{"gene":"DNM2","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2020,"finding":"DNM2 mediates scission of recycling endosome tubules to release nascent autophagosome precursors; this process is regulated by DNM2 binding to LC3 and is increased by autophagy-inducing stimuli. The CNM-causing DNM2-R465W mutant is defective in this scission step because it shows increased binding to the plasma membrane partner ITSN1, depleting normal DNM2 from autophagosome formation sites on recycling endosomes.","method":"Cell imaging, autophagy flux assays, co-immunoprecipitation of DNM2 with LC3 and ITSN1, expression of CNM mutant DNM2 in cells","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP (DNM2-LC3, DNM2-ITSN1), functional assays in cells and with CNM mutant, mechanistic explanation for mutant pathology, published in peer-reviewed journal","pmids":["32315611"],"is_preprint":false},{"year":2010,"finding":"DNM2 directly interacts with the adaptor protein CIN85 (SH3-domain-containing protein of 85 kDa) in a complex that is induced by EGF receptor stimulation. This DNM2-CIN85 interaction occurs at late endosomes and is required for late endosomal budding/scission; disruption of this interaction results in accumulation of internalized EGFR in aberrantly elongated late endosomal tubules and sustained downstream signaling.","method":"Co-immunoprecipitation, dominant-negative and knockdown experiments, live-cell and fluorescence imaging of late endosome morphology, EGFR trafficking assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function with defined morphological and signaling phenotypes, single lab with multiple orthogonal methods","pmids":["20711168"],"is_preprint":false},{"year":2013,"finding":"Expression of the CNM-causing DNM2-S619L mutation in zebrafish leads to accumulation of aberrant vesicular structures and defective excitation-contraction coupling; in COS7 cells, DNM2-S619L causes defective BIN1-dependent membrane tubule formation, indicating the mutation impairs membrane tubulation.","method":"Zebrafish transgenic expression, COS7 cell tubulation assay, electron microscopy, calcium imaging","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with multiple readouts, single lab","pmids":["24135484"],"is_preprint":false},{"year":2017,"finding":"DNM2 interacts with the scaffold protein AHI-1 via the AHI-1 SH3 domain binding to the DNM2 proline-rich domain, forming an AHI-1–BCR-ABL–DNM2 protein complex in CML stem/progenitor cells that regulates leukemic cell survival and TKI resistance through cellular endocytosis and ROS-mediated autophagy.","method":"Co-immunoprecipitation, domain-mapping experiments (SH3 and proline-rich domain truncations), DNM2 knockdown with survival/apoptosis assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, KD with functional readout, single lab","pmids":["28366933"],"is_preprint":false},{"year":2017,"finding":"HSV-1 neuronal infection triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 (DNM2), leading to fragmentation and scattering of the Golgi apparatus; pharmacological inhibition of Src kinase (PP2) markedly reduces these Golgi morphological alterations. HSV-1 tegument protein VP11/12 is necessary but not sufficient for Dyn2 phosphorylation.","method":"Immunofluorescence, transmission electron microscopy, pharmacological Src inhibition (PP2), primary neuronal cultures, Western blot for phospho-DNM2","journal":"Frontiers in cellular and infection microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation demonstrated by Western blot with Src inhibitor rescue, morphological validation by TEM and IF, single lab","pmids":["28879169"],"is_preprint":false},{"year":2019,"finding":"In transgenic zebrafish, wild-type DNM2 shows distinctive subcellular compartmentalization in muscle in vivo; CNM-related DNM2 mutations cause protein mislocalization and aggregation in muscle, whereas wild-type DNM2 does not aggregate.","method":"Transgenic zebrafish live imaging, subcellular localization analysis, motor function assays, muscle ultrastructure analysis","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live in vivo imaging with functional phenotype, direct comparison WT vs. mutant, single lab","pmids":["31691805"],"is_preprint":false},{"year":2013,"finding":"A novel DNM2 D614N mutation in the PH domain is associated with profound mislocalization of DNM2 and membrane trafficking proteins (concentrated at centrally located nuclei rather than normal distribution) in patient muscle fibers, without significant change in total DNM2 protein level, causally linking PH domain integrity to proper DNM2 subcellular localization and myofiber organization.","method":"Immunofluorescence of patient muscle biopsy, protein expression analysis, genetic analysis of family members","journal":"Neuromuscular disorders : NMD","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single patient/family, immunofluorescence localization without mechanistic reconstitution","pmids":["23374900"],"is_preprint":false},{"year":2017,"finding":"Genetic reduction of DNM2 (via antisense oligonucleotides) in Mtm1 knockout mice (a model of X-linked centronuclear myopathy) efficiently reduces DNM2 protein in muscle and prevents myopathy development; ASO injection into severely affected mice reverses muscle pathology within 2 weeks, establishing that elevated DNM2 is a pathogenic driver downstream of MTM1 loss.","method":"Antisense oligonucleotide (ASO) systemic delivery in Mtm1KO mice, histopathology, muscle force measurements, Western blot","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockdown with prevention and reversal of disease phenotype, multiple readouts, independently replicated across CNM models","pmids":["28589938"],"is_preprint":false},{"year":2018,"finding":"Reduction of DNM2 via AAV-shRNA or antisense oligonucleotides in Dnm2-R465W/+ knock-in mice (DNM2-related CNM model) rescues muscle mass, fiber size, histopathology, and ultrastructure, demonstrating that reducing both WT and mutant DNM2 alleles can correct a dominant gain-of-function myopathy.","method":"Intramuscular AAV-shRNA injection, systemic ASO delivery, histopathology, muscle force/mass measurements, Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knockdown strategies in the same disease model, multiple outcome measures, replication of ASO approach from prior work","pmids":["30291191"],"is_preprint":false},{"year":2019,"finding":"Allele-specific CRISPR/Cas9 inactivation or correction of the heterozygous DNM2-R465W mutation in patient fibroblasts and mouse myoblasts rescues altered transferrin uptake (endocytosis) and autophagy phenotypes, confirming the R465W mutation causes gain-of-function defects in these two DNM2-dependent cellular processes.","method":"CRISPR/Cas9 allele-specific editing, transferrin uptake assay, autophagy flux assay in patient and mouse cells","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — allele-specific correction with rescue of two functional phenotypes, single lab","pmids":["30925452"],"is_preprint":false},{"year":2025,"finding":"BIN1 (amphiphysin 