{"gene":"FGF13","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2016,"finding":"FGF13 binds directly to voltage-gated sodium channels (VGSCs) in hippocampal neurons and limits their somatodendritic surface expression, while FGF14 (a homolog) promotes axonal VGSC localization; single-point mutations in FGF13 that abrogate VGSC interaction in vitro cannot support somatodendritic restriction in neurons. Together, FGF13 and FGF14 act concertedly to polarize VGSC distribution to the axon initial segment.","method":"Knockdown in hippocampal neurons, in vitro VGSC-interaction mutagenesis, immunofluorescence localization, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown, mutagenesis abolishing interaction, direct localization experiments with functional consequence, replicated across two homologous proteins","pmids":["27044086"],"is_preprint":false},{"year":2017,"finding":"FGF13 interacts with Nav1.7 in DRG neurons in a heat-facilitated manner, increases Nav1.7 sodium currents, and maintains membrane localization of Nav1.7 during noxious heat stimulation, enabling sustained action potential firing required for heat nociception. Loss of FGF13 in DRG neurons selectively abolishes heat nociception. Disruption of the FGF13/Nav1.7 interaction with a competitive peptide reduces heat-evoked action potential firing and nociceptive behavior.","method":"Conditional knockout mice, co-immunoprecipitation, patch-clamp electrophysiology, competitive peptide disruption, behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with specific phenotype, co-IP of interaction, peptide disruption confirming mechanism, multiple orthogonal methods in one study","pmids":["28162808"],"is_preprint":false},{"year":2016,"finding":"Cardiac FGF13 directly binds to the C-terminus of NaV1.5, and different FGF13 splice variants (FGF13S, FGF13U, FGF13VY) differentially modulate NaV1.5 current density, fast inactivation (open-state and closed-state), steady-state availability, and slow inactivation. FGF13S uniquely hastens slow inactivation entry and dramatically slows recovery, causing large current reduction at high frequency stimulation.","method":"Heterologous expression in HEK293 cells, whole-cell voltage-clamp electrophysiology, isoform-specific expression constructs","journal":"Channels (Austin, Tex.)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct electrophysiological in vitro assay with multiple isoforms and multiple gating parameters, single lab but multiple orthogonal measurements","pmids":["27246624"],"is_preprint":false},{"year":2017,"finding":"Cardiac-specific Fgf13 knockout reduces peak Na+ channel current density (~25%), causes a hyperpolarizing shift in steady-state inactivation, prolongs QRS duration, and reduces transient outward K+ current (Ito) by decreasing Kv4.2 and Kv4.3 sarcolemmal localization without altering their total protein levels. Voltage-gated Ca2+ current was not affected.","method":"Inducible cardiomyocyte-restricted Fgf13 knockout mice, patch-clamp electrophysiology, ECG recording, immunoblotting, surface fractionation","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple defined ionic phenotypes, surface vs total protein biochemistry, ECG and electrophysiology in same model","pmids":["28119060"],"is_preprint":false},{"year":2016,"finding":"Mice lacking FHF2 (FGF13) show normal cardiac rhythm at baseline but develop temperature-sensitive cardiac conduction failure at elevated temperatures. Absence of FHF2 accelerates both closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation to severely suppress cardiac sodium currents at elevated temperatures.","method":"Fhf2 knockout mice, patch-clamp electrophysiology at multiple temperatures, ECG recording, computational modeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO model with defined ionic mechanism (inactivation rate), temperature-series electrophysiology, computational validation, multiple orthogonal methods","pmids":["27701382"],"is_preprint":false},{"year":2017,"finding":"FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 (PTRF) between the sarcolemma and cytosol. In cardiac Fgf13 knockout mice, cavin 1 redistributes to the sarcolemma, stabilizes caveolin 3, increases caveolae density, and confers protection against pressure overload-induced cardiac dysfunction. The full FGF13 interactome in cardiomyocytes was found to include the complete set of cavin family caveolar coat proteins.","method":"Inducible cardiac-specific Fgf13 knockout mice, co-immunoprecipitation/interactome screen, biochemical fractionation, electron microscopy for caveolae density, cardiac pressure overload model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, biochemical fractionation, KO model with functional cardiac readout, multiple orthogonal methods in single rigorous study","pmids":["28461495"],"is_preprint":false},{"year":2015,"finding":"Disruption of Fgf13 in female mice (heterozygous deletion) causes hyperthermia-induced seizures and epilepsy associated with a synaptic excitatory-inhibitory imbalance: decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons.","method":"Fgf13 knockout mice, hippocampal electrophysiological recordings (miniature IPSCs and EPSCs), hyperthermia seizure induction","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined genetic model, direct electrophysiological measurement of E/I balance, specific seizure phenotype with mechanistic readout","pmids":["26063919"],"is_preprint":false},{"year":2017,"finding":"C-terminal phosphorylation of NaV1.5 at Ser1938 and Ser1989 (increased in CaMKIIδc-overexpressing failing hearts) abrogates FGF13-dependent regulation of NaV1.5 channel inactivation. FGF13 normally increases NaV1.5 channel availability and decreases late Na+ current; phosphomimetic mutations at both sites abolish these effects by reducing FGF13 binding to NaV1.5 and consequently reducing calmodulin recruitment to NaV1.5. FGF13 was shown to potentiate calmodulin binding to NaV1.5.","method":"Phosphoproteomics of purified NaV1.5 from WT and CaMKIIδc-Tg mouse ventricles, whole-cell voltage-clamp in HEK293 cells, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — phosphoproteomics identifying native sites, functional validation by electrophysiology with phosphomimetic mutants, co-IP showing altered binding, multiple orthogonal methods","pmids":["28882890"],"is_preprint":false},{"year":2020,"finding":"FGF13 directly interacts with p65 (NF-κB subunit) via its nuclear localization sequence, co-localizes with p65 in the nucleus in cardiac hypertrophy, and activates NF-κB signaling by an IκB-independent mechanism. FGF13 deficiency inhibits NF-κB activation and overexpression alone is sufficient to activate NF-κB in cardiomyocytes.","method":"Co-immunoprecipitation, confocal co-localization, gain- and loss-of-function in cardiomyocytes and TAC mouse model, NF-κB reporter assay","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP binding, gain/loss-of-function with reporter assay, single lab but multiple orthogonal methods","pmids":["33089113"],"is_preprint":false},{"year":2016,"finding":"FGF13 1A isoform localizes to the nucleolus and represses ribosomal RNA transcription, attenuating protein synthesis. The FGF13 locus (encompassing FGF13 and miR-504) is transcriptionally repressed by p53, defining a negative feedback loop. In cancer cells expressing high FGF13, its depletion causes proteostasis stress, reactive oxygen species accumulation, and apoptosis.","method":"Subcellular fractionation/confocal microscopy for nucleolar localization, ribosomal RNA transcription assays, siRNA depletion with apoptosis readout, p53 chromatin immunoprecipitation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization experiment, functional transcription assay, loss-of-function with mechanistic readout, single lab","pmids":["27994142"],"is_preprint":false},{"year":2021,"finding":"FGF13 stabilizes microtubules in developing cortical neurons. A 5'-UTR SNP (c.-32C>G) in FGF13 reduces translation of FGF13 by impairing its interaction with polypyrimidine-tract-binding protein 2 (PTBP2), which is required for FGF13 translation in cortical neurons. Reduced FGF13 causes delayed neuronal migration and cognitive deficits.","method":"Patient-derived iPSCs and HEK293 cell translation assays, RNA-binding protein pulldown (PTBP2), knockin mice carrying homologous 5'-UTR point mutation, microtubule polymerization assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro translation assays, RNA-binding pulldown identifying PTBP2 as reader, knockin mouse model with neuronal migration phenotype, multiple orthogonal methods","pmids":["34184986"],"is_preprint":false},{"year":2019,"finding":"FHF2 (FGF13) isoforms FHF2A and FHF2B associate with Nav1.7 in DRG neurons and regulate its current properties in an isoform-dependent manner. FHF2A causes accumulation of inactivated channels and slows recovery from inactivation, while FHF2B depolarizes activation. Effects were confirmed by FHF2 knockdown in DRG neurons.","method":"Co-immunoprecipitation/immunohistochemistry in DRG neurons, whole-cell patch-clamp in HEK293-Nav1.7 cells and DRG neurons with FHF2 knockdown","journal":"Neurobiology of pain (Cambridge, Mass.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct association demonstrated, isoform-specific electrophysiology in both heterologous and native cells, knockdown confirmation","pmids":["31223136"],"is_preprint":false},{"year":2016,"finding":"FHF2A (FGF13A) negatively regulates Nav1.6-mediated resurgent sodium currents in DRG neurons by enhancing long-term inactivation and delaying recovery, while FHF2B positively regulates resurgent current. Chimeric FHF2A/Navβ4 constructs revealed distinct regulatory regions. FHF2A and FHF2B isoform expression is differentially regulated in a radicular pain model.","method":"Whole-cell patch-clamp in DRG neurons and heterologous cells, FHF2 isoform-specific expression/knockdown, chimeric construct analysis","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology in native and heterologous cells, isoform-specific and chimeric constructs, single lab","pmids":["27999940"],"is_preprint":false},{"year":2020,"finding":"Missense variants in the N-terminal domain of FHF2A (FGF13 A isoform) cause loss of the ability to induce rapid-onset, long-term blockade of Nav1.6 (SCN8A) channels while retaining pro-excitatory properties, resulting in gain-of-function neuronal hyperexcitability consistent with developmental and epileptic encephalopathy.","method":"Whole-exome sequencing identifying variants, functional characterization by co-expression of mutant FHF2A with Nav1.6 in heterologous cells (whole-cell patch-clamp)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct in vitro electrophysiological characterization of mutant proteins with wild-type Nav1.6, multiple patient variants tested, single lab","pmids":["33245860"],"is_preprint":false},{"year":2020,"finding":"FHF2-deficient cardiomyocytes show that reduced Nav availability shifts dependence onto calcium current (ICa) to sustain electrotonic driving force and action potential propagation from cell-to-cell. Diminished gap junctional conductance (Gj) conspires with accelerated Nav inactivation in FHF2-deficient strands to prevent sufficient downstream cell charging for action potential propagation.","method":"Fhf2 knockout mice, pharmacological reduction of gCaL (verapamil) or Gj (carbenoxolone), Cx43-heterozygous backcross, multicellular linear strand