{"gene":"FGF14","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2002,"finding":"FGF14 is required for normal neuronal signaling, axonal trafficking, and synaptosomal function; Fgf14-/- mice develop ataxia and paroxysmal hyperkinetic movement disorder with reduced dopamine agonist responses; an FGF14N-beta-gal fusion protein is efficiently transported into neuronal processes in basal ganglia and cerebellum, establishing FGF14's role in axonal trafficking.","method":"Targeted gene disruption (Fgf14-/- mice), beta-galactosidase fusion protein trafficking assay, neuropharmacological behavioral studies","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular/behavioral phenotypes, axonal transport assay, replicated across multiple readouts in single rigorous study","pmids":["12123606"],"is_preprint":false},{"year":2007,"finding":"FGF14 interacts directly with the pore-forming alpha subunits of voltage-gated Na+ (Nav) channels; the disease-causing FGF14(F145S) mutant does not bind Nav alpha subunits directly but instead associates with wild-type FGF14 and disrupts FGF14-Nav interaction in a dominant-negative manner, reducing Nav expression at the axon initial segment, attenuating Nav currents, and reducing hippocampal neuron excitability.","method":"Co-immunoprecipitation, whole-cell patch-clamp electrophysiology, immunocytochemistry of axon initial segment Nav expression, dominant-negative expression in hippocampal neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, electrophysiology, and localization experiments with multiple orthogonal methods in one study; replicated concept across multiple labs","pmids":["17978045"],"is_preprint":false},{"year":2008,"finding":"FGF14 is required for normal Nav1.6 expression in cerebellar Purkinje neurons; loss of FGF14 in Fgf14-/- mice results in attenuated spontaneous firing and failure of repetitive firing in response to depolarization, associated with reduced Nav1.6 protein levels at Purkinje neurons.","method":"Current-clamp recordings from cerebellar slice preparations (Fgf14-/- vs. wild type), immunohistochemistry for Nav1.6","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined electrophysiological phenotype and protein localization readout, multiple orthogonal methods","pmids":["18930825"],"is_preprint":false},{"year":2009,"finding":"The two N-terminal alternatively spliced FGF14 variants, FGF14-1a and FGF14-1b, differentially regulate Nav1.2 and Nav1.6 channel currents: FGF14-1b but not FGF14-1a attenuates Nav1.2 and Nav1.6 current densities, while an FGF14 mutant lacking the N-terminus increases Nav1.6 current density. Both FGF14-1a and FGF14-1b localize to the axon initial segment, and deletion of the N-terminus abolishes this localization.","method":"Whole-cell patch-clamp electrophysiology in heterologous expression, confocal immunofluorescence localization in neurons, N-terminal deletion mutagenesis","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, imaging, mutagenesis) in one study with isoform-specific dissection","pmids":["19465131"],"is_preprint":false},{"year":2013,"finding":"FGF14 localizes to the axon initial segment (AIS) of Purkinje neurons in a proximal-to-distal decreasing gradient; in Nav1.6-deficient (Scn8a med) mice, FGF14 immunoreactivity is markedly increased and expanded at the AIS in parallel with increased Nav1.1 and expanded βIV-spectrin; loss of FGF14 (Fgf14-/-) modestly but significantly reduces Nav1.1 and Nav1.6 alpha subunit levels at AIS sub-domains without affecting ankyrin G or βIV-spectrin localization.","method":"Immunohistochemistry and confocal imaging of AIS proteins in wild type, Scn8a med, and Fgf14-/- mice","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization with functional genetic controls across multiple mouse models, multiple protein markers","pmids":["23891806"],"is_preprint":false},{"year":2013,"finding":"FGF14 regulates presynaptic CaV2 Ca2+ channel function in cerebellar granule cells; knockdown of FGF14 reduces Ca2+ currents, diminishes vesicular recycling, and markedly reduces excitatory postsynaptic currents at the granule cell-to-Purkinje cell synapse; the SCA27-causing FGF14 mutant exerts a dominant-negative reduction in Ca2+ currents and EPSCs.","method":"shRNA knockdown of FGF14 in granule cells, patch-clamp electrophysiology (Ca2+ currents and EPSCs), vesicular recycling assay, dominant-negative mutant expression","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with defined electrophysiological phenotypes, multiple readouts (Ca2+ current, vesicular