2) inhibits the GTPase activity of DNM2; genetic reduction of BIN1 in Dnm2-K562E/+ CMT mice increases the activity of the K562E DNM2 mutant, restores motor performance, ameliorates muscle and nerve structural defects, and normalizes integrin localization in muscle. Conversely, increasing BIN1 exacerbates Dnm2-K562E/+ phenotypes, establishing BIN1 as a modifier of DNM2 activity and disease severity.","method":"In vitro GTPase activity assay with BIN1, genetic epistasis (Dnm2K562E/+ × Bin1+/- mice), motor and histological phenotyping, integrin immunofluorescence","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical GTPase assay plus in vivo genetic epistasis with multiple phenotypic readouts, single lab but multiple orthogonal methods","pmids":["40042903"],"is_preprint":false},{"year":2026,"finding":"DNM2 lipid binding (via PH domain) is the specific molecular function driving CNM pathology: a lipid-binding-defective K562E mutant of DNM2, when expressed in Mtm1-/y mice, fully rescues survival, motor function, muscle force, fiber size, and organelle positioning despite persistently elevated DNM2 protein levels, while GTPase-active or other mutants fail to rescue. This establishes DNM2 lipid binding, not protein level or GTPase activity per se, as the pathogenic driver in MTM1-CNM.","method":"AAV-mediated delivery of WT and DNM2 mutants in WT and Mtm1-/y mice, muscle force measurements, histopathology, fiber sizing, organelle positioning; genetic epistasis (Mtm1-/y Dnm2K562E/+ mice)","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic in vivo structure-function analysis with multiple DNM2 mutants, rescue experiments in disease model, genetic epistasis cross, multiple orthogonal readouts","pmids":["42100875"],"is_preprint":false},{"year":2016,"finding":"DNM2 (dynamin 2) is required for efficient Japanese encephalitis virus (JEV) replication; siRNA knockdown of DNM2 in PK15 cells significantly reduces JEV replication, identifying DNM2-dependent vesicle scission as a host factor exploited by JEV for cellular entry/replication.","method":"siRNA knockdown of DNM2, viral replication assay (JEV), miR-124 overexpression with DNM2 target validation","journal":"Virology journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single siRNA knockdown experiment in one cell type, single lab, no mechanistic reconstitution","pmids":["27329300"],"is_preprint":false},{"year":2023,"finding":"Tamoxifen reduces the abnormally elevated DNM2 protein level in both BIN1-CNM and DNM2-CNM mouse models through a mechanism involving normalization of cullin 3 (E3 ubiquitin ligase) protein level, suggesting ubiquitin-proteasome-mediated regulation of DNM2 abundance underlies the therapeutic effect.","method":"Tamoxifen dietary treatment in CNM mouse models, Western blot for DNM2 and ubiquitin-proteasome markers (cullin 3, p62), transcriptome analysis, muscle contractility measurements","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein-level measurements with mechanistic correlate (cullin 3), in vivo model, single lab with multiple markers","pmids":["36562127"],"is_preprint":false},{"year":2024,"finding":"DNM2 interacts with Drp1 via its GTPase domain, enabling mitochondrial translocation and facilitating the terminal steps of mitochondrial fission; silencing DNM2 in pulmonary arterial smooth muscle cells inhibits mitochondrial fission and causes G1/G0 cell cycle arrest, while DNM2 overexpression accelerates fission and proliferation. RGCC is identified as a downstream cell-cycle effector of this DNM2-Drp1 axis.","method":"Co-immunoprecipitation, super-resolution microscopy for colocalization at fission sites, truncated-domain expression constructs, RNA-seq after DNM2 silencing, flow cytometry for cell cycle, siRNA knockdown","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus domain mapping, super-resolution colocalization, functional cell-cycle readouts; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.12.05.24318153"],"is_preprint":true},{"year":2024,"finding":"DNM2 is recruited to the neck of vacuole-like protrusions (VLPs) formed during Shigella flexneri cell-to-cell spread, dependent on PIK3C3-mediated PtdIns(3)P accumulation, where it mediates membrane scission to resolve protrusions into double-membrane vacuoles.","method":"Live-fluorescence confocal microscopy tracking, PIK3C3 inhibition, DNM2 localization imaging at VLP necks during bacterial spread","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization by imaging without direct functional validation of DNM2 scission activity at this site; preprint","pmids":["bio_10.1101_2024.10.31.621244"],"is_preprint":true},{"year":2021,"finding":"Novel DNM2 variants associated with CNM induce gain-of-function phenotypes in a cell-based imaging assay (T-tubule-like structure formation); the degree of impairment in cellulo correlates with biochemical gain-of-function GTPase activity measurements and clinical disease severity, providing evidence that DNM2 CNM mutations act via hyperactivity.","method":"In cellulo imaging assay for T-tubule-like structures, biochemical GTPase activity assay for mutant proteins","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro GTPase assay plus cell-based functional assay, multiple variants tested, correlation with clinical phenotype; single lab","pmids":["34837441"],"is_preprint":false},{"year":2026,"finding":"Muscle-specific DNM2 overexpression in Dnm2-K562E/+ CMT mice ameliorates desmin and integrin mislocalization, membrane trafficking defects, mitochondrial abnormalities, and fibrosis in skeletal muscle independently of nerve involvement. Systemic postnatal AAV-DNM2 delivery paradoxically worsened muscle pathology producing CNM-like features, revealing that precise DNM2 dosage is critical and that the therapeutic window for DNM2 augmentation in muscle is narrow.","method":"Tissue-specific transgenic overexpression, AAV systemic delivery, histopathology, immunofluorescence for desmin/integrin, electron microscopy for mitochondria","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific genetic and AAV approaches with multiple structural readouts, functional phenotyping; single lab, single study","pmids":["41683892"],"is_preprint":false}],"current_model":"DNM2 is a ubiquitously expressed large GTPase that mediates membrane fission through oligomerization around membrane necks; its established molecular functions include: (1) clathrin-mediated endocytosis and late endosomal scission (interacting with CIN85 at late endosomes), (2) scission of recycling endosome tubules to release autophagosome precursors via direct LC3 binding, (3) interaction with Drp1 via its GTPase domain to complete mitochondrial fission, (4) lipid binding via its PH domain as the primary pathogenic driver of CNM, and (5) modulation by BIN1 which inhibits its GTPase activity; dominant CNM mutations (e.g., R465W, S619L) cause gain-of-function hyperactivity or mislocalization leading to defective membrane tubulation, impaired autophagy, and abnormal muscle ultrastructure, whereas CMT mutations (e.g., K562E) cause lipid-binding and activity defects; reducing DNM2 expression rescues multiple forms of centronuclear myopathy in preclinical models."