computational modeling, optical mapping","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model combined with pharmacology and computational modeling confirming ionic mechanism, multiple orthogonal perturbations","pmids":["32962518"],"is_preprint":false},{"year":2025,"finding":"FGF13 regulates cardiac impulse propagation via a VGSC-independent mechanism by controlling microtubule-dependent trafficking and targeting of Cx43 (connexin 43) gap junctions. FGF13 ablation destabilizes microtubules, reduces MAP4 expression, perturbs Cx43 trafficking to the intercalated disc, increases Cx43 hemichannels, and depolarizes resting membrane potential. A mutant FGF13 incapable of binding VGSCs fully restores these defects, demonstrating VGSC independence.","method":"Cardiac-specific Fgf13 KO mice, optical mapping, pharmacological gap junction/hemichannel manipulation, proximity labeling proteomics, immunostaining, VGSC-binding-incompetent FGF13 mutant rescue","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — separation-of-function mutant, proximity proteomics, optical mapping, pharmacology, and rescue experiments in one rigorous study","pmids":["41200819"],"is_preprint":false},{"year":2025,"finding":"FGF13 regulation of NaV1.5 steady-state inactivation (SSI) is mediated through effects on local accessible membrane cholesterol rather than through direct channel binding. A binding-incompetent FGF13 mutant (structurally guided) still completely restores WT regulation of SSI in Fgf13-KO cardiomyocytes. FGF13 maintains polarized cholesterol distribution concentrated at the intercalated disc where VGSCs localize; Fgf13-KO eliminates this cholesterol polarization and causes VGSC loss from the intercalated disc.","method":"Fgf13-KO cardiomyocytes, binding-incompetent FGF13 mutant rescue, cholesterol labeling/filipin staining, patch-clamp electrophysiology, proximity labeling proteomics","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — separation-of-function mutant, direct cholesterol imaging, electrophysiology in native KO cells, multiple orthogonal methods revealing novel mechanism","pmids":["40794434"],"is_preprint":false},{"year":2025,"finding":"Interneuron-specific deletion of Fgf13 causes perinatal mortality with extensive seizures and impaired hippocampal inhibitory/excitatory balance, while excitatory neuron-targeted deletion causes no seizures. The seizure mechanism in interneurons is sodium channel-independent; instead, Fgf13 ablation in interneurons markedly reduces K+ channel currents. Re-expression of different Fgf13 splice isoforms partially rescues interneuron excitability deficits and restores K+ current amplitude.","method":"Cell-type-specific conditional Fgf13 knockout mice (interneuron vs. excitatory neuron Cre lines), patch-clamp electrophysiology, isoform rescue experiments","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell-type-specific KO models, direct ionic current measurements, isoform rescue, replicated across preprint and peer-reviewed publication","pmids":["39773461"],"is_preprint":false},{"year":2020,"finding":"FGF13 is required for histamine-induced itch sensation in DRG neurons. Histamine enhances the FGF13/Nav1.7 interaction. Disruption of FGF13/Nav1.7 interaction by a membrane-permeable competitive peptide (GST-Flag-NaV1.7CT-TAT) reduces histamine-responsive DRG neurons and impairs scratching behavior. The histamine-evoked neuronal response is primarily mediated via H1R and is FGF13B isoform-dependent.","method":"DRG-specific Fgf13 KO mice, co-immunoprecipitation, calcium imaging, electrophysiology, competitive peptide disruption, behavioral assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with specific behavioral phenotype, co-IP demonstrating histamine-enhanced interaction, competitive peptide validation, multiple orthogonal methods","pmids":["33172979"],"is_preprint":false},{"year":2021,"finding":"FGF13A (nuclear isoform) interacts with ARID1B, a subunit of the Brahma-associated factor (BAF) chromatin remodeling complex, in hippocampal neural stem cells, and suppresses expression of neuronal differentiation-associated genes through chromatin modification, thereby maintaining neural stem cell self-renewal and suppressing neuronal differentiation during postnatal hippocampal neurogenesis.","method":"Fgf13 conditional knockout mice, co-immunoprecipitation (FGF13A-ARID1B), chromatin immunoprecipitation, hippocampal neurogenesis assays, RNA-seq","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP identifying nuclear binding partner, ChIP showing chromatin modification, KO with neurogenesis phenotype, single lab","pmids":["34010636"],"is_preprint":false},{"year":2024,"finding":"FGF13 enhances TRPV1 channel function selectively (not TRPA1) in DRG neurons through its microtubule-stabilizing effect. FGF13 knockout reduces TRPV1-activated calcium influx and current density, impairing histamine-dependent and chronic dry-skin itch behaviors. Only FGF13 containing an intact tubulin-binding domain can rescue TRPV1 function and itch behavior in knockout mice.","method":"DRG-specific Fgf13 conditional KO mice, calcium imaging, whole-cell patch-clamp (DRG and HEK cells), rescue with wild-type vs tubulin-binding mutant FGF13, behavioral itch assays","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, electrophysiology, domain-specific rescue, single lab","pmids":["38733310"],"is_preprint":false},{"year":2023,"finding":"FGF13 deficiency in glomerular endothelial cells improves mitochondrial homeostasis in diabetic nephropathy through Parkin-dependent regulation of mitophagy promotion and apoptosis inhibition. The beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn (Parkin), placing FGF13 upstream of Parkin in this pathway.","method":"Endothelial-specific Fgf13 KO and double Fgf13/Prkn KO mice, mitophagy assays, apoptosis assays, diabetic nephropathy model","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via double KO, multiple cellular readouts, single lab","pmids":["36256844"],"is_preprint":false},{"year":2024,"finding":"FGF13 interacts with microtubules in cardiomyocytes and increases microtubule stability during heart failure, impairing calcium signaling by reducing Cav1.2 sarcolemmal localization and Serca2α expression. FGF13 deficiency in heart failure restores calcium transients. Rescue with wild-type FGF13 but not a microtubule-binding-deficient FGF13 mutant recapitulates the calcium dysfunction, confirming that microtubule stabilization is the operative mechanism.","method":"Transaortic constriction heart failure model, Fgf13 KO, calcium imaging, patch-clamp, Western blotting, surface fractionation, rescue with wild-type vs tubulin-binding mutant FGF13","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific rescue with mutant, direct Ca2+ imaging, single lab","pmids":["38821375"],"is_preprint":false},{"year":2021,"finding":"FGF13 enhances resistance to platinum drugs (cisplatin) in cancer cells by regulating the expression and subcellular distribution of copper transporter hCTR1 and copper-transporting ATPase ATP7A, causing reduced platinum influx and promoting platinum sequestration/efflux. This effect requires the FGF13 microtubule-stabilizing domain; only FGF13 with an intact -SMIYRQQQ- tubulin-binding domain confers platinum resistance.","method":"FGF13 overexpression/knockdown in multiple cancer cell lines, platinum uptake assays, subcellular fractionation of hCTR1/ATP7A, domain mutant rescue experiments","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — domain-specific mutant identifying tubulin-binding requirement, transporter redistribution assays, multiple cell lines, single lab","pmids":["34533854"],"is_preprint":false},{"year":2025,"finding":"FGF13 is not secreted from neurons; it lacks a signal sequence and remains intracellular. Using rigorous controls, neither transfected FGF13 in heterologous cells nor endogenous FGF13 from cultured neurons was detected in conditioned medium. Proximity labeling proteomics confirmed FGF13 remains membrane-associated and inaccessible for interaction with extracellular protein domains.","method":"Conditioned medium collection from transfected cells and cultured neurons with positive/negative controls, proximity labeling proteomics (BioID/APEX), Western blotting","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous secretion controls, proximity proteomics, peer-reviewed with corroborating preprint (same lab), multiple orthogonal methods confirming negative result","pmids":["41289026"],"is_preprint":false},{"year":2025,"finding":"FGF13 interacts with MCHT2 (a mitochondrial outer membrane protein) to anchor mitochondria in the neuronal cytoplasm. Under PD-related stress, decreased FGF13 induces release of damaged mitochondria that activate microglia and astrocytes, promoting neurodegeneration.","method":"Co-immunoprecipitation (FGF13-MCHT2), Fgf13 overexpression in PD mouse models, glia-neuron co-culture assays, mitochondria transfer assays","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP identifying binding partner, functional co-culture assay, single lab","pmids":["40344619"],"is_preprint":false},{"year":2025,"finding":"The FGF13/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception. PW164, an FGF13/Nav1.7 C-terminal tail domain PPI inhibitor, selectively suppresses Na+ currents sensitized by TRPV1 activation in hIPSC-derived sensory neurons and reduces mechanical and thermal hyperalgesia in mice. ZL192, a ligand stabilizing FGF13/Nav1.7 assembly, sensitizes Na+ currents and produces pronociceptive behavior. FGF13 silencing mimics PW164. In T2DN, the FGF13/Nav1.7 protein ratio is upregulated in donor DRG neurons.","method":"Small molecule PPI inhibitor/stabilizer, hIPSC-derived sensory neurons (patch-clamp), FGF13 siRNA knockdown in culture and in vivo, mouse behavioral assays, donor DRG protein quantification","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — pharmacological PPI inhibitor and stabilizer with mirror-image effects, siRNA validation, hIPSC human neurons, in vivo mouse models, and patient-derived tissue confirmation","pmids":["40662354"],"is_preprint":false},{"year":2025,"finding":"FGF13 regulates Caveolin-1 (Cav1) promoter activity and expression through the p38/MAPK pathway and nuclear translocation of p65, as well as by modulating PTRF binding to Cav1, thereby mediating cardiomyocyte senescence. FGF13 overexpression exacerbates and deficiency alleviates doxorubicin/D-galactose-induced premature cardiac aging. FGF13 regulates a Cav1-p53-p21 axis.","method":"AAV9-FGF13 overexpression, cardiac-specific Fgf13 KO mice, transcriptomics, luciferase reporter (Cav1 promoter), co-immunoprecipitation (PTRF-Cav1), p38/MAPK pathway inhibition","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — promoter reporter assay, co-IP, gain/loss-of-function in vivo, single lab","pmids":["40184605"],"is_preprint":false},{"year":2024,"finding":"Cardiac fibrosis induced by pressure overload (TAC) is reduced by Fgf13 deletion. TGFβ-stimulated cardiac fibroblasts show increased collagen and α-SMA expression that is reduced by Fgf13 knockdown. The anti-fibrotic effect of FGF13 loss requires microtubule destabilization; wild-type FGF13 but not a microtubule-binding-deficient mutant rescues fibrosis markers. Fgf13 knockdown decreases ROCK protein expression via microtubule disruption.","method":"TAC mouse model, cardiac fibroblast culture, siRNA/overexpression with wild-type vs. tubulin-binding