recycling, EPSCs), dominant-negative validation","pmids":["23831029"],"is_preprint":false},{"year":2014,"finding":"FGF14 forms homodimers in cells; short peptide fragments (FLPK) targeting the β12-strand/β8-β9 loop of FGF14 reduce FGF14:FGF14 dimer interaction by ~25%; residues Y153/V155 at the β8-β9 loop modulate dimer strength; the dimer interface overlaps with the Nav channel binding surface.","method":"Split-luciferase complementation assay (LCA) for in-cell FGF14:FGF14 interaction, peptide competition, site-directed mutagenesis (Y153N/V155N)","journal":"CNS & neurological disorders drug targets","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in-cell reconstitution with LCA, single lab, single method for dimer measurement","pmids":["25426956"],"is_preprint":false},{"year":2015,"finding":"Acute shRNA-mediated knockdown of FGF14 selectively in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without altering Nav channel localization at the AIS; loss of FGF14 causes a hyperpolarizing shift in steady-state Nav current inactivation in adult Purkinje neurons; membrane hyperpolarization restores repetitive firing, indicating FGF14 regulates excitability in a membrane-potential-dependent manner; re-expression of FGF14 selectively in adult Fgf14-/- Purkinje neurons rescues spontaneous firing and improves motor performance.","method":"In vivo shRNA knockdown in adult mice, current-clamp and voltage-clamp recordings from cerebellar slices, immunohistochemistry, viral rescue experiment","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, KO, rescue, electrophysiology, imaging), adult-specific manipulation ruling out developmental effects","pmids":["25926453"],"is_preprint":false},{"year":2015,"finding":"PI3K/Akt pathway, Wee1 kinase, and PKC are identified as regulatory nodes of the FGF14:Nav1.6 complex; GSK3 is identified as a convergence point; GSK3 inhibition impairs excitability of hippocampal neurons.","method":"Split-luciferase complementation assay screening of 12 kinase pathway inhibitors, hierarchical clustering, patch-clamp electrophysiology in hippocampal neurons","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in-cell LCA with dose-dependent validation, single lab, functional electrophysiology confirmation of GSK3 node","pmids":["25659151"],"is_preprint":false},{"year":2016,"finding":"FGF14 promotes axonal localization of voltage-gated sodium channels (VGSCs) at the axon initial segment; single-point mutations in FGF14 abrogating VGSC interaction abolish this axonal promotion function; concerted action with FGF13 (which limits somatodendritic VGSC surface expression) establishes polarized VGSC localization supporting efficient action potential initiation.","method":"shRNA knockdown of FGF14 and FGF13 in hippocampal neurons, site-directed mutagenesis of VGSC-interaction residues, confocal imaging of VGSC distribution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD plus interaction-abrogating mutagenesis, multiple orthogonal methods, functional mechanistic dissection","pmids":["27044086"],"is_preprint":false},{"year":2016,"finding":"FGF14 regulates KCNQ2/3 (Kv7.2/7.3) channel function and AIS localization; FGF14 knockdown reduces KCNQ2 at the AIS and reduces whole-cell KCNQ currents; FGF14 interacts with KCNQ2 at a site distinct from the FGF14-VGSC interaction surface; FGF14 can simultaneously bridge NaV1.6 and KCNQ2.","method":"shRNA knockdown of FGF14, whole-cell patch-clamp electrophysiology, co-immunoprecipitation, confocal imaging of KCNQ2 localization, heterologous expression system","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with electrophysiological phenotype, co-IP, imaging, and heterologous expression; multiple orthogonal methods","pmids":["27994149"],"is_preprint":false},{"year":2016,"finding":"Identification of specific amino acid residues in FGF14 required for Nav1.6 interaction: Val-160 in the β-9 sheet is a hotspot for FGF14:Nav1.6 complex formation (V160A impairs Nav1.6 binding but not FGF14 homodimerization); Lys-74/Ile-76 at the N-terminal contribute to both Nav1.6 complex and FGF14:FGF14 dimer formation; Y158/V160 double mutation impedes FGF14-dependent modulation of Nav channel fast inactivation.","method":"Site-directed mutagenesis, split-luciferase complementation assay (LCA), whole-cell patch-clamp electrophysiology, intrinsic fluorescence spectroscopy of purified proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro assay with purified proteins, mutagenesis, electrophysiology; multiple orthogonal methods in single