},"narrative":{"mechanistic_narrative":"DNM2 is a large GTPase that mediates membrane fission across multiple intracellular compartments by acting at the necks of membrane tubules and vesicles [PMID:20711168, PMID:bio_10.1101_2024.12.05.24318153]. It drives scission events in the endolysosomal and autophagic pathways: at late endosomes it forms an EGF-induced complex with the adaptor CIN85 required for late endosomal budding and EGFR downregulation, with loss producing elongated late-endosomal tubules and sustained signaling [PMID:20711168], and it severs recycling endosome tubules to release autophagosome precursors through direct binding to LC3 [PMID:32315611]. DNM2 also interacts with Drp1 via its GTPase domain to complete the terminal steps of mitochondrial fission [PMID:bio_10.1101_2024.12.05.24318153]. Its activity is restrained by BIN1 (amphiphysin 2), which inhibits DNM2 GTPase activity and acts as a genetic modifier of DNM2-dependent disease [PMID:40042903]. DNM2 is a central pathogenic node in centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) neuropathy: dominant CNM mutations such as R465W and S619L act through gain-of-function hyperactivity and protein mislocalization that impair membrane tubulation, endocytosis, and autophagy [PMID:30925452, PMID:34837441, PMID:24135484, PMID:31691805], and lipid binding through the PH domain — rather than protein level or GTPase activity alone — is the specific molecular function driving CNM pathology downstream of MTM1 loss [PMID:42100875]. Reducing DNM2 expression genetically rescues multiple forms of CNM in vivo, establishing elevated or hyperactive DNM2 as the driver of disease [PMID:28589938, PMID:30291191].","teleology":[{"year":2010,"claim":"Established that DNM2 acts in a regulated, signal-dependent complex at late endosomes, extending its fission role beyond the plasma membrane into endolysosomal trafficking.","evidence":"Reciprocal Co-IP of DNM2 with CIN85, knockdown/dominant-negative experiments with EGFR trafficking and morphology readouts","pmids":["20711168"],"confidence":"High","gaps":["Does not define how DNM2 oligomerization is nucleated at the late endosomal neck","Structural basis of the DNM2-CIN85 interaction not resolved"]},{"year":2013,"claim":"Connected a specific CNM mutation to defective membrane tubulation and excitation-contraction coupling, linking DNM2 dysfunction to muscle pathology in vivo.","evidence":"Zebrafish transgenic expression of DNM2-S619L, COS7 BIN1-dependent tubulation assay, EM and calcium imaging","pmids":["24135484"],"confidence":"Medium","gaps":["Does not establish whether the tubulation defect reflects gain or loss of function","Mechanistic link between vesicular accumulation and EC-coupling defect unresolved"]},{"year":2013,"claim":"Implicated PH domain integrity in proper DNM2 subcellular localization, hinting at the lipid-interaction basis of CNM later confirmed mechanistically.","evidence":"Immunofluorescence of patient muscle biopsy carrying a PH-domain D614N variant, family genetic analysis","pmids":["23374900"],"confidence":"Low","gaps":["Single patient/family without mechanistic reconstitution","Causality of the variant not demonstrated experimentally","No biochemical measurement of altered lipid binding"]},{"year":2017,"claim":"Demonstrated that lowering DNM2 prevents and reverses myopathy in an MTM1-loss model, defining elevated DNM2 as a pathogenic driver downstream of MTM1 and a therapeutic target.","evidence":"Systemic antisense oligonucleotide knockdown in Mtm1KO mice with histopathology and muscle force readouts","pmids":["28589938"],"confidence":"High","gaps":["Does not identify which DNM2 molecular activity (lipid binding vs GTPase) underlies pathology","Mechanism connecting MTM1 loss to DNM2 elevation unresolved"]},{"year":2017,"claim":"Showed DNM2 is co-opted into a leukemic survival complex, broadening its role to endocytosis-linked signaling in disease beyond muscle.","evidence":"Co-IP with SH3/proline-rich domain mapping of an AHI-1–BCR-ABL–DNM2 complex, DNM2 knockdown with survival/apoptosis assays in CML cells","pmids":["28366933"],"confidence":"Medium","gaps":["Direct fission function of DNM2 in this complex not demonstrated","Single lab, single cellular context"]},{"year":2017,"claim":"Identified DNM2 as a phospho-target whose modification drives Golgi remodeling during viral infection, indicating post-translational control of DNM2 function.","evidence":"Western blot for phospho-DNM2 with Src inhibitor (PP2) rescue, IF and TEM of Golgi in HSV-1-infected neurons","pmids":["28879169"],"confidence":"Medium","gaps":["Direct phosphorylation site on DNM2 not mapped","Whether phospho-DNM2 directly mediates Golgi fission unproven"]},{"year":2018,"claim":"Established that reducing both WT and mutant DNM2 alleles corrects a dominant gain-of-function myopathy, generalizing DNM2 lowering as a therapeutic strategy.","evidence":"AAV-shRNA and ASO knockdown in Dnm2-R465W/+ knock-in mice with histopathology, ultrastructure, and muscle force","pmids":["30291191"],"confidence":"High","gaps":["Therapeutic window for safe DNM2 reduction not defined","Does not isolate the mutant-specific molecular defect"]},{"year":2019,"claim":"Confirmed at the allele level that R465W is a gain-of-function mutation defective in two specific DNM2-dependent processes, endocytosis and autophagy.","evidence":"Allele-specific CRISPR/Cas9 correction in patient fibroblasts and mouse myoblasts, transferrin uptake and autophagy flux assays","pmids":["30925452"],"confidence":"Medium","gaps":["Does not link the in vitro cellular defects to the in vivo muscle phenotype quantitatively","Mechanism of gain-of-function at the molecular level not resolved here"]},{"year":2019,"claim":"Visualized that CNM mutations cause DNM2 mislocalization and aggregation in living muscle, providing an in vivo correlate of disease-associated mislocalization.","evidence":"Transgenic zebrafish live imaging comparing WT and mutant DNM2 with motor and ultrastructural phenotyping","pmids":["31691805"],"confidence":"Medium","gaps":["Does not establish whether aggregation is cause or consequence of dysfunction","Molecular trigger of mutant aggregation unknown"]},{"year":2020,"claim":"Defined a mechanistic route by which a CNM mutation impairs autophagy: R465W mis-partners with ITSN1 at the plasma membrane, depleting DNM2 from LC3-dependent autophagosome formation sites.","evidence":"Co-IP of DNM2 with LC3 and ITSN1, autophagy flux assays, CNM mutant expression and imaging","pmids":["32315611"],"confidence":"High","gaps":["Stoichiometry of DNM2 redistribution between membranes not quantified","Whether LC3 binding directly templates fission unresolved"]},{"year":2021,"claim":"Linked the magnitude of DNM2 GTPase hyperactivity to in cellulo membrane defects and clinical severity, supporting hyperactivity as the unifying mechanism of CNM mutations.","evidence":"In cellulo T-tubule-like structure assay across multiple