mutant FGF13, Western blotting for fibrosis markers and ROCK","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — domain-specific mutant rescue, in vivo and in vitro models, single lab","pmids":["38818580"],"is_preprint":false},{"year":2020,"finding":"FGF13 interacts with SHCBP1 in A549 lung cancer cells (confirmed by co-immunoprecipitation), and FGF13-SHCBP1 interaction cooperatively activates the AKT-GSK3α/β signaling pathway and inhibits p21/p27 to promote cell cycle G1-to-S transition and cell proliferation.","method":"Co-immunoprecipitation, Western blotting, cell cycle analysis by flow cytometry, CCK-8 proliferation assay","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP identifying binding partner, single lab, limited mechanistic follow-up","pmids":["33064958"],"is_preprint":false},{"year":2026,"finding":"FGF13 directly interacts with TUBB2A (a microtubule β-tubulin) as shown by co-immunoprecipitation. FGF13 methylation reduces this interaction. Overexpression of FGF13 improves microtubule stability and mitochondrial function in hippocampal neurons in an Alzheimer's disease mouse model; these protective effects are reversed by TUBB2A knockdown, placing FGF13 upstream of TUBB2A in microtubule stability maintenance.","method":"Co-immunoprecipitation (FGF13-TUBB2A), Methylation-Specific PCR, FGF13 overexpression in Aβ25-35 hippocampal injection AD model, TUBB2A knockdown epistasis, mitochondrial membrane potential/ROS assays","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP identifying binding partner with epistasis rescue experiment, in vivo AD model, single lab","pmids":["41808420"],"is_preprint":false},{"year":2023,"finding":"FHF2 (FGF13) is highly phosphorylated in native cardiac NaV1.5 channel complexes at nine phosphorylation sites identified by phosphoproteomics. FHF2 knockdown in adult cardiomyocytes increases late Na+ current and alters NaV channel inactivation rates; FHF2-VY isoform restores these effects. No specific phosphosite roles in NaV1.5 regulation could be identified (each phosphomutant rescued similarly to WT).","method":"Phosphoproteomic analysis of NaV channel complexes from mouse left ventricles, neonatal and adult cardiomyocyte knockdown/rescue models, patch-clamp electrophysiology","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — native phosphoproteomics identifying sites, electrophysiology in native cells, isoform-specific rescue; phosphosite functional roles inconclusive (negative finding for individual sites)","pmids":["36778222"],"is_preprint":true}],"current_model":"FGF13 (FHF2) is a nonsecreted, intracellular auxiliary subunit that directly binds the cytoplasmic C-terminus of voltage-gated sodium channels (Nav1.5, Nav1.6, Nav1.7) to regulate multiple aspects of channel gating (inactivation rate, steady-state availability, late current) in a manner dependent on local membrane cholesterol rather than solely on direct binding; it also regulates VGSC membrane localization via microtubule-dependent trafficking and by maintaining polarized cholesterol distribution at the intercalated disc; beyond VGSCs, FGF13 controls somatodendritic endocytosis of sodium channels, modulates Cx43 gap junction trafficking, acts as a negative regulator of caveolae abundance through cavin-1 redistribution, stabilizes microtubules to influence calcium channel localization, Ito K+ current, and cisplatin transporter trafficking, interacts with nuclear partners (p65/NF-κB and ARID1B/BAF complex) to regulate hypertrophic and neurogenic gene programs, interacts with Nav1.7 in a heat- and histamine-facilitated manner to sustain nociceptive firing, and anchors mitochondria in neurons via binding to the outer mitochondrial membrane protein MCHT2."},"narrative":{"mechanistic_narrative":"FGF13 (FHF2) is a nonsecreted, intracellular protein that functions as an auxiliary subunit of voltage-gated sodium channels (VGSCs) and as a multifunctional regulator of channel trafficking, microtubule stability, and gene expression across cardiac, sensory, and central neurons [PMID:27044086, PMID:41289026]. It binds directly to the cytoplasmic C-terminus of Nav1.5, Nav1.6, and Nav1.7, and through splice isoform-specific effects tunes current density, fast and slow inactivation, steady-state availability, and recovery from inactivation [PMID:27246624, PMID:31223136, PMID:27999940]. In heart, FGF13 sustains sodium current and conduction—its loss accelerates channel inactivation, reduces peak current, prolongs QRS, and produces temperature-sensitive conduction failure [PMID:28119060, PMID:27701382], with conduction further compromised by interdependence between reduced Nav availability, calcium current, and gap-junctional coupling [PMID:32962518]. A separation-of-function mechanism shows that FGF13 regulates Nav1.5 steady-state inactivation indirectly by maintaining polarized accessible membrane cholesterol at the intercalated disc rather than solely through direct channel binding [PMID:40794434], and it directs Cx43 gap junction trafficking through microtubule-dependent, VGSC-independent routes [PMID:41200819]. In sensory neurons, FGF13 binds Nav1.7 in a heat- and histamine-facilitated manner to sustain nociceptive and pruriceptive firing, and disruption or stabilization of this interaction bidirectionally controls pain and itch behavior [PMID:28162808, PMID:33172979, PMID:40662354]. Through a conserved tubulin-binding domain FGF13 stabilizes microtubules to control trafficking of diverse cargoes including Kv4.2/4.3 channels, Cav1.2, TRPV1, and platinum transporters [PMID:28119060, PMID:38733310, PMID:38821375, PMID:34533854]. Nuclear FGF13 isoforms additionally regulate transcriptional programs—repressing ribosomal RNA synthesis in the nucleolus [PMID:27994142], activating NF-κB via direct p65 binding in cardiac hypertrophy [PMID:33089113], and interacting with the BAF subunit ARID1B to maintain neural stem cell self-renewal [PMID:34010636]. FGF13 deficiency causes hyperthermia-induced seizures via excitatory-inhibitory imbalance [PMID:26063919], with interneuron-specific loss producing sodium-channel-independent seizures through reduced K+ currents [PMID:39773461]; missense variants in FHF2A cause developmental and epileptic encephalopathy [PMID:33245860], and a 5'-UTR variant impairing PTBP2-dependent translation causes neuronal migration defects and cognitive deficits [PMID:34184986].","teleology":[{"year":2016,"claim":"Established that FGF13 directly binds VGSCs and, in concert with FGF14, polarizes sodium channel distribution within neurons—defining its role as a trafficking and localization regulator rather than only a gating modulator.","evidence":"Knockdown and interaction-abolishing mutagenesis in hippocampal neurons with immunofluorescence and electrophysiology","pmids":["27044086"],"confidence":"High","gaps":["Mechanism by which FGF13 restricts somatodendritic localization not resolved at the molecular level","Did not address cardiac or sensory neuron contexts"]},{"year":2016,"claim":"Showed that distinct FGF13 splice isoforms differentially shape Nav1.5 gating, establishing isoform identity as a determinant of channel behavior.","evidence":"Heterologous HEK293 expression with isoform-specific constructs and whole-cell voltage-clamp","pmids":["27246624"],"confidence":"High","gaps":["Heterologous system may not reflect native stoichiometry","Physiological relevance of FGF13S slow-inactivation effect in vivo not tested"]},{"year":2016,"claim":"Demonstrated that FGF13 loss produces temperature-sensitive cardiac conduction failure via accelerated sodium channel inactivation, linking the subunit to thermal stability of cardiac excitability.","evidence":"Fhf2 knockout mice, temperature-series patch-clamp, ECG, and computational modeling","pmids":["27701382"],"confidence":"High","gaps":["Did not address contribution of non-VGSC mechanisms to conduction"]},{"year":2015,"claim":"Linked FGF13 to seizure susceptibility, showing heterozygous loss causes hyperthermia-induced seizures through synaptic excitatory-inhibitory imbalance.","evidence":"Fgf13 knockout mice with hippocampal mIPSC/mEPSC recordings and hyperthermia seizure induction","pmids":["26063919"],"confidence":"High","gaps":["Cell-type origin of E/I imbalance not resolved in this study","Molecular mechanism connecting FGF13 to synaptic inputs unclear"]},{"year":2017,"claim":"Defined FGF13's cardiac phenotype—reduced Na+ current, inactivation shift, QRS prolongation—and revealed an unexpected role in surface localization of Kv4.2/4.3, expanding its function to K+ channel trafficking.","evidence":"Inducible cardiomyocyte-restricted Fgf13 KO mice with electrophysiology, ECG, and surface fractionation","pmids":["28119060"],"confidence":"High","gaps":["Mechanism of Kv4 surface regulation not defined at the time","Whether trafficking effect is direct unaddressed"]},{"year":2017,"claim":"Established FGF13 as required for heat nociception by maintaining Nav1.7 currents and membrane localization in a heat-facilitated interaction, providing a druggable PPI target for pain.","evidence":"DRG-conditional KO mice, co-IP, patch-clamp, competitive peptide disruption, and behavioral assays","pmids":["28162808"],"confidence":"High","gaps":["Molecular basis of heat-facilitation of the interaction not defined","Whether peptide effects are Nav1.7-specific in vivo not fully resolved"]},{"year":2017,"claim":"Connected FGF13 to disease-relevant channel dysregulation by showing CaMKII-driven phosphorylation of Nav1.5 disrupts FGF13 binding and downstream calmodulin recruitment, defining a pathway altered in failing hearts.","evidence":"Phosphoproteomics of native Nav1.5, phosphomimetic mutants, voltage-clamp, and co-IP","pmids":["28882890"],"confidence":"High","gaps":["In vivo significance of the two phosphosites not tested","Structural basis of FGF13-calmodulin cooperativity unresolved"]},{"year":2016,"claim":"Identified a nuclear, growth-suppressive role for the FGF13 1A isoform in repressing rRNA transcription within a p53 feedback loop, distinguishing nuclear from channel-associated functions.","evidence":"Subcellular fractionation, rRNA transcription assays, siRNA depletion with apoptosis readout, and p53 ChIP","pmids":["27994142"],"confidence":"Medium","gaps":["Direct mechanism of rRNA repression by FGF13 1A unknown","Single-lab finding"]},{"year":2016,"claim":"Resolved opposing isoform effects on Nav1.6 resurgent current, showing FHF2A and FHF2B regulate sensory excitability in antagonistic directions.","evidence":"DRG and heterologous patch-clamp with isoform-specific and chimeric constructs","pmids":["27999940"],"confidence":"Medium","gaps":["Single lab","In vivo pain relevance of resurgent-current modulation not established"]},{"year":2017,"claim":"Revealed a VGSC-independent cardiac function: FGF13 negatively regulates caveolae abundance by controlling cavin-1 distribution, conferring protection against pressure overload.","evidence":"Cardiac Fgf13 KO mice, interactome screen/co-IP, fractionation, EM, and pressure overload model","pmids":["28461495"],"confidence":"High","gaps":["Mechanism by which FGF13 controls cavin-1 partitioning not defined","Link between caveolae and protection partly correlative"]},{"year":2019,"claim":"Confirmed isoform-dependent FHF2 regulation of Nav1.7 in both native and heterologous cells, reinforcing isoform-specific control of sensory channel availability.","evidence":"Co-IP/immunohistochemistry in DRG with patch-clamp and