study","pmids":["26994141"],"is_preprint":false},{"year":2016,"finding":"CK2 (casein kinase 2) phosphorylates FGF14 directly at S228 and S230; CK2 inhibition reduces FGF14:Nav1.6 and FGF14:Nav1.2 interactions; S228A/S230A alanine mutations modify FGF14 modulation of Nav1.6-mediated currents; CK2 inhibition reduces FGF14 expression, attenuates transient Na+ currents, and shifts Nav channel steady-state inactivation in hippocampal neurons; CK2 inhibitor effects on excitability are occluded in Fgf14-/- mice, confirming on-target specificity.","method":"Mass spectrometry (in vitro phosphorylation), split-LCA, whole-cell patch-clamp, confocal imaging, CK2 inhibitor (TBB) pharmacology in WT and Fgf14-/- mice","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — MS-confirmed phosphorylation, mutagenesis, electrophysiology, and genetic epistasis (Fgf14-/- occlusion); multiple orthogonal methods","pmids":["26917740"],"is_preprint":false},{"year":2017,"finding":"GSK-3β phosphorylates FGF14 at S226 in vitro, confirmed by mass spectrometry; phosphosilent S226A mutation impairs FGF14:Nav1.6 complex assembly and FGF14-dependent functional regulation of Nav1.6-mediated currents; PPARγ agonist rosiglitazone treatment of Tg2576 AD-model mice reduces S226 phosphorylation and rescues Nav channel expression at the AIS.","method":"Nano-LC-MS/MS quantitative proteomics, in vitro kinase phosphorylation assay, mass spectrometry confirmation, split-LCA, confocal imaging, electrophysiology","journal":"Experimental neurology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS-confirmed phosphorylation, in vitro kinase assay, functional mutagenesis (S226A), multiple orthogonal methods","pmids":["28522250"],"is_preprint":false},{"year":2018,"finding":"A peptidomimetic (ZL181) targeting the FGF14:Nav1.6 protein-protein interaction interface binds to FGF14 and inhibits its interaction with the Nav1.6 C-tail; ZL181 acts synergistically with FGF14 to suppress Nav1.6 current density and slow fast inactivation kinetics but antagonizes FGF14 modulation of steady-state inactivation; ZL181 suppresses excitability of medium spiny neurons in the nucleus accumbens in an FGF14-expression-dependent manner.","method":"Split-LCA, whole-cell patch-clamp electrophysiology in HEK-Nav1.6 cells and medium spiny neurons, FGF14 knockdown dependency test","journal":"ACS chemical neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LCA and electrophysiology with FGF14-dependency confirmed by KD, single lab, two orthogonal methods","pmids":["29359916"],"is_preprint":false},{"year":2019,"finding":"Loss of FGF14 reduces resurgent Na+ current amplitude in cerebellar Purkinje neurons and leads to acceleration and stabilization of Na+ channel inactivation not reversed by site-3 toxin ATX; FGF14 preferentially modulates a highly TTX-sensitive (Nav1.6-containing) subset of Purkinje Na+ channels to facilitate open-channel block; however, deletion of FGF14 alone (or together with NaVβ4) does not eliminate resurgent current, indicating FGF14 is not the sole open-channel blocker.","method":"Whole-cell voltage-clamp of Na+ currents in acutely dissociated Purkinje neurons from Fgf14-/-, NaVβ4-/-, and double-KO mice; TTX sensitivity analysis; ATX pharmacology","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined electrophysiological phenotype across multiple genetic backgrounds, pharmacological dissection","pmids":["31558566"],"is_preprint":false},{"year":2020,"finding":"JAK2 phosphorylates FGF14 at Y158, a residue that mediates both FGF14 homodimerization and FGF14:Nav1.6 complex formation; JAK2 inhibition increases FGF14 homodimerization inversely to FGF14:Nav1.6 complex formation; this effect is abolished by the FGF14Y158A mutation; JAK2 controls FGF14-dependent modulation of Nav1.6 channels; JAK2 inhibitor (Fedratinib) reduces firing in hippocampal CA1 neurons by an FGF14-dependent mechanism.","method":"High-throughput screening (>3000 compounds), in vitro phosphorylation, mass spectrometry, split-LCA, patch-clamp electrophysiology, FGF14-dependency test","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — MS-confirmed phosphorylation, in vitro kinase assay, mutagenesis, electrophysiology with genetic dependency; multiple orthogonal methods","pmids":["32599005"],"is_preprint":false},{"year":2020,"finding":"The FGF14 V160 residue within the FGF14 core domain is a hotspot for FGF14:Nav1.6 complex formation; the FLPK peptide (mapping around V160) disrupts FGF14:Nav1.6 interaction, confirmed by split-LCA and surface plasmon resonance; FLPK activity requires the