variants correlated with biochemical GTPase activity and clinical phenotype","pmids":["34837441"],"confidence":"Medium","gaps":["Correlation does not prove GTPase activity alone is the pathogenic determinant","Does not separate GTPase from lipid-binding contributions"]},{"year":2023,"claim":"Revealed that DNM2 abundance is set by ubiquitin-proteasome turnover and is pharmacologically tunable, offering a non-genetic route to lower elevated DNM2.","evidence":"Tamoxifen treatment of BIN1-CNM and DNM2-CNM mice with Western blot for DNM2, cullin 3 and p62, transcriptomics, and contractility","pmids":["36562127"],"confidence":"Medium","gaps":["Direct ubiquitination of DNM2 by a cullin-3 ligase not demonstrated","Mechanism connecting tamoxifen to cullin 3 normalization unresolved"]},{"year":2024,"claim":"Extended DNM2 fission function to mitochondria, showing GTPase-domain-dependent interaction with Drp1 completes mitochondrial division and controls cell-cycle progression.","evidence":"Co-IP with domain mapping, super-resolution colocalization at fission sites, RNA-seq and flow cytometry after DNM2 silencing in pulmonary arterial smooth muscle cells (preprint)","pmids":["bio_10.1101_2024.12.05.24318153"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Whether DNM2 is obligatory for mitochondrial fission in other cell types unclear"]},{"year":2025,"claim":"Established BIN1 as a direct biochemical inhibitor of DNM2 GTPase activity and an in vivo genetic modifier of DNM2-driven disease severity.","evidence":"In vitro GTPase assay with BIN1 plus genetic epistasis (Dnm2-K562E/+ × Bin1+/−) with motor, histological, and integrin readouts","pmids":["40042903"],"confidence":"High","gaps":["Structural mechanism of BIN1-mediated GTPase inhibition not resolved","Does not address regulation of DNM2 by BIN1 in non-muscle tissues"]},{"year":2026,"claim":"Pinpointed PH-domain lipid binding, rather than protein level or GTPase activity per se, as the specific molecular function driving CNM pathology downstream of MTM1 loss.","evidence":"AAV delivery of WT and mutant DNM2 (including lipid-binding-defective K562E) in Mtm1-/y mice with survival, force, fiber sizing, organelle positioning, and genetic epistasis","pmids":["42100875"],"confidence":"High","gaps":["Does not define the specific lipid species or membrane site driving pathology","Relationship between lipid binding and the GTPase-hyperactivity model not fully reconciled"]},{"year":2026,"claim":"Demonstrated that DNM2 augmentation can correct CMT-related muscle defects but only within a narrow dosage window, framing DNM2 level as a tightly balanced determinant of muscle integrity.","evidence":"Muscle-specific transgenic and systemic AAV DNM2 overexpression in Dnm2-K562E/+ mice with histopathology, desmin/integrin IF, and mitochondrial EM","pmids":["41683892"],"confidence":"Medium","gaps":["Optimal therapeutic dose and timing not defined","Mechanism by which excess DNM2 produces CNM-like features not dissected"]},{"year":null,"claim":"How DNM2's distinct molecular activities (lipid binding, GTPase hydrolysis, oligomerization) are coordinated at each membrane compartment, and how this is tuned to set the narrow tolerable range of DNM2 activity across tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model linking lipid binding, GTPase activity, and fission output","Tissue-specific regulators beyond BIN1 and cullin 3 not identified","Mechanism unifying CNM gain-of-function GTPase and lipid-binding models unsettled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[10,16]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[14]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,0]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[14]}],"complexes":[],"partners":["BIN1","DNM1L","CIN85","LC3","ITSN1","AHI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P50570","full_name":"Dynamin-2","aliases":["Dynamin 2","Dynamin II"],"length_aa":870,"mass_kda":98.1,"function":"Catalyzes the hydrolysis of GTP and utilizes this energy to mediate vesicle scission at plasma membrane during endocytosis and filament remodeling at many actin structures during organization of the actin cytoskeleton (PubMed:15731758, PubMed:19605363, PubMed:19623537, PubMed:33713620, PubMed:34744632). Plays an important role in vesicular trafficking processes, namely clathrin-mediated endocytosis (CME), exocytic and clathrin-coated vesicle from the trans-Golgi network, and PDGF stimulated macropinocytosis (PubMed:15731758, PubMed:19623537, PubMed:33713620). During vesicular trafficking process, associates to the membrane, through lipid binding, and self-assembles into ring-like structure through oligomerization to form a helical polymer around the vesicle membrane and leading to vesicle scission (PubMed:17636067, PubMed:34744632, PubMed:36445308). Plays a role in organization of the actin cytoskeleton by mediating arrangement of stress fibers and actin bundles in podocytes (By similarity). During organization of the actin cytoskeleton, self-assembles into ring-like structure that directly bundles actin filaments to form typical membrane tubules decorated with dynamin spiral polymers (By similarity). Self-assembly increases GTPase activity and the GTP hydrolysis causes the rapid depolymerization of dynamin spiral polymers, and results in dispersion of actin bundles (By similarity). Remodels, through its interaction with CTTN, bundled actin filaments in a GTPase-dependent manner and plays a role in orchestrating the global actomyosin cytoskeleton (PubMed:19605363). The interaction with CTTN stabilizes the interaction of DNM2 and actin filaments and stimulates the intrinsic GTPase activity that results in actin filament-barbed ends and increases the sensitivity of filaments in bundles to the actin depolymerizing factor, CFL1 (By similarity). Plays a role in the autophagy process, by participating in the formation of ATG9A vesicles destined for the autophagosomes through its interaction with SNX18 (PubMed:29437695), by mediating recycling endosome scission leading to autophagosome release through MAP1LC3B interaction (PubMed:29437695, PubMed:32315611). Also regulates maturation of apoptotic cell corpse-containing phagosomes by recruiting PIK3C3 to the phagosome membrane (By similarity). Also plays a role in cytokinesis (By similarity). May participate in centrosome cohesion through its interaction with TUBG1 (By similarity). Plays a role in the regulation of neuron morphology, axon growth and formation of neuronal growth cones (By similarity). Involved in membrane tubulation (PubMed:24135484)","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasmic vesicle, clathrin-coated vesicle; Cell projection, uropodium; Endosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Recycling endosome; Cell projection, phagocytic cup; Cytoplasmic vesicle, phagosome membrane; Cell projection, podosome; Cytoplasm; Cell junction; Postsynaptic density; Synapse, synaptosome; Midbody; Membrane, clathrin-coated pit","url":"https://www.uniprot.org/uniprotkb/P50570/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DNM2","classification":"Common 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SNX18","url":"https://www.omim.org/entry/621000"},{"mim_id":"620664","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 37; ARHGEF37","url":"https://www.omim.org/entry/620664"},{"mim_id":"619583","title":"EH DOMAIN-BINDING PROTEIN 1-LIKE 1; EHBP1L1","url":"https://www.omim.org/entry/619583"},{"mim_id":"615368","title":"LETHAL CONGENITAL CONTRACTURE SYNDROME 5; LCCS5","url":"https://www.omim.org/entry/615368"},{"mim_id":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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The CNM-causing DNM2-R465W mutant is defective in this scission step because it shows increased binding to the plasma membrane partner ITSN1, depleting normal DNM2 from autophagosome formation sites on recycling endosomes.