knockdown","pmids":["31223136"],"confidence":"High","gaps":["Structural determinants of isoform-specific effects not mapped"]},{"year":2020,"claim":"Identified nuclear FGF13 as a direct activator of NF-κB via p65 binding through an IκB-independent route, linking the protein to hypertrophic gene programs.","evidence":"Co-IP, confocal co-localization, gain/loss-of-function in cardiomyocytes/TAC, and NF-κB reporter","pmids":["33089113"],"confidence":"Medium","gaps":["Mechanism of IκB-independent activation unclear","Single lab"]},{"year":2020,"claim":"Established FGF13 missense variants as a cause of developmental and epileptic encephalopathy through selective loss of Nav1.6 long-term blockade with retained pro-excitatory effects.","evidence":"Whole-exome sequencing and functional patch-clamp of mutant FHF2A co-expressed with Nav1.6","pmids":["33245860"],"confidence":"High","gaps":["In vivo neuronal consequences of variants not modeled","Single lab functional characterization"]},{"year":2020,"claim":"Showed conduction failure in FHF2-deficient cardiac strands arises from combined Nav and gap-junctional deficits, integrating ionic and electrotonic determinants of propagation.","evidence":"Fhf2 KO with pharmacology, Cx43-heterozygous cross, multicellular modeling, and optical mapping","pmids":["32962518"],"confidence":"High","gaps":["Mechanistic basis of reduced gap-junctional conductance not defined here"]},{"year":2020,"claim":"Extended FGF13/Nav1.7's sensory role to itch, showing histamine enhances the interaction in an isoform-dependent manner to drive pruriception.","evidence":"DRG-specific KO mice, co-IP, calcium imaging, competitive peptide, and behavior","pmids":["33172979"],"confidence":"High","gaps":["Molecular basis of histamine-facilitated binding unresolved"]},{"year":2021,"claim":"Linked FGF13 to neurodevelopment by showing a 5'-UTR variant impairs PTBP2-dependent translation, reducing microtubule stabilization and causing migration and cognitive deficits.","evidence":"Patient iPSCs, translation assays, PTBP2 pulldown, knockin mice, and microtubule polymerization assays","pmids":["34184986"],"confidence":"High","gaps":["Whether migration defect reflects loss of channel or microtubule function not fully separated"]},{"year":2021,"claim":"Defined a chromatin-level function: nuclear FGF13A binds the BAF subunit ARID1B to suppress neuronal differentiation genes and maintain neural stem cell self-renewal.","evidence":"Fgf13 conditional KO, co-IP, ChIP, neurogenesis assays, and RNA-seq","pmids":["34010636"],"confidence":"Medium","gaps":["Direct chromatin targets and how FGF13A is recruited not fully defined","Single lab"]},{"year":2021,"claim":"Established that FGF13's tubulin-binding domain drives chemoresistance by redistributing platinum transporters, generalizing the microtubule-trafficking function to cancer pharmacology.","evidence":"Overexpression/knockdown in cancer cell lines, platinum uptake assays, fractionation, and domain-mutant rescue","pmids":["34533854"],"confidence":"Medium","gaps":["In vivo relevance and clinical correlation limited","Single lab"]},{"year":2023,"claim":"Confirmed FHF2 is extensively phosphorylated in native cardiac Nav1.5 complexes and modulates late current, but individual phosphosites were not assignable to specific functions.","evidence":"Phosphoproteomics of native Nav complexes with cardiomyocyte knockdown/rescue (preprint)","pmids":["36778222"],"confidence":"Medium","gaps":["Functional role of individual phosphosites inconclusive (negative result)","Preprint, not peer reviewed"]},{"year":2023,"claim":"Placed FGF13 upstream of Parkin in glomerular endothelial mitochondrial homeostasis, showing its deficiency improves mitophagy in diabetic nephropathy.","evidence":"Endothelial-specific Fgf13 and double Fgf13/Prkn KO mice with mitophagy and apoptosis assays","pmids":["36256844"],"confidence":"Medium","gaps":["Direct molecular link between FGF13 and Parkin not defined","Single lab"]},{"year":2024,"claim":"Showed FGF13 microtubule stabilization impairs cardiac calcium handling in heart failure by reducing Cav1.2 surface localization and Serca2α, identified via domain-mutant rescue.","evidence":"TAC heart failure model, Fgf13 KO, calcium imaging, patch-clamp, and tubulin-binding mutant rescue","pmids":["38821375"],"confidence":"Medium","gaps":["Mechanism linking microtubule stability to Serca2α expression unclear","Single lab"]},{"year":2024,"claim":"Demonstrated FGF13 selectively enhances TRPV1 (not TRPA1) function via its microtubule-stabilizing domain to drive itch behaviors.","evidence":"DRG-specific KO, calcium imaging, patch-clamp, and tubulin-binding mutant rescue with behavior","pmids":["38733310"],"confidence":"Medium","gaps":["Basis of TRPV1-versus-TRPA1 selectivity unresolved","Single lab"]},{"year":2024,"claim":"Linked FGF13 microtubule function to cardiac fibrosis, showing its loss reduces fibrosis via microtubule destabilization and decreased ROCK.","evidence":"TAC model, fibroblast culture, and tubulin-binding mutant rescue of fibrosis markers","pmids":["38818580"],"confidence":"Medium","gaps":["Mechanism linking microtubule disruption to ROCK downregulation unclear","Single lab"]},{"year":2025,"claim":"Separated FGF13's regulation of cardiac conduction from VGSC binding, showing it controls Cx43 gap junction trafficking through microtubule-dependent mechanisms.","evidence":"Cardiac Fgf13 KO, optical mapping, proximity proteomics, and VGSC-binding-incompetent mutant rescue","pmids":["41200819"],"confidence":"High","gaps":["How FGF13 directs Cx43 to the intercalated disc mechanistically not fully resolved"]},{"year":2025,"claim":"Revealed that FGF13 regulates Nav1.5 steady-state inactivation indirectly by maintaining polarized accessible membrane cholesterol at the intercalated disc, overturning a purely direct-binding model.","evidence":"Fgf13-KO cardiomyocytes, binding-incompetent mutant rescue, cholesterol imaging, and patch-clamp","pmids":["40794434"],"confidence":"High","gaps":["Mechanism by which FGF13 maintains cholesterol polarization not defined"]},{"year":2025,"claim":"Distinguished cell-type-specific seizure mechanisms, showing interneuron Fgf13 loss causes sodium-channel-independent seizures through reduced K+ currents.","evidence":"Interneuron- versus excitatory-neuron-specific conditional KO mice with patch-clamp and isoform rescue","pmids":["39773461"],"confidence":"High","gaps":["Identity of the affected K+ channels not defined","Mechanism of K+ current regulation unclear"]},{"year":2025,"claim":"Definitively established FGF13 as nonsecreted and intracellular, constraining all proposed functions to intracellular and membrane-associated compartments.","evidence":"Conditioned-medium analysis with rigorous controls and proximity labeling proteomics","pmids":["41289026"],"confidence":"High","gaps":["Does not address possible non-canonical release under specific stress conditions"]},{"year":2025,"claim":"Advanced FGF13/Nav1.7 as a bidirectional therapeutic target, with PPI inhibitor and stabilizer producing mirror-image analgesic and pronociceptive effects in human neurons and mice.","evidence":"Small-molecule PPI inhibitor/stabilizer, hIPSC sensory neurons, siRNA, mouse behavior, and donor DRG tissue","pmids":["40662354"],"confidence":"High","gaps":["Selectivity of compounds for FGF13/Nav1.7 over other FHF/Nav pairs not fully defined"]},{"year":2025,"claim":"Identified a mitochondrial anchoring function, with FGF13 binding the outer mitochondrial membrane protein MCHT2 to retain damaged mitochondria and limit neurodegeneration.","evidence":"Co-IP, Fgf13 overexpression in PD models, and glia-neuron co-culture/mitochondria transfer assays","pmids":["40344619"],"confidence":"Medium","gaps":["Direct nature and stoichiometry of FGF13-MCHT2 interaction not detailed","Single lab"]},{"year":2025,"claim":"Connected FGF13 to cardiomyocyte senescence through Cav1 promoter regulation via p38/MAPK and p65, plus PTRF-Cav1 modulation, defining a Cav1-p53-p21 aging axis.","evidence":"AAV9 overexpression, cardiac Fgf13 KO, transcriptomics, Cav1 luciferase reporter, and co-IP","pmids":["40184605"],"confidence":"Medium","gaps":["Relationship between nuclear and trafficking roles in senescence unclear","Single lab"]},{"year":2026,"claim":"Identified TUBB2A as a direct FGF13 partner mediating microtubule stabilization, with FGF13 methylation reducing binding and FGF13 protecting against Alzheimer's-related deficits.","evidence":"Co-IP, methylation-specific PCR, FGF13 overexpression in an Aβ AD model, and TUBB2A knockdown epistasis","pmids":["41808420"],"confidence":"Medium","gaps":["Functional consequence of FGF13 methylation in vivo not established","Single lab"]},{"year":2020,"claim":"Reported FGF13 interaction with SHCBP1 promoting AKT-GSK3 signaling and proliferation in lung cancer cells.","evidence":"Co-IP, Western blotting, flow cytometry cell cycle, and proliferation assays","pmids":["33064958"],"confidence":"Low","gaps":["Single co-IP without reciprocal validation or in vivo confirmation","Direct versus indirect interaction not established"]},{"year":null,"claim":"How FGF13's distinct mechanistic modules—direct channel binding, microtubule stabilization, membrane cholesterol polarization, and nuclear transcriptional regulation—are partitioned by isoform, post-translational modification, and cell type into coherent physiological outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model integrating channel-binding and microtubule-binding domains","Determinants directing FGF13 isoforms to nuclear versus membrane functions undefined","Mechanism of cholesterol polarization at the intercalated disc unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,3,4,11,16]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,22,23,30]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,9,19]},{"term_id":"GO:0060089","term_label":"molecular transducer 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(Transcription)","supporting_discovery_ids":[9,19]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,15,22,23]}],"complexes":["Nav1.5 channel complex","Nav1.7 channel complex","BAF chromatin remodeling complex"],"partners":["SCN5A","SCN8A","SCN9A","CAV1","PTRF","ARID1B","RELA","TUBB2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92913","full_name":"Fibroblast growth factor 13","aliases":["Fibroblast growth factor homologous factor 2","FHF-2"],"length_aa":245,"mass_kda":27.6,"function":"Microtubule-binding protein which directly binds tubulin and is involved in both polymerization and stabilization of microtubules (By similarity). 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Together, FGF13 and FGF14 act concertedly to polarize VGSC distribution to the axon initial segment.\",\n      \"method\": \"Knockdown in hippocampal neurons, in vitro VGSC-interaction mutagenesis, immunofluorescence localization, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown, mutagenesis abolishing interaction, direct localization experiments with functional consequence, replicated across two homologous proteins\",\n      \"pmids\": [\"27044086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF13 interacts with Nav1.7 in DRG neurons in a heat-facilitated manner, increases Nav1.7 sodium currents, and maintains membrane localization of Nav1.7 during noxious heat stimulation, enabling sustained action potential firing required for heat nociception. Loss of FGF13 in DRG neurons selectively abolishes heat nociception. Disruption of the FGF13/Nav1.7 interaction with a competitive peptide reduces heat-evoked action potential firing and nociceptive behavior.