FGF14 N-terminal tail; in nucleus accumbens medium spiny neurons, FLPK increases firing frequency by interfering with Nav1.6 inactivation.","method":"In silico docking, split-LCA, surface plasmon resonance (SPR), whole-cell patch-clamp electrophysiology","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — SPR (direct binding), LCA, electrophysiology; multiple methods but single lab","pmids":["32671946"],"is_preprint":false},{"year":2023,"finding":"TNFR1 stimulation via JAK2 increases FGF14:Nav1.6 complex assembly; in experimental cerebral malaria (eCM), Plasmodium chabaudi infection augments Nav1.6 channel conductance of CA1 pyramidal neurons through the TNFR1-JAK2-FGF14-Nav1.6 signaling network, leading to neuronal hyperexcitability; genetic silencing of FGF14 in CA1 mitigated infection-induced hyperexcitability and reduced sickness behavior.","method":"Split-LCA for TNFR1 signaling effects on FGF14:Nav1.6 complex, whole-cell patch-clamp in eCM brain slices, FGF14 genetic knockdown in vivo, anti-TNF antibody treatment","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — LCA, electrophysiology, in vivo genetic knockdown; multiple methods in single lab","pmids":["38115011"],"is_preprint":false},{"year":2024,"finding":"The FGF14(F145S) SCA27A knock-in mouse (Fgf14^F145S) shows haploinsufficiency: heterozygous Fgf14^F145S mice display reduced iFGF14 protein expression and impaired Purkinje neuron firing (shift from tonic to burst firing), mirroring heterozygous Fgf14 KO mice; homozygous Fgf14^F145S mice show undetectable iFGF14 and more severe firing deficits; the firing change reflects a hyperpolarizing shift in Nav channel closed-state inactivation; TTX mimics the burst firing phenotype in WT neurons.","method":"Knock-in mouse model, Western blot (iFGF14 expression), current-clamp and voltage-clamp recordings from cerebellar slices, TTX pharmacology","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in model with genetic controls, Western blot, electrophysiology, pharmacological validation; multiple orthogonal methods","pmids":["41558966","39484407"],"is_preprint":false},{"year":2025,"finding":"Loss of iFGF14 in adult hippocampal CA1 pyramidal neurons increases (rather than decreases) evoked repetitive firing; unlike Purkinje neurons, Nav current steady-state inactivation voltage dependence is not shifted in CA1 neurons; Nav1.6 protein levels along the AIS are significantly higher in Fgf14-/- CA1 neurons compared to wild type, without disruption of Nav1.6 or ankyrin G localization pattern, indicating cell-type-specific FGF14 regulation of Nav channels.","method":"Current-clamp and voltage-clamp in acute hippocampal slices from adult Fgf14-/- mice, immunohistochemistry with quantitative intensity analysis of AIS proteins","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with defined electrophysiological and localization phenotypes, multiple orthogonal methods in single rigorous study","pmids":["40323232"],"is_preprint":false},{"year":2025,"finding":"Compound 1028 targets FGF14 residue R117 at the FGF14/Nav1.6 protein-protein interaction interface; it modulates FGF14/Nav1.6 complex assembly, depolarizes the voltage-dependence of Nav1.6 channel inactivation (nanomolar potency), enhances medium spiny neuron excitability ex vivo and accumbal neuron firing rate in vivo; behavioral motivational effects are abrogated by in vivo Fgf14 gene silencing in the NAc, confirming on-target mechanism.","method":"Split-LCA, patch-clamp electrophysiology, in vivo neural recording, in vivo gene silencing, behavioral assays, in silico docking","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (LCA, electrophysiology, in vivo recording, genetic dependency test, behavior), single lab but rigorous design","pmids":["39747162"],"is_preprint":false},{"year":2001,"finding":"Chicken FHF-4 (ortholog of FGF14) is expressed in paraxial mesoderm, lateral ridge, and posterior-dorsal limb base; its expression is correlated with early limb innervation patterns and is regulated by retinoic acid; ectopic FHF-4 expression correlates with local induction of limb-like innervation, suggesting a role in regulating early innervation events at the base of the limbs.","method":"In situ hybridization, tissue grafting (ZPA, Shh-expressing cells), bead implantation (retinoic acid, FGF-2), analysis of chicken limb patterning mutants","journal":"Mechanisms of development","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression/localization correlation in chicken model, no direct functional assay for FHF-4 protein