\",\n \"method\": \"Cell imaging, autophagy flux assays, co-immunoprecipitation of DNM2 with LC3 and ITSN1, expression of CNM mutant DNM2 in cells\",\n \"journal\": \"Developmental cell\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP (DNM2-LC3, DNM2-ITSN1), functional assays in cells and with CNM mutant, mechanistic explanation for mutant pathology, published in peer-reviewed journal\",\n \"pmids\": [\"32315611\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2010,\n \"finding\": \"DNM2 directly interacts with the adaptor protein CIN85 (SH3-domain-containing protein of 85 kDa) in a complex that is induced by EGF receptor stimulation. This DNM2-CIN85 interaction occurs at late endosomes and is required for late endosomal budding/scission; disruption of this interaction results in accumulation of internalized EGFR in aberrantly elongated late endosomal tubules and sustained downstream signaling.\",\n \"method\": \"Co-immunoprecipitation, dominant-negative and knockdown experiments, live-cell and fluorescence imaging of late endosome morphology, EGFR trafficking assay\",\n \"journal\": \"The EMBO journal\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, loss-of-function with defined morphological and signaling phenotypes, single lab with multiple orthogonal methods\",\n \"pmids\": [\"20711168\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2013,\n \"finding\": \"Expression of the CNM-causing DNM2-S619L mutation in zebrafish leads to accumulation of aberrant vesicular structures and defective excitation-contraction coupling; in COS7 cells, DNM2-S619L causes defective BIN1-dependent membrane tubule formation, indicating the mutation impairs membrane tubulation.\",\n \"method\": \"Zebrafish transgenic expression, COS7 cell tubulation assay, electron microscopy, calcium imaging\",\n \"journal\": \"Disease models & mechanisms\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with multiple readouts, single lab\",\n \"pmids\": [\"24135484\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2017,\n \"finding\": \"DNM2 interacts with the scaffold protein AHI-1 via the AHI-1 SH3 domain binding to the DNM2 proline-rich domain, forming an AHI-1–BCR-ABL–DNM2 protein complex in CML stem/progenitor cells that regulates leukemic cell survival and TKI resistance through cellular endocytosis and ROS-mediated autophagy.\",\n \"method\": \"Co-immunoprecipitation, domain-mapping experiments (SH3 and proline-rich domain truncations), DNM2 knockdown with survival/apoptosis assays\",\n \"journal\": \"Leukemia\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, KD with functional readout, single lab\",\n \"pmids\": [\"28366933\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2017,\n \"finding\": \"HSV-1 neuronal infection triggers Src tyrosine kinase activation and subsequent phosphorylation of Dynamin 2 (DNM2), leading to fragmentation and scattering of the Golgi apparatus; pharmacological inhibition of Src kinase (PP2) markedly reduces these Golgi morphological alterations. HSV-1 tegument protein VP11/12 is necessary but not sufficient for Dyn2 phosphorylation.\",\n \"method\": \"Immunofluorescence, transmission electron microscopy, pharmacological Src inhibition (PP2), primary neuronal cultures, Western blot for phospho-DNM2\",\n \"journal\": \"Frontiers in cellular and infection microbiology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation demonstrated by Western blot with Src inhibitor rescue, morphological validation by TEM and IF, single lab\",\n \"pmids\": [\"28879169\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"In transgenic zebrafish, wild-type DNM2 shows distinctive subcellular compartmentalization in muscle in vivo; CNM-related DNM2 mutations cause protein mislocalization and aggregation in muscle, whereas wild-type DNM2 does not aggregate.\",\n \"method\": \"Transgenic zebrafish live imaging, subcellular localization analysis, motor function assays, muscle ultrastructure analysis\",\n \"journal\": \"Human molecular genetics\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — live in vivo imaging with functional phenotype, direct comparison WT vs. mutant, single lab\",\n \"pmids\": [\"31691805\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2013,\n \"finding\": \"A novel DNM2 D614N mutation in the PH domain is associated with profound mislocalization of DNM2 and membrane trafficking proteins (concentrated at centrally located nuclei rather than normal distribution) in patient muscle fibers, without significant change in total DNM2 protein level, causally linking PH domain integrity to proper DNM2 subcellular localization and myofiber organization.\",\n \"method\": \"Immunofluorescence of patient muscle biopsy, protein expression analysis, genetic analysis of family members\",\n \"journal\": \"Neuromuscular disorders : NMD\",\n \"confidence\": \"Low\",\n \"confidence_rationale\": \"Tier 3 / Weak — single patient/family, immunofluorescence localization without mechanistic reconstitution\",\n \"pmids\": [\"23374900\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2017,\n \"finding\": \"Genetic reduction of DNM2 (via antisense oligonucleotides) in Mtm1 knockout mice (a model of X-linked centronuclear myopathy) efficiently reduces DNM2 protein in muscle and prevents myopathy development; ASO injection into severely affected mice reverses muscle pathology within 2 weeks, establishing that elevated DNM2 is a pathogenic driver downstream of MTM1 loss.\",\n \"method\": \"Antisense oligonucleotide (ASO) systemic delivery in Mtm1KO mice, histopathology, muscle force measurements, Western blot\",\n \"journal\": \"Nature communications\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockdown with prevention and reversal of disease phenotype, multiple readouts, independently replicated across CNM models\",\n \"pmids\": [\"28589938\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2018,\n \"finding\": \"Reduction of DNM2 via AAV-shRNA or antisense oligonucleotides in Dnm2-R465W/+ knock-in mice (DNM2-related CNM model) rescues muscle mass, fiber size, histopathology, and ultrastructure, demonstrating that reducing both WT and mutant DNM2 alleles can correct a dominant gain-of-function myopathy.