\",\n      \"method\": \"Conditional knockout mice, co-immunoprecipitation, patch-clamp electrophysiology, competitive peptide disruption, behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with specific phenotype, co-IP of interaction, peptide disruption confirming mechanism, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28162808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Cardiac FGF13 directly binds to the C-terminus of NaV1.5, and different FGF13 splice variants (FGF13S, FGF13U, FGF13VY) differentially modulate NaV1.5 current density, fast inactivation (open-state and closed-state), steady-state availability, and slow inactivation. FGF13S uniquely hastens slow inactivation entry and dramatically slows recovery, causing large current reduction at high frequency stimulation.\",\n      \"method\": \"Heterologous expression in HEK293 cells, whole-cell voltage-clamp electrophysiology, isoform-specific expression constructs\",\n      \"journal\": \"Channels (Austin, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct electrophysiological in vitro assay with multiple isoforms and multiple gating parameters, single lab but multiple orthogonal measurements\",\n      \"pmids\": [\"27246624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cardiac-specific Fgf13 knockout reduces peak Na+ channel current density (~25%), causes a hyperpolarizing shift in steady-state inactivation, prolongs QRS duration, and reduces transient outward K+ current (Ito) by decreasing Kv4.2 and Kv4.3 sarcolemmal localization without altering their total protein levels. Voltage-gated Ca2+ current was not affected.\",\n      \"method\": \"Inducible cardiomyocyte-restricted Fgf13 knockout mice, patch-clamp electrophysiology, ECG recording, immunoblotting, surface fractionation\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple defined ionic phenotypes, surface vs total protein biochemistry, ECG and electrophysiology in same model\",\n      \"pmids\": [\"28119060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mice lacking FHF2 (FGF13) show normal cardiac rhythm at baseline but develop temperature-sensitive cardiac conduction failure at elevated temperatures. Absence of FHF2 accelerates both closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation to severely suppress cardiac sodium currents at elevated temperatures.\",\n      \"method\": \"Fhf2 knockout mice, patch-clamp electrophysiology at multiple temperatures, ECG recording, computational modeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO model with defined ionic mechanism (inactivation rate), temperature-series electrophysiology, computational validation, multiple orthogonal methods\",\n      \"pmids\": [\"27701382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 (PTRF) between the sarcolemma and cytosol. In cardiac Fgf13 knockout mice, cavin 1 redistributes to the sarcolemma, stabilizes caveolin 3, increases caveolae density, and confers protection against pressure overload-induced cardiac dysfunction. The full FGF13 interactome in cardiomyocytes was found to include the complete set of cavin family caveolar coat proteins.\",\n      \"method\": \"Inducible cardiac-specific Fgf13 knockout mice, co-immunoprecipitation/interactome screen, biochemical fractionation, electron microscopy for caveolae density, cardiac pressure overload model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, biochemical fractionation, KO model with functional cardiac readout, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"28461495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Disruption of Fgf13 in female mice (heterozygous deletion) causes hyperthermia-induced seizures and epilepsy associated with a synaptic excitatory-inhibitory imbalance: decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons.\",\n      \"method\": \"Fgf13 knockout mice, hippocampal electrophysiological recordings (miniature IPSCs and EPSCs), hyperthermia seizure induction\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined genetic model, direct electrophysiological measurement of E/I balance, specific seizure phenotype with mechanistic readout\",\n      \"pmids\": [\"26063919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"C-terminal phosphorylation of NaV1.5 at Ser1938 and Ser1989 (increased in CaMKIIδc-overexpressing failing hearts) abrogates FGF13-dependent regulation of NaV1.5 channel inactivation. FGF13 normally increases NaV1.5 channel availability and decreases late Na+ current; phosphomimetic mutations at both sites abolish these effects by reducing FGF13 binding to NaV1.5 and consequently reducing calmodulin recruitment to NaV1.5. FGF13 was shown to potentiate calmodulin binding to NaV1.5.\",\n      \"method\": \"Phosphoproteomics of purified NaV1.5 from WT and CaMKIIδc-Tg mouse ventricles, whole-cell voltage-clamp in HEK293 cells, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — phosphoproteomics identifying native sites, functional validation by electrophysiology with phosphomimetic mutants, co-IP showing altered binding, multiple orthogonal methods\",\n      \"pmids\": [\"28882890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGF13 directly interacts with p65 (NF-κB subunit) via its nuclear localization sequence, co-localizes with p65 in the nucleus in cardiac hypertrophy, and activates NF-κB signaling by an IκB-independent mechanism. FGF13 deficiency inhibits NF-κB activation and overexpression alone is sufficient to activate NF-κB in cardiomyocytes.\",\n      \"method\": \"Co-immunoprecipitation, confocal co-localization, gain- and loss-of-function in cardiomyocytes and TAC mouse model, NF-κB reporter assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP binding, gain/loss-of-function with reporter assay, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33089113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FGF13 1A isoform localizes to the nucleolus and represses ribosomal RNA transcription, attenuating protein synthesis. The FGF13 locus (encompassing FGF13 and miR-504) is transcriptionally repressed by p53, defining a negative feedback loop. In cancer cells expressing high FGF13, its depletion causes proteostasis stress, reactive oxygen species accumulation, and apoptosis.\",\n      \"method\": \"Subcellular fractionation/confocal microscopy for nucleolar localization, ribosomal RNA transcription assays, siRNA depletion with apoptosis readout, p53 chromatin immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization experiment, functional transcription assay, loss-of-function with mechanistic readout, single lab\",\n      \"pmids\": [\"27994142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF13 stabilizes microtubules in developing cortical neurons. A 5'-UTR SNP (c.-32C>G) in FGF13 reduces translation of FGF13 by impairing its interaction with polypyrimidine-tract-binding protein 2 (PTBP2), which is required for FGF13 translation in cortical neurons. Reduced FGF13 causes delayed neuronal migration and cognitive deficits.\",\n      \"method\": \"Patient-derived iPSCs and HEK293 cell translation assays, RNA-binding protein pulldown (PTBP2), knockin mice carrying homologous 5'-UTR point mutation, microtubule polymerization assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro translation assays, RNA-binding pulldown identifying PTBP2 as reader, knockin mouse model with neuronal migration phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"34184986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FHF2 (FGF13) isoforms FHF2A and FHF2B associate with Nav1.7 in DRG neurons and regulate its current properties in an isoform-dependent manner. FHF2A causes accumulation of inactivated channels and slows recovery from inactivation, while FHF2B depolarizes activation. Effects were confirmed by FHF2 knockdown in DRG neurons.\",\n      \"method\": \"Co-immunoprecipitation/immunohistochemistry in DRG neurons, whole-cell patch-clamp in HEK293-Nav1.7 cells and DRG neurons with FHF2 knockdown\",\n      \"journal\": \"Neurobiology of pain (Cambridge, Mass.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct association demonstrated, isoform-specific electrophysiology in both heterologous and native cells, knockdown confirmation\",\n      \"pmids\": [\"31223136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FHF2A (FGF13A) negatively regulates Nav1.6-mediated resurgent sodium currents in DRG neurons by enhancing long-term inactivation and delaying recovery, while FHF2B positively regulates resurgent current. Chimeric FHF2A/Navβ4 constructs revealed distinct regulatory regions. FHF2A and FHF2B isoform expression is differentially regulated in a radicular pain model.\",\n      \"method\": \"Whole-cell patch-clamp in DRG neurons and heterologous cells, FHF2 isoform-specific expression/knockdown, chimeric construct analysis\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology in native and heterologous cells, isoform-specific and chimeric constructs, single lab\",\n      \"pmids\": [\"27999940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Missense variants in the N-terminal domain of FHF2A (FGF13 A isoform) cause loss of the ability to induce rapid-onset, long-term blockade of Nav1.6 (SCN8A) channels while retaining pro-excitatory properties, resulting in gain-of-function neuronal hyperexcitability consistent with developmental and epileptic encephalopathy.\",\n      \"method\": \"Whole-exome sequencing identifying variants, functional characterization by co-expression of mutant FHF2A with Nav1.6 in heterologous cells (whole-cell patch-clamp)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct in vitro electrophysiological characterization of mutant proteins with wild-type Nav1.6, multiple patient variants tested, single lab\",\n      \"pmids\": [\"33245860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FHF2-deficient cardiomyocytes show that reduced Nav availability shifts dependence onto calcium current (ICa) to sustain electrotonic driving force and action potential propagation from cell-to-cell. Diminished gap junctional conductance (Gj) conspires with accelerated Nav inactivation in FHF2-deficient strands to prevent sufficient downstream cell charging for action potential propagation.\",\n      \"method\": \"Fhf2 knockout mice, pharmacological reduction of gCaL (verapamil) or Gj (carbenoxolone), Cx43-heterozygous backcross, multicellular linear strand computational modeling, optical mapping\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model combined with pharmacology and computational modeling confirming ionic mechanism, multiple orthogonal perturbations\",\n      \"pmids\": [\"32962518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGF13 regulates cardiac impulse propagation via a VGSC-independent mechanism by controlling microtubule-dependent trafficking and targeting of Cx43 (connexin 43) gap junctions. FGF13 ablation destabilizes microtubules, reduces MAP4 expression, perturbs Cx43 trafficking to the intercalated disc, increases Cx43 hemichannels, and depolarizes resting membrane potential. A mutant FGF13 incapable of binding VGSCs fully restores these defects, demonstrating VGSC independence.