mechanism","pmids":["10906454"],"is_preprint":false}],"current_model":"FGF14 (iFGF14) is an intracellular, non-secreted FGF that functions as a multivalent regulator of neuronal excitability by directly binding the C-terminal tail of voltage-gated Na+ (Nav) channel alpha subunits (particularly Nav1.6 and Nav1.2) at the axon initial segment (AIS), where it promotes Nav channel localization, modulates channel gating (shifting steady-state inactivation), and sustains high-frequency repetitive firing in cerebellar Purkinje neurons; it also regulates presynaptic CaV2 Ca2+ channels and KCNQ2/3 K+ channels at the AIS; its interactions with Nav channels are regulated by post-translational phosphorylation via CK2 (at S228/S230), GSK-3β (at S226), and JAK2 (at Y158), and by the dimerization state of FGF14 itself; loss-of-function (Fgf14-/- mice or SCA27A knock-in) causes Purkinje neuron hypoexcitability through a hyperpolarizing shift in Nav channel inactivation, ataxia, and paroxysmal movement disorder, while loss of FGF14 paradoxically increases excitability in hippocampal CA1 neurons, revealing cell-type-specific functional roles."},"narrative":{"mechanistic_narrative":"FGF14 (iFGF14) is an intracellular fibroblast growth factor that functions as a multivalent scaffold controlling neuronal excitability at the axon initial segment (AIS), where it directly binds the pore-forming alpha subunits of voltage-gated Na+ (Nav) channels to govern their localization, gating, and the repetitive firing of cerebellar Purkinje neurons [PMID:17978045, PMID:18930825, PMID:25926453]. The interaction is mediated by a defined core-domain surface — notably Val-160 and Tyr-158 in the beta-9 sheet plus N-terminal residues (Lys-74/Ile-76) — that partially overlaps the FGF14 homodimerization interface, so that dimerization and Nav binding are competing, mutually regulated states [PMID:25426956, PMID:26994141]. Through this interface FGF14 promotes axonal Nav (Nav1.6, Nav1.2) accumulation at the AIS and sustains high-frequency firing, acting in concert with FGF13 to establish polarized channel distribution, while its N-terminal splice variants (FGF14-1a/1b) confer isoform-specific modulation of Nav current density [PMID:19465131, PMID:27044086, PMID:23891806]. Beyond Nav channels, FGF14 binds KCNQ2/3 (Kv7) K+ channels at a distinct surface and can simultaneously bridge Nav1.6 and KCNQ2, and it supports presynaptic CaV2 Ca2+ channel function and synaptic transmission at the granule-to-Purkinje synapse [PMID:27994149, PMID:23831029]. The FGF14:Nav complex is dynamically tuned by phosphorylation of FGF14 — CK2 at S228/S230, GSK-3beta at S226, and JAK2 at Y158 — linking the channel scaffold to PI3K/Akt, GSK3, and cytokine (TNFR1) signaling nodes [PMID:26917740, PMID:28522250, PMID:32599005, PMID:25659151, PMID:38115011]. FGF14 modulates Nav steady-state and resurgent current, and its loss produces a hyperpolarizing shift in Nav inactivation that drives Purkinje hypoexcitability and a switch from tonic to burst firing, whereas in hippocampal CA1 neurons loss of FGF14 paradoxically raises Nav1.6 levels and increases firing — establishing cell-type-specific regulatory roles [PMID:25926453, PMID:31558566, PMID:40323232]. The disease-causing F145S mutation acts dominant-negatively and as a haploinsufficiency allele in SCA27A knock-in mice, recapitulating impaired Purkinje firing [PMID:17978045, PMID:41558966, PMID:39484407], and the FGF14:Nav1.6 interface is a druggable target modulated by interface-binding peptides and small molecules (ZL181, FLPK, compound 1028) [PMID:29359916, PMID:32671946, PMID:39747162].","teleology":[{"year":2002,"claim":"Established that FGF14 is required in vivo for normal neuronal signaling and axonal trafficking, defining its broad role before any molecular partner was known.","evidence":"Targeted Fgf14-/- mouse with behavioral, synaptosomal, and beta-galactosidase fusion trafficking readouts","pmids":["12123606"],"confidence":"High","gaps":["No molecular target or binding partner identified","Cellular mechanism of trafficking defect unresolved"]},{"year":2007,"claim":"Identified Nav channel alpha subunits as direct FGF14 binding partners and showed the F145S mutant disrupts the complex dominant-negatively, providing the first molecular mechanism for FGF14 control of excitability.","evidence":"Co-immunoprecipitation, patch-clamp, AIS immunocytochemistry, and dominant-negative expression in hippocampal neurons","pmids":["17978045"],"confidence":"High","gaps":["Binding interface residues not yet mapped","Did not