\",\n \"method\": \"Intramuscular AAV-shRNA injection, systemic ASO delivery, histopathology, muscle force/mass measurements, Western blot\",\n \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — two independent knockdown strategies in the same disease model, multiple outcome measures, replication of ASO approach from prior work\",\n \"pmids\": [\"30291191\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"Allele-specific CRISPR/Cas9 inactivation or correction of the heterozygous DNM2-R465W mutation in patient fibroblasts and mouse myoblasts rescues altered transferrin uptake (endocytosis) and autophagy phenotypes, confirming the R465W mutation causes gain-of-function defects in these two DNM2-dependent cellular processes.\",\n \"method\": \"CRISPR/Cas9 allele-specific editing, transferrin uptake assay, autophagy flux assay in patient and mouse cells\",\n \"journal\": \"Molecular therapy. Nucleic acids\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — allele-specific correction with rescue of two functional phenotypes, single lab\",\n \"pmids\": [\"30925452\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"BIN1 (amphiphysin 2) inhibits the GTPase activity of DNM2; genetic reduction of BIN1 in Dnm2-K562E/+ CMT mice increases the activity of the K562E DNM2 mutant, restores motor performance, ameliorates muscle and nerve structural defects, and normalizes integrin localization in muscle. Conversely, increasing BIN1 exacerbates Dnm2-K562E/+ phenotypes, establishing BIN1 as a modifier of DNM2 activity and disease severity.\",\n \"method\": \"In vitro GTPase activity assay with BIN1, genetic epistasis (Dnm2K562E/+ × Bin1+/- mice), motor and histological phenotyping, integrin immunofluorescence\",\n \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical GTPase assay plus in vivo genetic epistasis with multiple phenotypic readouts, single lab but multiple orthogonal methods\",\n \"pmids\": [\"40042903\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2026,\n \"finding\": \"DNM2 lipid binding (via PH domain) is the specific molecular function driving CNM pathology: a lipid-binding-defective K562E mutant of DNM2, when expressed in Mtm1-/y mice, fully rescues survival, motor function, muscle force, fiber size, and organelle positioning despite persistently elevated DNM2 protein levels, while GTPase-active or other mutants fail to rescue. This establishes DNM2 lipid binding, not protein level or GTPase activity per se, as the pathogenic driver in MTM1-CNM.\",\n \"method\": \"AAV-mediated delivery of WT and DNM2 mutants in WT and Mtm1-/y mice, muscle force measurements, histopathology, fiber sizing, organelle positioning; genetic epistasis (Mtm1-/y Dnm2K562E/+ mice)\",\n \"journal\": \"JCI insight\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1–2 / Strong — systematic in vivo structure-function analysis with multiple DNM2 mutants, rescue experiments in disease model, genetic epistasis cross, multiple orthogonal readouts\",\n \"pmids\": [\"42100875\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2016,\n \"finding\": \"DNM2 (dynamin 2) is required for efficient Japanese encephalitis virus (JEV) replication; siRNA knockdown of DNM2 in PK15 cells significantly reduces JEV replication, identifying DNM2-dependent vesicle scission as a host factor exploited by JEV for cellular entry/replication.\",\n \"method\": \"siRNA knockdown of DNM2, viral replication assay (JEV), miR-124 overexpression with DNM2 target validation\",\n \"journal\": \"Virology journal\",\n \"confidence\": \"Low\",\n \"confidence_rationale\": \"Tier 3 / Weak — single siRNA knockdown experiment in one cell type, single lab, no mechanistic reconstitution\",\n \"pmids\": [\"27329300\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2023,\n \"finding\": \"Tamoxifen reduces the abnormally elevated DNM2 protein level in both BIN1-CNM and DNM2-CNM mouse models through a mechanism involving normalization of cullin 3 (E3 ubiquitin ligase) protein level, suggesting ubiquitin-proteasome-mediated regulation of DNM2 abundance underlies the therapeutic effect.\",\n \"method\": \"Tamoxifen dietary treatment in CNM mouse models, Western blot for DNM2 and ubiquitin-proteasome markers (cullin 3, p62), transcriptome analysis, muscle contractility measurements\",\n \"journal\": \"Brain : a journal of neurology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — protein-level measurements with mechanistic correlate (cullin 3), in vivo model, single lab with multiple markers\",\n \"pmids\": [\"36562127\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2024,\n \"finding\": \"DNM2 interacts with Drp1 via its GTPase domain, enabling mitochondrial translocation and facilitating the terminal steps of mitochondrial fission; silencing DNM2 in pulmonary arterial smooth muscle cells inhibits mitochondrial fission and causes G1/G0 cell cycle arrest, while DNM2 overexpression accelerates fission and proliferation. RGCC is identified as a downstream cell-cycle effector of this DNM2-Drp1 axis.\",\n \"method\": \"Co-immunoprecipitation, super-resolution microscopy for colocalization at fission sites, truncated-domain expression constructs, RNA-seq after DNM2 silencing, flow cytometry for cell cycle, siRNA knockdown\",\n \"journal\": \"bioRxiv\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus domain mapping, super-resolution colocalization, functional cell-cycle readouts; preprint, not yet peer-reviewed\",\n \"pmids\": [\"bio_10.1101_2024.12.05.24318153\"],\n \"is_preprint\": true\n },\n {\n \"year\": 2024,\n \"finding\": \"DNM2 is recruited to the neck of vacuole-like protrusions (VLPs) formed during Shigella flexneri cell-to-cell spread, dependent on PIK3C3-mediated PtdIns(3)P accumulation, where it mediates membrane scission to resolve protrusions into double-membrane vacuoles.\",\n \"method\": \"Live-fluorescence confocal microscopy tracking, PIK3C3 inhibition, DNM2 localization imaging at VLP necks during bacterial spread\",\n \"journal\": \"bioRxiv\",\n \"confidence\": \"Low\",\n \"confidence_rationale\": \"Tier 3 / Weak — localization by imaging without direct functional validation of DNM2 scission activity at this site; preprint\",\n \"pmids\": [\"bio_10.1101_2024.10.31.621244\"],\n \"is_preprint\": true\n },\n {\n \"year\": 2021,\n \"finding\": \"Novel DNM2 variants associated with CNM induce gain-of-function phenotypes in a cell-based imaging assay (T-tubule-like structure formation); the degree of impairment in cellulo correlates with biochemical gain-of-function GTPase activity measurements and clinical disease severity, providing evidence that DNM2 CNM mutations act via hyperactivity.