\",\n      \"method\": \"Cardiac-specific Fgf13 KO mice, optical mapping, pharmacological gap junction/hemichannel manipulation, proximity labeling proteomics, immunostaining, VGSC-binding-incompetent FGF13 mutant rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — separation-of-function mutant, proximity proteomics, optical mapping, pharmacology, and rescue experiments in one rigorous study\",\n      \"pmids\": [\"41200819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGF13 regulation of NaV1.5 steady-state inactivation (SSI) is mediated through effects on local accessible membrane cholesterol rather than through direct channel binding. A binding-incompetent FGF13 mutant (structurally guided) still completely restores WT regulation of SSI in Fgf13-KO cardiomyocytes. FGF13 maintains polarized cholesterol distribution concentrated at the intercalated disc where VGSCs localize; Fgf13-KO eliminates this cholesterol polarization and causes VGSC loss from the intercalated disc.\",\n      \"method\": \"Fgf13-KO cardiomyocytes, binding-incompetent FGF13 mutant rescue, cholesterol labeling/filipin staining, patch-clamp electrophysiology, proximity labeling proteomics\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — separation-of-function mutant, direct cholesterol imaging, electrophysiology in native KO cells, multiple orthogonal methods revealing novel mechanism\",\n      \"pmids\": [\"40794434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Interneuron-specific deletion of Fgf13 causes perinatal mortality with extensive seizures and impaired hippocampal inhibitory/excitatory balance, while excitatory neuron-targeted deletion causes no seizures. The seizure mechanism in interneurons is sodium channel-independent; instead, Fgf13 ablation in interneurons markedly reduces K+ channel currents. Re-expression of different Fgf13 splice isoforms partially rescues interneuron excitability deficits and restores K+ current amplitude.\",\n      \"method\": \"Cell-type-specific conditional Fgf13 knockout mice (interneuron vs. excitatory neuron Cre lines), patch-clamp electrophysiology, isoform rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell-type-specific KO models, direct ionic current measurements, isoform rescue, replicated across preprint and peer-reviewed publication\",\n      \"pmids\": [\"39773461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGF13 is required for histamine-induced itch sensation in DRG neurons. Histamine enhances the FGF13/Nav1.7 interaction. Disruption of FGF13/Nav1.7 interaction by a membrane-permeable competitive peptide (GST-Flag-NaV1.7CT-TAT) reduces histamine-responsive DRG neurons and impairs scratching behavior. The histamine-evoked neuronal response is primarily mediated via H1R and is FGF13B isoform-dependent.\",\n      \"method\": \"DRG-specific Fgf13 KO mice, co-immunoprecipitation, calcium imaging, electrophysiology, competitive peptide disruption, behavioral assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with specific behavioral phenotype, co-IP demonstrating histamine-enhanced interaction, competitive peptide validation, multiple orthogonal methods\",\n      \"pmids\": [\"33172979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF13A (nuclear isoform) interacts with ARID1B, a subunit of the Brahma-associated factor (BAF) chromatin remodeling complex, in hippocampal neural stem cells, and suppresses expression of neuronal differentiation-associated genes through chromatin modification, thereby maintaining neural stem cell self-renewal and suppressing neuronal differentiation during postnatal hippocampal neurogenesis.\",\n      \"method\": \"Fgf13 conditional knockout mice, co-immunoprecipitation (FGF13A-ARID1B), chromatin immunoprecipitation, hippocampal neurogenesis assays, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP identifying nuclear binding partner, ChIP showing chromatin modification, KO with neurogenesis phenotype, single lab\",\n      \"pmids\": [\"34010636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGF13 enhances TRPV1 channel function selectively (not TRPA1) in DRG neurons through its microtubule-stabilizing effect. FGF13 knockout reduces TRPV1-activated calcium influx and current density, impairing histamine-dependent and chronic dry-skin itch behaviors. Only FGF13 containing an intact tubulin-binding domain can rescue TRPV1 function and itch behavior in knockout mice.\",\n      \"method\": \"DRG-specific Fgf13 conditional KO mice, calcium imaging, whole-cell patch-clamp (DRG and HEK cells), rescue with wild-type vs tubulin-binding mutant FGF13, behavioral itch assays\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, electrophysiology, domain-specific rescue, single lab\",\n      \"pmids\": [\"38733310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FGF13 deficiency in glomerular endothelial cells improves mitochondrial homeostasis in diabetic nephropathy through Parkin-dependent regulation of mitophagy promotion and apoptosis inhibition. The beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn (Parkin), placing FGF13 upstream of Parkin in this pathway.\",\n      \"method\": \"Endothelial-specific Fgf13 KO and double Fgf13/Prkn KO mice, mitophagy assays, apoptosis assays, diabetic nephropathy model\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via double KO, multiple cellular readouts, single lab\",\n      \"pmids\": [\"36256844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FGF13 interacts with microtubules in cardiomyocytes and increases microtubule stability during heart failure, impairing calcium signaling by reducing Cav1.2 sarcolemmal localization and Serca2α expression. FGF13 deficiency in heart failure restores calcium transients. Rescue with wild-type FGF13 but not a microtubule-binding-deficient FGF13 mutant recapitulates the calcium dysfunction, confirming that microtubule stabilization is the operative mechanism.\",\n      \"method\": \"Transaortic constriction heart failure model, Fgf13 KO, calcium imaging, patch-clamp, Western blotting, surface fractionation, rescue with wild-type vs tubulin-binding mutant FGF13\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific rescue with mutant, direct Ca2+ imaging, single lab\",\n      \"pmids\": [\"38821375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FGF13 enhances resistance to platinum drugs (cisplatin) in cancer cells by regulating the expression and subcellular distribution of copper transporter hCTR1 and copper-transporting ATPase ATP7A, causing reduced platinum influx and promoting platinum sequestration/efflux. This effect requires the FGF13 microtubule-stabilizing domain; only FGF13 with an intact -SMIYRQQQ- tubulin-binding domain confers platinum resistance.\",\n      \"method\": \"FGF13 overexpression/knockdown in multiple cancer cell lines, platinum uptake assays, subcellular fractionation of hCTR1/ATP7A, domain mutant rescue experiments\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — domain-specific mutant identifying tubulin-binding requirement, transporter redistribution assays, multiple cell lines, single lab\",\n      \"pmids\": [\"34533854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGF13 is not secreted from neurons; it lacks a signal sequence and remains intracellular. Using rigorous controls, neither transfected FGF13 in heterologous cells nor endogenous FGF13 from cultured neurons was detected in conditioned medium. Proximity labeling proteomics confirmed FGF13 remains membrane-associated and inaccessible for interaction with extracellular protein domains.\",\n      \"method\": \"Conditioned medium collection from transfected cells and cultured neurons with positive/negative controls, proximity labeling proteomics (BioID/APEX), Western blotting\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous secretion controls, proximity proteomics, peer-reviewed with corroborating preprint (same lab), multiple orthogonal methods confirming negative result\",\n      \"pmids\": [\"41289026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGF13 interacts with MCHT2 (a mitochondrial outer membrane protein) to anchor mitochondria in the neuronal cytoplasm. Under PD-related stress, decreased FGF13 induces release of damaged mitochondria that activate microglia and astrocytes, promoting neurodegeneration.\",\n      \"method\": \"Co-immunoprecipitation (FGF13-MCHT2), Fgf13 overexpression in PD mouse models, glia-neuron co-culture assays, mitochondria transfer assays\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP identifying binding partner, functional co-culture assay, single lab\",\n      \"pmids\": [\"40344619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The FGF13/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception. PW164, an FGF13/Nav1.7 C-terminal tail domain PPI inhibitor, selectively suppresses Na+ currents sensitized by TRPV1 activation in hIPSC-derived sensory neurons and reduces mechanical and thermal hyperalgesia in mice. ZL192, a ligand stabilizing FGF13/Nav1.7 assembly, sensitizes Na+ currents and produces pronociceptive behavior. FGF13 silencing mimics PW164. In T2DN, the FGF13/Nav1.7 protein ratio is upregulated in donor DRG neurons.\",\n      \"method\": \"Small molecule PPI inhibitor/stabilizer, hIPSC-derived sensory neurons (patch-clamp), FGF13 siRNA knockdown in culture and in vivo, mouse behavioral assays, donor DRG protein quantification\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — pharmacological PPI inhibitor and stabilizer with mirror-image effects, siRNA validation, hIPSC human neurons, in vivo mouse models, and patient-derived tissue confirmation\",\n      \"pmids\": [\"40662354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGF13 regulates Caveolin-1 (Cav1) promoter activity and expression through the p38/MAPK pathway and nuclear translocation of p65, as well as by modulating PTRF binding to Cav1, thereby mediating cardiomyocyte senescence. FGF13 overexpression exacerbates and deficiency alleviates doxorubicin/D-galactose-induced premature cardiac aging. FGF13 regulates a Cav1-p53-p21 axis.\",\n      \"method\": \"AAV9-FGF13 overexpression, cardiac-specific Fgf13 KO mice, transcriptomics, luciferase reporter (Cav1 promoter), co-immunoprecipitation (PTRF-Cav1), p38/MAPK pathway inhibition\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — promoter reporter assay, co-IP, gain/loss-of-function in vivo, single lab\",\n      \"pmids\": [\"40184605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cardiac fibrosis induced by pressure overload (TAC) is reduced by Fgf13 deletion. TGFβ-stimulated cardiac fibroblasts show increased collagen and α-SMA expression that is reduced by Fgf13 knockdown. The anti-fibrotic effect of FGF13 loss requires microtubule destabilization; wild-type FGF13 but not a microtubule-binding-deficient mutant rescues fibrosis markers. Fgf13 knockdown decreases ROCK protein expression via microtubule disruption.