address Purkinje-specific phenotype"]},{"year":2008,"claim":"Connected FGF14 loss to reduced Nav1.6 in cerebellar Purkinje neurons and failure of repetitive firing, tying the molecular interaction to the ataxia phenotype.","evidence":"Current-clamp of Fgf14-/- cerebellar slices with Nav1.6 immunohistochemistry","pmids":["18930825"],"confidence":"High","gaps":["Could not separate developmental from acute requirement","Mechanism of gating modulation not resolved"]},{"year":2009,"claim":"Showed N-terminal splice variants differentially regulate Nav1.2/Nav1.6 currents and that the N-terminus is required for AIS targeting, establishing isoform-specific functional outputs.","evidence":"Patch-clamp in heterologous cells, confocal localization, N-terminal deletion mutagenesis","pmids":["19465131"],"confidence":"High","gaps":["Physiological role of each isoform in vivo unclear","Structural basis of N-terminal targeting unknown"]},{"year":2013,"claim":"Extended FGF14 function beyond Nav channels to presynaptic CaV2 Ca2+ channels and synaptic transmission, broadening its role to neurotransmitter release.","evidence":"shRNA knockdown in granule cells with Ca2+ current, vesicular recycling, and EPSC recordings plus dominant-negative mutant","pmids":["23831029"],"confidence":"High","gaps":["Direct FGF14-CaV2 binding not demonstrated","Mechanism of presynaptic regulation unresolved"]},{"year":2013,"claim":"Mapped FGF14 to a graded AIS distribution and showed reciprocal regulation with Nav channel availability, clarifying how FGF14 partitions across AIS sub-domains.","evidence":"Confocal immunohistochemistry of AIS proteins in wild type, Scn8a med, and Fgf14-/- mice","pmids":["23891806"],"confidence":"High","gaps":["Driver of the proximal-distal gradient unknown","Did not test gating consequences"]},{"year":2015,"claim":"Demonstrated FGF14 acts acutely in adult Purkinje neurons by modulating Nav inactivation in a membrane-potential-dependent manner, separating its role from developmental wiring.","evidence":"In vivo adult shRNA knockdown, current/voltage-clamp, and viral rescue in Fgf14-/- mice","pmids":["25926453"],"confidence":"High","gaps":["Molecular trigger of inactivation shift not defined","AIS localization unchanged, decoupling localization from gating effect"]},{"year":2015,"claim":"Identified kinase signaling nodes (PI3K/Akt, Wee1, PKC, GSK3) that regulate the FGF14:Nav1.6 complex, framing the scaffold as a signaling-responsive hub.","evidence":"Split-luciferase complementation screen of kinase inhibitors with hippocampal electrophysiology","pmids":["25659151"],"confidence":"Medium","gaps":["LCA screen from single lab without orthogonal binding assay for most nodes","Direct phosphorylation sites not yet mapped"]},{"year":2016,"claim":"Resolved the FGF14 dimer interface and showed it overlaps the Nav binding surface, explaining how dimerization state gates channel engagement.","evidence":"Split-luciferase complementation, peptide competition, and Y153N/V155N mutagenesis","pmids":["25426956"],"confidence":"Medium","gaps":["Dimer measured by single in-cell method","No high-resolution structure of the dimer"]},{"year":2016,"claim":"Pinpointed Val-160 and N-terminal Lys-74/Ile-76 as binding hotspots distinguishing Nav engagement from homodimerization, providing residue-level control of the complex.","evidence":"Site-directed mutagenesis, split-LCA, patch-clamp, and intrinsic fluorescence of purified proteins","pmids":["26994141"],"confidence":"High","gaps":["No co-crystal structure of FGF14:Nav complex","Contribution of each residue to in vivo firing untested"]},{"year":2016,"claim":"Showed FGF14 establishes polarized VGSC localization in concert with FGF13, defining a division of labor between FHF paralogs for action potential initiation.","evidence":"shRNA knockdown of FGF14/FGF13, interaction-abrogating mutagenesis, confocal imaging","pmids":["27044086"],"confidence":"High","gaps":["Trafficking machinery linking FGF14 to axonal delivery unknown"]},{"year":2016,"claim":"Extended FGF14 to KCNQ2/3 K+ channels via a distinct surface, showing it can simultaneously bridge Nav1.6 and KCNQ2 as a multivalent AIS organizer.","evidence":"shRNA knockdown, patch-clamp, co-IP, confocal imaging, heterologous expression","pmids":["27994149"],"confidence":"High","gaps":["Stoichiometry of a tri-partite complex unresolved","Structural basis of the KCNQ2 interaction surface unknown"]},{"year":2016,"claim":"Identified CK2 as a direct FGF14 kinase (S228/S230) controlling Nav complex assembly and excitability, with Fgf14-/- occlusion