \"pmids\": [\"41967179\", \"41644016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MBNL2 acts on Ccr2 via the same RNA-binding mode used for splicing untested\", \"oRG-specific MBNL2 targets driving migration defects not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full target set MBNL2 regulates and how its distinct splicing versus mRNA-stability activities are partitioned across tissues remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transcriptome-wide MBNL2 binding map integrating splicing and stability roles\", \"Structural basis of MBNL2 RNA recognition not addressed in this corpus\", \"Causal MBNL2-specific contribution to human DM phenotypes vs MBNL1 not isolated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 5, 13]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 7, 9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 8, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MBNL1\", \"CDKN1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}