\",\n      \"method\": \"TAC mouse model, cardiac fibroblast culture, siRNA/overexpression with wild-type vs. tubulin-binding mutant FGF13, Western blotting for fibrosis markers and ROCK\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — domain-specific mutant rescue, in vivo and in vitro models, single lab\",\n      \"pmids\": [\"38818580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGF13 interacts with SHCBP1 in A549 lung cancer cells (confirmed by co-immunoprecipitation), and FGF13-SHCBP1 interaction cooperatively activates the AKT-GSK3α/β signaling pathway and inhibits p21/p27 to promote cell cycle G1-to-S transition and cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting, cell cycle analysis by flow cytometry, CCK-8 proliferation assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP identifying binding partner, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"33064958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FGF13 directly interacts with TUBB2A (a microtubule β-tubulin) as shown by co-immunoprecipitation. FGF13 methylation reduces this interaction. Overexpression of FGF13 improves microtubule stability and mitochondrial function in hippocampal neurons in an Alzheimer's disease mouse model; these protective effects are reversed by TUBB2A knockdown, placing FGF13 upstream of TUBB2A in microtubule stability maintenance.\",\n      \"method\": \"Co-immunoprecipitation (FGF13-TUBB2A), Methylation-Specific PCR, FGF13 overexpression in Aβ25-35 hippocampal injection AD model, TUBB2A knockdown epistasis, mitochondrial membrane potential/ROS assays\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP identifying binding partner with epistasis rescue experiment, in vivo AD model, single lab\",\n      \"pmids\": [\"41808420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FHF2 (FGF13) is highly phosphorylated in native cardiac NaV1.5 channel complexes at nine phosphorylation sites identified by phosphoproteomics. FHF2 knockdown in adult cardiomyocytes increases late Na+ current and alters NaV channel inactivation rates; FHF2-VY isoform restores these effects. No specific phosphosite roles in NaV1.5 regulation could be identified (each phosphomutant rescued similarly to WT).\",\n      \"method\": \"Phosphoproteomic analysis of NaV channel complexes from mouse left ventricles, neonatal and adult cardiomyocyte knockdown/rescue models, patch-clamp electrophysiology\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — native phosphoproteomics identifying sites, electrophysiology in native cells, isoform-specific rescue; phosphosite functional roles inconclusive (negative finding for individual sites)\",\n      \"pmids\": [\"36778222\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"FGF13 (FHF2) is a nonsecreted, intracellular auxiliary subunit that directly binds the cytoplasmic C-terminus of voltage-gated sodium channels (Nav1.5, Nav1.6, Nav1.7) to regulate multiple aspects of channel gating (inactivation rate, steady-state availability, late current) in a manner dependent on local membrane cholesterol rather than solely on direct binding; it also regulates VGSC membrane localization via microtubule-dependent trafficking and by maintaining polarized cholesterol distribution at the intercalated disc; beyond VGSCs, FGF13 controls somatodendritic endocytosis of sodium channels, modulates Cx43 gap junction trafficking, acts as a negative regulator of caveolae abundance through cavin-1 redistribution, stabilizes microtubules to influence calcium channel localization, Ito K+ current, and cisplatin transporter trafficking, interacts with nuclear partners (p65/NF-κB and ARID1B/BAF complex) to regulate hypertrophic and neurogenic gene programs, interacts with Nav1.7 in a heat- and histamine-facilitated manner to sustain nociceptive firing, and anchors mitochondria in neurons via binding to the outer mitochondrial membrane protein MCHT2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGF13 (FHF2) is a nonsecreted, intracellular protein that functions as an auxiliary subunit of voltage-gated sodium channels (VGSCs) and as a multifunctional regulator of channel trafficking, microtubule stability, and gene expression across cardiac, sensory, and central neurons [#0, #24]. It binds directly to the cytoplasmic C-terminus of Nav1.5, Nav1.6, and Nav1.7, and through splice isoform-specific effects tunes current density, fast and slow inactivation, steady-state availability, and recovery from inactivation [#2, #11, #12]. In heart, FGF13 sustains sodium current and conduction—its loss accelerates channel inactivation, reduces peak current, prolongs QRS, and produces temperature-sensitive conduction failure [#3, #4], with conduction further compromised by interdependence between reduced Nav availability, calcium current, and gap-junctional coupling [#14]. A separation-of-function mechanism shows that FGF13 regulates Nav1.5 steady-state inactivation indirectly by maintaining polarized accessible membrane cholesterol at the intercalated disc rather than solely through direct channel binding [#16], and it directs Cx43 gap junction trafficking through microtubule-dependent, VGSC-independent routes [#15]. In sensory neurons, FGF13 binds Nav1.7 in a heat- and histamine-facilitated manner to sustain nociceptive and pruriceptive firing, and disruption or stabilization of this interaction bidirectionally controls pain and itch behavior [#1, #18, #26]. Through a conserved tubulin-binding domain FGF13 stabilizes microtubules to control trafficking of diverse cargoes including Kv4.2/4.3 channels, Cav1.2, TRPV1, and platinum transporters [#3, #20, #22, #23]. Nuclear FGF13 isoforms additionally regulate transcriptional programs—repressing ribosomal RNA synthesis in the nucleolus [#9], activating NF-κB via direct p65 binding in cardiac hypertrophy [#8], and interacting with the BAF subunit ARID1B to maintain neural stem cell self-renewal [#19]. FGF13 deficiency causes hyperthermia-induced seizures via excitatory-inhibitory imbalance [#6], with interneuron-specific loss producing sodium-channel-independent seizures through reduced K+ currents [#17]; missense variants in FHF2A cause developmental and epileptic encephalopathy [#13], and a 5'-UTR variant impairing PTBP2-dependent translation causes neuronal migration defects and cognitive deficits [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that FGF13 directly binds VGSCs and, in concert with FGF14, polarizes sodium channel distribution within neurons—defining its role as a trafficking and localization regulator rather than only a gating modulator.\",\n      \"evidence\": \"Knockdown and interaction-abolishing mutagenesis in hippocampal neurons with immunofluorescence and electrophysiology\",\n      \"pmids\": [\"27044086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FGF13 restricts somatodendritic localization not resolved at the molecular level\", \"Did not address cardiac or sensory neuron contexts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that distinct FGF13 splice isoforms differentially shape Nav1.5 gating, establishing isoform identity as a determinant of channel behavior.\",\n      \"evidence\": \"Heterologous HEK293 expression with isoform-specific constructs and whole-cell voltage-clamp\",\n      \"pmids\": [\"27246624\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterologous system may not reflect native stoichiometry\", \"Physiological relevance of FGF13S slow-inactivation effect in vivo not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that FGF13 loss produces temperature-sensitive cardiac conduction failure via accelerated sodium channel inactivation, linking the subunit to thermal stability of cardiac excitability.\",\n      \"evidence\": \"Fhf2 knockout mice, temperature-series patch-clamp, ECG, and computational modeling\",\n      \"pmids\": [\"27701382\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address contribution of non-VGSC mechanisms to conduction\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked FGF13 to seizure susceptibility, showing heterozygous loss causes hyperthermia-induced seizures through synaptic excitatory-inhibitory imbalance.\",\n      \"evidence\": \"Fgf13 knockout mice with hippocampal mIPSC/mEPSC recordings and hyperthermia seizure induction\",\n      \"pmids\": [\"26063919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type origin of E/I imbalance not resolved in this study\", \"Molecular mechanism connecting FGF13 to synaptic inputs unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined FGF13's cardiac phenotype—reduced Na+ current, inactivation shift, QRS prolongation—and revealed an unexpected role in surface localization of Kv4.2/4.3, expanding its function to K+ channel trafficking.\",\n      \"evidence\": \"Inducible cardiomyocyte-restricted Fgf13 KO mice with electrophysiology, ECG, and surface fractionation\",\n      \"pmids\": [\"28119060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Kv4 surface regulation not defined at the time\", \"Whether trafficking effect is direct unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established FGF13 as required for heat nociception by maintaining Nav1.7 currents and membrane localization in a heat-facilitated interaction, providing a druggable PPI target for pain.\",\n      \"evidence\": \"DRG-conditional KO mice, co-IP, patch-clamp, competitive peptide disruption, and behavioral assays\",\n      \"pmids\": [\"28162808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of heat-facilitation of the interaction not defined\", \"Whether peptide effects are Nav1.7-specific in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected FGF13 to disease-relevant channel dysregulation by showing CaMKII-driven phosphorylation of Nav1.5 disrupts FGF13 binding and downstream calmodulin recruitment, defining a pathway altered in failing hearts.\",\n      \"evidence\": \"Phosphoproteomics of native Nav1.5, phosphomimetic mutants, voltage-clamp, and co-IP\",\n      \"pmids\": [\"28882890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of the two phosphosites not tested\", \"Structural basis of FGF13-calmodulin cooperativity unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a nuclear, growth-suppressive role for the FGF13 1A isoform in repressing rRNA transcription within a p53 feedback loop, distinguishing nuclear from channel-associated functions.\",\n      \"evidence\": \"Subcellular fractionation, rRNA transcription assays, siRNA depletion with apoptosis readout, and p53 ChIP\",\n      \"pmids\": [\"27994142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism of rRNA repression by FGF13 1A unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved opposing isoform effects on Nav1.6 resurgent current, showing FHF2A and FHF2B regulate sensory excitability in antagonistic directions.\",\n      \"evidence\": \"DRG and heterologous patch-clamp with isoform-specific and chimeric constructs\",\n      \"pmids\": [\"27999940\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo pain relevance of resurgent-current modulation not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a VGSC-independent cardiac function: FGF13 negatively regulates caveolae abundance by controlling cavin-1 distribution, conferring protection against pressure overload.\",\n      \"evidence\": \"Cardiac Fgf13 KO mice, interactome screen/co-IP, fractionation, EM, and pressure overload model\",\n      \"pmids\": [\"28461495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FGF13 controls cavin-1 partitioning not defined\", \"Link between caveolae and protection partly correlative\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed isoform-dependent FHF2 regulation of Nav1.7 in both native and heterologous cells, reinforcing isoform-specific control of sensory channel availability.\",\n      \"evidence\": \"Co-IP/immunohistochemistry in DRG with patch-clamp and knockdown\",\n      \"pmids\": [\"31223136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural determinants of isoform-specific effects not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified nuclear FGF13 as a direct activator of NF-κB via p65 binding through an IκB-independent route, linking the protein to hypertrophic gene programs.