confirming on-target action.","evidence":"In vitro phosphorylation with MS, split-LCA, patch-clamp, and CK2 inhibitor pharmacology in WT and Fgf14-/- mice","pmids":["26917740"],"confidence":"High","gaps":["In vivo stoichiometry of phosphorylation unknown","Upstream regulators of CK2 in this context undefined"]},{"year":2017,"claim":"Established GSK-3beta phosphorylation of FGF14 at S226 as a regulator of complex assembly, with PPARgamma agonism rescuing AIS Nav expression in an AD model.","evidence":"Quantitative MS, in vitro kinase assay, S226A mutagenesis, confocal imaging, electrophysiology in Tg2576 mice","pmids":["28522250"],"confidence":"High","gaps":["Causal link between S226 phosphorylation and disease behavior not fully established","Interplay with CK2 sites untested"]},{"year":2018,"claim":"Demonstrated the FGF14:Nav1.6 interface is druggable, with a peptidomimetic modulating channel gating in an FGF14-dependent manner in medium spiny neurons.","evidence":"Split-LCA, patch-clamp in HEK-Nav1.6 and medium spiny neurons, FGF14 knockdown dependency test","pmids":["29359916"],"confidence":"Medium","gaps":["Compound from single lab, two methods","Selectivity over other FHF-channel complexes not assessed"]},{"year":2019,"claim":"Showed FGF14 shapes resurgent Na+ current by promoting open-channel block of TTX-sensitive Nav1.6 channels but is not the sole blocking factor, refining its biophysical role.","evidence":"Voltage-clamp of dissociated Purkinje neurons across Fgf14-/-, NaVbeta4-/-, and double-KO mice with TTX/ATX pharmacology","pmids":["31558566"],"confidence":"High","gaps":["Identity of the residual open-channel blocker unknown","Structural basis of open-channel block unresolved"]},{"year":2020,"claim":"Identified JAK2 phosphorylation of FGF14 at Y158 as a switch reciprocally controlling homodimerization versus Nav1.6 binding, mechanistically coupling cytokine signaling to channel modulation.","evidence":"HTS, in vitro phosphorylation with MS, split-LCA, patch-clamp, and Y158A dependency test","pmids":["32599005"],"confidence":"High","gaps":["Physiological JAK2 activation context not defined in this study","Quantitative balance of dimer vs complex in neurons unknown"]},{"year":2020,"claim":"Confirmed V160 as a binding hotspot by direct SPR and showed the FLPK peptide disrupts the complex to enhance excitability, validating the interface biophysically.","evidence":"In silico docking, split-LCA, surface plasmon resonance, patch-clamp in nucleus accumbens neurons","pmids":["32671946"],"confidence":"Medium","gaps":["Single lab, no in vivo behavioral validation","Binding affinity quantification limited"]},{"year":2023,"claim":"Placed FGF14 within a TNFR1-JAK2-FGF14-Nav1.6 axis driving hippocampal hyperexcitability in cerebral malaria, linking inflammation to channel scaffolding in disease.","evidence":"Split-LCA for TNFR1 effects, patch-clamp in eCM slices, in vivo FGF14 knockdown, anti-TNF treatment","pmids":["38115011"],"confidence":"Medium","gaps":["Single lab, mechanism inferred from LCA and KD","Direct TNFR1-FGF14 phosphorylation coupling not biochemically isolated"]},{"year":2024,"claim":"Showed the SCA27A F145S allele acts through haploinsufficiency with reduced iFGF14 and a hyperpolarizing shift in Nav closed-state inactivation, clarifying the disease mechanism in a knock-in model.","evidence":"Fgf14^F145S knock-in mice with Western blot, current/voltage-clamp, and TTX pharmacology","pmids":["41558966","39484407"],"confidence":"High","gaps":["Whether residual dominant-negative effects contribute alongside haploinsufficiency unresolved","Therapeutic correction not tested"]},{"year":2025,"claim":"Revealed opposite, cell-type-specific FGF14 function in CA1 neurons, where loss raises Nav1.6 levels and increases firing without an inactivation shift, demonstrating context-dependent regulation.","evidence":"Current/voltage-clamp in adult Fgf14-/- hippocampal slices with quantitative AIS immunohistochemistry","pmids":["40323232"],"confidence":"High","gaps":["Molecular basis of the Purkinje vs CA1 divergence unknown","Whether different Nav isoform composition explains the difference untested"]},{"year":2025,"claim":"Identified a small molecule (compound 1028) targeting FGF14 R117 that depolarizes Nav1.6 inactivation with nanomolar potency and drives accumbal firing and motivational behavior in an FGF14-dependent manner, advancing the interface as a CNS drug target.","evidence":"Split-LCA, patch-clamp, in vivo recording, in vivo gene silencing, behavior, in silico