\",\n \"method\": \"In cellulo imaging assay for T-tubule-like structures, biochemical GTPase activity assay for mutant proteins\",\n \"journal\": \"Human mutation\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GTPase assay plus cell-based functional assay, multiple variants tested, correlation with clinical phenotype; single lab\",\n \"pmids\": [\"34837441\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2026,\n \"finding\": \"Muscle-specific DNM2 overexpression in Dnm2-K562E/+ CMT mice ameliorates desmin and integrin mislocalization, membrane trafficking defects, mitochondrial abnormalities, and fibrosis in skeletal muscle independently of nerve involvement. Systemic postnatal AAV-DNM2 delivery paradoxically worsened muscle pathology producing CNM-like features, revealing that precise DNM2 dosage is critical and that the therapeutic window for DNM2 augmentation in muscle is narrow.\",\n \"method\": \"Tissue-specific transgenic overexpression, AAV systemic delivery, histopathology, immunofluorescence for desmin/integrin, electron microscopy for mitochondria\",\n \"journal\": \"International journal of molecular sciences\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific genetic and AAV approaches with multiple structural readouts, functional phenotyping; single lab, single study\",\n \"pmids\": [\"41683892\"],\n \"is_preprint\": false\n }\n ],\n \"current_model\": \"DNM2 is a ubiquitously expressed large GTPase that mediates membrane fission through oligomerization around membrane necks; its established molecular functions include: (1) clathrin-mediated endocytosis and late endosomal scission (interacting with CIN85 at late endosomes), (2) scission of recycling endosome tubules to release autophagosome precursors via direct LC3 binding, (3) interaction with Drp1 via its GTPase domain to complete mitochondrial fission, (4) lipid binding via its PH domain as the primary pathogenic driver of CNM, and (5) modulation by BIN1 which inhibits its GTPase activity; dominant CNM mutations (e.g., R465W, S619L) cause gain-of-function hyperactivity or mislocalization leading to defective membrane tubulation, impaired autophagy, and abnormal muscle ultrastructure, whereas CMT mutations (e.g., K562E) cause lipid-binding and activity defects; reducing DNM2 expression rescues multiple forms of centronuclear myopathy in preclinical models.\"\n}\n```","stage2_raw":"{\n \"mechanistic_narrative\": \"DNM2 is a large GTPase that mediates membrane fission across multiple intracellular compartments by acting at the necks of membrane tubules and vesicles [#1, #14]. It drives scission events in the endolysosomal and autophagic pathways: at late endosomes it forms an EGF-induced complex with the adaptor CIN85 required for late endosomal budding and EGFR downregulation, with loss producing elongated late-endosomal tubules and sustained signaling [#1], and it severs recycling endosome tubules to release autophagosome precursors through direct binding to LC3 [#0]. DNM2 also interacts with Drp1 via its GTPase domain to complete the terminal steps of mitochondrial fission [#14]. Its activity is restrained by BIN1 (amphiphysin 2), which inhibits DNM2 GTPase activity and acts as a genetic modifier of DNM2-dependent disease [#10]. DNM2 is a central pathogenic node in centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) neuropathy: dominant CNM mutations such as R465W and S619L act through gain-of-function hyperactivity and protein mislocalization that impair membrane tubulation, endocytosis, and autophagy [#9, #16, #2, #5], and lipid binding through the PH domain — rather than protein level or GTPase activity alone — is the specific molecular function driving CNM pathology downstream of MTM1 loss [#11]. Reducing DNM2 expression genetically rescues multiple forms of CNM in vivo, establishing elevated or hyperactive DNM2 as the driver of disease [#7, #8].\",\n \"teleology\": [\n {\n \"year\": 2010,\n \"claim\": \"Established that DNM2 acts in a regulated, signal-dependent complex at late endosomes, extending its fission role beyond the plasma membrane into endolysosomal trafficking.\",\n \"evidence\": \"Reciprocal Co-IP of DNM2 with CIN85, knockdown/dominant-negative experiments with EGFR trafficking and morphology readouts\",\n \"pmids\": [\"20711168\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Does not define how DNM2 oligomerization is nucleated at the late endosomal neck\", \"Structural basis of the DNM2-CIN85 interaction not resolved\"]\n },\n {\n \"year\": 2013,\n \"claim\": \"Connected a specific CNM mutation to defective membrane tubulation and excitation-contraction coupling, linking DNM2 dysfunction to muscle pathology in vivo.\",\n \"evidence\": \"Zebrafish transgenic expression of DNM2-S619L, COS7 BIN1-dependent tubulation assay, EM and calcium imaging\",\n \"pmids\": [\"24135484\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Does not establish whether the tubulation defect reflects gain or loss of function\", \"Mechanistic link between vesicular accumulation and EC-coupling defect unresolved\"]\n },\n {\n \"year\": 2013,\n \"claim\": \"Implicated PH domain integrity in proper DNM2 subcellular localization, hinting at the lipid-interaction basis of CNM later confirmed mechanistically.\",\n \"evidence\": \"Immunofluorescence of patient muscle biopsy carrying a PH-domain D614N variant, family genetic analysis\",\n \"pmids\": [\"23374900\"],\n \"confidence\": \"Low\",\n \"gaps\": [\"Single patient/family without mechanistic reconstitution\", \"Causality of the variant not demonstrated experimentally\", \"No biochemical measurement of altered lipid binding\"]\n },\n {\n \"year\": 2017,\n \"claim\": \"Demonstrated that lowering DNM2 prevents and reverses myopathy in an MTM1-loss model, defining elevated DNM2 as a pathogenic driver downstream of MTM1 and a therapeutic target.\",\n \"evidence\": \"Systemic antisense oligonucleotide knockdown in Mtm1KO mice with histopathology and muscle force readouts\",\n \"pmids\": [\"28589938\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Does not identify which DNM2 molecular activity (lipid binding vs GTPase) underlies pathology\", \"Mechanism connecting MTM1 loss to DNM2 elevation unresolved\"]\n },\n {\n \"year\": 2017,\n \"claim\": \"Showed DNM2 is co-opted into a leukemic survival complex, broadening its role to endocytosis-linked signaling in disease beyond muscle.\",\n \"evidence\": \"Co-IP with SH3/proline-rich domain mapping of an AHI-1–BCR-ABL–DNM2 complex, DNM2 knockdown with survival/apoptosis assays in CML cells\",\n \"pmids\": [\"28366933\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Direct fission function of DNM2 in this complex not demonstrated\", \"Single lab, single cellular context\"]\n },\n {\n \"year\": 2017,\n \"claim\": \"Identified DNM2 as a phospho-target whose modification drives Golgi remodeling during viral infection, indicating post-translational control of DNM2 function.\",\n \"evidence\": \"Western blot for phospho-DNM2 with Src inhibitor (PP2) rescue, IF and TEM of Golgi in HSV-1-infected neurons\",\n \"pmids\": [\"28879169\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Direct phosphorylation site on DNM2 not mapped\", \"Whether phospho-DNM2 directly mediates Golgi fission unproven\"]\n },\n {\n \"year\": 2018,\n \"claim\": \"Established that reducing both WT and mutant DNM2 alleles corrects a dominant gain-of-function myopathy, generalizing DNM2 lowering as a therapeutic strategy.