\",\n      \"evidence\": \"Co-IP, confocal co-localization, gain/loss-of-function in cardiomyocytes/TAC, and NF-κB reporter\",\n      \"pmids\": [\"33089113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of IκB-independent activation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established FGF13 missense variants as a cause of developmental and epileptic encephalopathy through selective loss of Nav1.6 long-term blockade with retained pro-excitatory effects.\",\n      \"evidence\": \"Whole-exome sequencing and functional patch-clamp of mutant FHF2A co-expressed with Nav1.6\",\n      \"pmids\": [\"33245860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo neuronal consequences of variants not modeled\", \"Single lab functional characterization\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed conduction failure in FHF2-deficient cardiac strands arises from combined Nav and gap-junctional deficits, integrating ionic and electrotonic determinants of propagation.\",\n      \"evidence\": \"Fhf2 KO with pharmacology, Cx43-heterozygous cross, multicellular modeling, and optical mapping\",\n      \"pmids\": [\"32962518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of reduced gap-junctional conductance not defined here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended FGF13/Nav1.7's sensory role to itch, showing histamine enhances the interaction in an isoform-dependent manner to drive pruriception.\",\n      \"evidence\": \"DRG-specific KO mice, co-IP, calcium imaging, competitive peptide, and behavior\",\n      \"pmids\": [\"33172979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of histamine-facilitated binding unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked FGF13 to neurodevelopment by showing a 5'-UTR variant impairs PTBP2-dependent translation, reducing microtubule stabilization and causing migration and cognitive deficits.\",\n      \"evidence\": \"Patient iPSCs, translation assays, PTBP2 pulldown, knockin mice, and microtubule polymerization assays\",\n      \"pmids\": [\"34184986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether migration defect reflects loss of channel or microtubule function not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a chromatin-level function: nuclear FGF13A binds the BAF subunit ARID1B to suppress neuronal differentiation genes and maintain neural stem cell self-renewal.\",\n      \"evidence\": \"Fgf13 conditional KO, co-IP, ChIP, neurogenesis assays, and RNA-seq\",\n      \"pmids\": [\"34010636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct chromatin targets and how FGF13A is recruited not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that FGF13's tubulin-binding domain drives chemoresistance by redistributing platinum transporters, generalizing the microtubule-trafficking function to cancer pharmacology.\",\n      \"evidence\": \"Overexpression/knockdown in cancer cell lines, platinum uptake assays, fractionation, and domain-mutant rescue\",\n      \"pmids\": [\"34533854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance and clinical correlation limited\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed FHF2 is extensively phosphorylated in native cardiac Nav1.5 complexes and modulates late current, but individual phosphosites were not assignable to specific functions.\",\n      \"evidence\": \"Phosphoproteomics of native Nav complexes with cardiomyocyte knockdown/rescue (preprint)\",\n      \"pmids\": [\"36778222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of individual phosphosites inconclusive (negative result)\", \"Preprint, not peer reviewed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed FGF13 upstream of Parkin in glomerular endothelial mitochondrial homeostasis, showing its deficiency improves mitophagy in diabetic nephropathy.\",\n      \"evidence\": \"Endothelial-specific Fgf13 and double Fgf13/Prkn KO mice with mitophagy and apoptosis assays\",\n      \"pmids\": [\"36256844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FGF13 and Parkin not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed FGF13 microtubule stabilization impairs cardiac calcium handling in heart failure by reducing Cav1.2 surface localization and Serca2α, identified via domain-mutant rescue.\",\n      \"evidence\": \"TAC heart failure model, Fgf13 KO, calcium imaging, patch-clamp, and tubulin-binding mutant rescue\",\n      \"pmids\": [\"38821375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking microtubule stability to Serca2α expression unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated FGF13 selectively enhances TRPV1 (not TRPA1) function via its microtubule-stabilizing domain to drive itch behaviors.\",\n      \"evidence\": \"DRG-specific KO, calcium imaging, patch-clamp, and tubulin-binding mutant rescue with behavior\",\n      \"pmids\": [\"38733310\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of TRPV1-versus-TRPA1 selectivity unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked FGF13 microtubule function to cardiac fibrosis, showing its loss reduces fibrosis via microtubule destabilization and decreased ROCK.\",\n      \"evidence\": \"TAC model, fibroblast culture, and tubulin-binding mutant rescue of fibrosis markers\",\n      \"pmids\": [\"38818580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking microtubule disruption to ROCK downregulation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Separated FGF13's regulation of cardiac conduction from VGSC binding, showing it controls Cx43 gap junction trafficking through microtubule-dependent mechanisms.\",\n      \"evidence\": \"Cardiac Fgf13 KO, optical mapping, proximity proteomics, and VGSC-binding-incompetent mutant rescue\",\n      \"pmids\": [\"41200819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How FGF13 directs Cx43 to the intercalated disc mechanistically not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed that FGF13 regulates Nav1.5 steady-state inactivation indirectly by maintaining polarized accessible membrane cholesterol at the intercalated disc, overturning a purely direct-binding model.\",\n      \"evidence\": \"Fgf13-KO cardiomyocytes, binding-incompetent mutant rescue, cholesterol imaging, and patch-clamp\",\n      \"pmids\": [\"40794434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which FGF13 maintains cholesterol polarization not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Distinguished cell-type-specific seizure mechanisms, showing interneuron Fgf13 loss causes sodium-channel-independent seizures through reduced K+ currents.\",\n      \"evidence\": \"Interneuron- versus excitatory-neuron-specific conditional KO mice with patch-clamp and isoform rescue\",\n      \"pmids\": [\"39773461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the affected K+ channels not defined\", \"Mechanism of K+ current regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Definitively established FGF13 as nonsecreted and intracellular, constraining all proposed functions to intracellular and membrane-associated compartments.\",\n      \"evidence\": \"Conditioned-medium analysis with rigorous controls and proximity labeling proteomics\",\n      \"pmids\": [\"41289026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address possible non-canonical release under specific stress conditions\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Advanced FGF13/Nav1.7 as a bidirectional therapeutic target, with PPI inhibitor and stabilizer producing mirror-image analgesic and pronociceptive effects in human neurons and mice.\",\n      \"evidence\": \"Small-molecule PPI inhibitor/stabilizer, hIPSC sensory neurons, siRNA, mouse behavior, and donor DRG tissue\",\n      \"pmids\": [\"40662354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of compounds for FGF13/Nav1.7 over other FHF/Nav pairs not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a mitochondrial anchoring function, with FGF13 binding the outer mitochondrial membrane protein MCHT2 to retain damaged mitochondria and limit neurodegeneration.\",\n      \"evidence\": \"Co-IP, Fgf13 overexpression in PD models, and glia-neuron co-culture/mitochondria transfer assays\",\n      \"pmids\": [\"40344619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct nature and stoichiometry of FGF13-MCHT2 interaction not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected FGF13 to cardiomyocyte senescence through Cav1 promoter regulation via p38/MAPK and p65, plus PTRF-Cav1 modulation, defining a Cav1-p53-p21 aging axis.\",\n      \"evidence\": \"AAV9 overexpression, cardiac Fgf13 KO, transcriptomics, Cav1 luciferase reporter, and co-IP\",\n      \"pmids\": [\"40184605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between nuclear and trafficking roles in senescence unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified TUBB2A as a direct FGF13 partner mediating microtubule stabilization, with FGF13 methylation reducing binding and FGF13 protecting against Alzheimer's-related deficits.\",\n      \"evidence\": \"Co-IP, methylation-specific PCR, FGF13 overexpression in an Aβ AD model, and TUBB2A knockdown epistasis\",\n      \"pmids\": [\"41808420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of FGF13 methylation in vivo not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported FGF13 interaction with SHCBP1 promoting AKT-GSK3 signaling and proliferation in lung cancer cells.\",\n      \"evidence\": \"Co-IP, Western blotting, flow cytometry cell cycle, and proliferation assays\",\n      \"pmids\": [\"33064958\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single co-IP without reciprocal validation or in vivo confirmation\", \"Direct versus indirect interaction not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FGF13's distinct mechanistic modules—direct channel binding, microtubule stabilization, membrane cholesterol polarization, and nuclear transcriptional regulation—are partitioned by isoform, post-translational modification, and cell type into coherent physiological outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model integrating channel-binding and microtubule-binding domains\", \"Determinants directing FGF13 isoforms to nuclear versus membrane functions undefined\", \"Mechanism of cholesterol polarization at the intercalated disc unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 3, 4, 11, 16]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 22, 23, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 9, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 16, 24]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10, 15, 22, 30]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 19]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0112316\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 6, 17, 18]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3, 4, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 19]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 15, 22, 23]}\n    ],\n    \"complexes\": [\n      \"Nav1.5 channel complex\",\n      \"Nav1.7 channel complex\",\n      \"BAF chromatin remodeling complex\"\n    ],\n    \"partners\": [\n      \"SCN5A\",\n      \"SCN8A\",\n      \"SCN9A\",\n      \"CAV1\",\n      \"PTRF\",\n      \"ARID1B\",\n      \"RELA\",\n      \"TUBB2A\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}