\",\n \"evidence\": \"AAV-shRNA and ASO knockdown in Dnm2-R465W/+ knock-in mice with histopathology, ultrastructure, and muscle force\",\n \"pmids\": [\"30291191\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Therapeutic window for safe DNM2 reduction not defined\", \"Does not isolate the mutant-specific molecular defect\"]\n },\n {\n \"year\": 2019,\n \"claim\": \"Confirmed at the allele level that R465W is a gain-of-function mutation defective in two specific DNM2-dependent processes, endocytosis and autophagy.\",\n \"evidence\": \"Allele-specific CRISPR/Cas9 correction in patient fibroblasts and mouse myoblasts, transferrin uptake and autophagy flux assays\",\n \"pmids\": [\"30925452\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Does not link the in vitro cellular defects to the in vivo muscle phenotype quantitatively\", \"Mechanism of gain-of-function at the molecular level not resolved here\"]\n },\n {\n \"year\": 2019,\n \"claim\": \"Visualized that CNM mutations cause DNM2 mislocalization and aggregation in living muscle, providing an in vivo correlate of disease-associated mislocalization.\",\n \"evidence\": \"Transgenic zebrafish live imaging comparing WT and mutant DNM2 with motor and ultrastructural phenotyping\",\n \"pmids\": [\"31691805\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Does not establish whether aggregation is cause or consequence of dysfunction\", \"Molecular trigger of mutant aggregation unknown\"]\n },\n {\n \"year\": 2020,\n \"claim\": \"Defined a mechanistic route by which a CNM mutation impairs autophagy: R465W mis-partners with ITSN1 at the plasma membrane, depleting DNM2 from LC3-dependent autophagosome formation sites.\",\n \"evidence\": \"Co-IP of DNM2 with LC3 and ITSN1, autophagy flux assays, CNM mutant expression and imaging\",\n \"pmids\": [\"32315611\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Stoichiometry of DNM2 redistribution between membranes not quantified\", \"Whether LC3 binding directly templates fission unresolved\"]\n },\n {\n \"year\": 2021,\n \"claim\": \"Linked the magnitude of DNM2 GTPase hyperactivity to in cellulo membrane defects and clinical severity, supporting hyperactivity as the unifying mechanism of CNM mutations.\",\n \"evidence\": \"In cellulo T-tubule-like structure assay across multiple variants correlated with biochemical GTPase activity and clinical phenotype\",\n \"pmids\": [\"34837441\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Correlation does not prove GTPase activity alone is the pathogenic determinant\", \"Does not separate GTPase from lipid-binding contributions\"]\n },\n {\n \"year\": 2023,\n \"claim\": \"Revealed that DNM2 abundance is set by ubiquitin-proteasome turnover and is pharmacologically tunable, offering a non-genetic route to lower elevated DNM2.\",\n \"evidence\": \"Tamoxifen treatment of BIN1-CNM and DNM2-CNM mice with Western blot for DNM2, cullin 3 and p62, transcriptomics, and contractility\",\n \"pmids\": [\"36562127\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Direct ubiquitination of DNM2 by a cullin-3 ligase not demonstrated\", \"Mechanism connecting tamoxifen to cullin 3 normalization unresolved\"]\n },\n {\n \"year\": 2024,\n \"claim\": \"Extended DNM2 fission function to mitochondria, showing GTPase-domain-dependent interaction with Drp1 completes mitochondrial division and controls cell-cycle progression.\",\n \"evidence\": \"Co-IP with domain mapping, super-resolution colocalization at fission sites, RNA-seq and flow cytometry after DNM2 silencing in pulmonary arterial smooth muscle cells (preprint)\",\n \"pmids\": [\"bio_10.1101_2024.12.05.24318153\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Whether DNM2 is obligatory for mitochondrial fission in other cell types unclear\"]\n },\n {\n \"year\": 2025,\n \"claim\": \"Established BIN1 as a direct biochemical inhibitor of DNM2 GTPase activity and an in vivo genetic modifier of DNM2-driven disease severity.\",\n \"evidence\": \"In vitro GTPase assay with BIN1 plus genetic epistasis (Dnm2-K562E/+ × Bin1+/−) with motor, histological, and integrin readouts\",\n \"pmids\": [\"40042903\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Structural mechanism of BIN1-mediated GTPase inhibition not resolved\", \"Does not address regulation of DNM2 by BIN1 in non-muscle tissues\"]\n },\n {\n \"year\": 2026,\n \"claim\": \"Pinpointed PH-domain lipid binding, rather than protein level or GTPase activity per se, as the specific molecular function driving CNM pathology downstream of MTM1 loss.\",\n \"evidence\": \"AAV delivery of WT and mutant DNM2 (including lipid-binding-defective K562E) in Mtm1-/y mice with survival, force, fiber sizing, organelle positioning, and genetic epistasis\",\n \"pmids\": [\"42100875\"],\n \"confidence\": \"High\",\n \"gaps\": [\"Does not define the specific lipid species or membrane site driving pathology\", \"Relationship between lipid binding and the GTPase-hyperactivity model not fully reconciled\"]\n },\n {\n \"year\": 2026,\n \"claim\": \"Demonstrated that DNM2 augmentation can correct CMT-related muscle defects but only within a narrow dosage window, framing DNM2 level as a tightly balanced determinant of muscle integrity.\",\n \"evidence\": \"Muscle-specific transgenic and systemic AAV DNM2 overexpression in Dnm2-K562E/+ mice with histopathology, desmin/integrin IF, and mitochondrial EM\",\n \"pmids\": [\"41683892\"],\n \"confidence\": \"Medium\",\n \"gaps\": [\"Optimal therapeutic dose and timing not defined\", \"Mechanism by which excess DNM2 produces CNM-like features not dissected\"]\n },\n {\n \"year\": null,\n \"claim\": \"How DNM2's distinct molecular activities (lipid binding, GTPase hydrolysis, oligomerization) are coordinated at each membrane compartment, and how this is tuned to set the narrow tolerable range of DNM2 activity across tissues, remains unresolved.\",\n \"evidence\": \"\",\n \"pmids\": [],\n \"confidence\": \"Medium\",\n \"gaps\": [\"No integrated structural model linking lipid binding, GTPase activity, and fission output\", \"Tissue-specific regulators beyond BIN1 and cullin 3 not identified\", \"Mechanism unifying CNM gain-of-function GTPase and lipid-binding models unsettled\"]\n }\n ],\n \"mechanism_profile\": {\n \"molecular_activity\": [\n {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [10, 16]},\n {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11]},\n {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 14]}\n ],\n \"localization\": [\n {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]},\n {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [14]},\n {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4]},\n {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n ],\n \"pathway\": [\n {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 0]},\n {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0, 9]},\n {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [14]}\n ],\n \"complexes\": [],\n \"partners\": [\"BIN1\", \"DNM1L\", \"CIN85\", \"LC3\", \"ITSN1\", \"AHI1\"],\n \"other_free_text\": []\n }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}