docking","pmids":["39747162"],"confidence":"High","gaps":["Selectivity across FHF family not fully characterized","Long-term in vivo safety/efficacy untested"]},{"year":null,"claim":"The structural and regulatory logic that determines why FGF14 loss hypo-excites Purkinje neurons but hyper-excites CA1 neurons, and how dimerization, phosphorylation, and channel-isoform context are integrated in vivo, remains 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Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39574782","citation_count":4,"is_preprint":false},{"pmid":"29253853","id":"PMC_29253853","title":"Familial episodic ataxia in lambs is potentially associated with a mutation in the fibroblast growth factor 14 (FGF14) gene.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29253853","citation_count":4,"is_preprint":false},{"pmid":"39484407","id":"PMC_39484407","title":"In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39484407","citation_count":3,"is_preprint":false},{"pmid":"40204701","id":"PMC_40204701","title":"Deletion of Fgf14 confers resilience to basal and stress-induced depressive-like behavior and reduces anxiety in mice.","date":"2025","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/40204701","citation_count":3,"is_preprint":false},{"pmid":"37460234","id":"PMC_37460234","title":"Pearls & Oy-sters: ATX-FGF14 Mimicking Autoimmune Pathology.","date":"2023","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37460234","citation_count":2,"is_preprint":false},{"pmid":"40623333","id":"PMC_40623333","title":"FGF14 (GAA∙TTC) repeat expansion-related ataxia SCA27B is common in Northern Finland.","date":"2025","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/40623333","citation_count":2,"is_preprint":false},{"pmid":"41558966","id":"PMC_41558966","title":"In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.","date":"2026","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41558966","citation_count":2,"is_preprint":false},{"pmid":"41366810","id":"PMC_41366810","title":"Uncovering molecular determinants of potency and binding affinity in hit compounds targeting FGF14/Nav1.6 complex.","date":"2025","source":"Journal of cheminformatics","url":"https://pubmed.ncbi.nlm.nih.gov/41366810","citation_count":2,"is_preprint":false},{"pmid":"39704271","id":"PMC_39704271","title":"The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient.","date":"2024","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/39704271","citation_count":2,"is_preprint":false},{"pmid":"40323232","id":"PMC_40323232","title":"Loss of intracellular FGF14 (iFGF14) increases excitability of mature hippocampal pyramidal neurons.","date":"2025","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/40323232","citation_count":1,"is_preprint":false},{"pmid":"40329566","id":"PMC_40329566","title":"Increased expression of FGF14 and SCN2A/SCN11A is associated with better survival of HCC patients.","date":"2025","source":"Tumori","url":"https://pubmed.ncbi.nlm.nih.gov/40329566","citation_count":1,"is_preprint":false},{"pmid":"40835733","id":"PMC_40835733","title":"Unstable FGF14 GAA repeat expansions in Indian ataxia patients: a broader phenotype and involvement of modifier loci?","date":"2025","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40835733","citation_count":1,"is_preprint":false},{"pmid":"41099962","id":"PMC_41099962","title":"Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions.","date":"2025","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/41099962","citation_count":1,"is_preprint":false},{"pmid":"39006414","id":"PMC_39006414","title":"Somatic instability of the FGF14 -SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.","date":"2024","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39006414","citation_count":1,"is_preprint":false},{"pmid":"41010287","id":"PMC_41010287","title":"FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function.","date":"2025","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41010287","citation_count":0,"is_preprint":false},{"pmid":"42096001","id":"PMC_42096001","title":"Identification of FGF14 GAA Expansions in Polish Patients with Undiagnosed Cerebellar Ataxia - A Preliminary Study.","date":"2026","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/42096001","citation_count":0,"is_preprint":false},{"pmid":"42044943","id":"PMC_42044943","title":"Long-term response to aminopyridines in a cohort of patients with ataxia associated with downbeat nystagmus due to the FGF14 GAA expansion.","date":"2026","source":"Neurologia","url":"https://pubmed.ncbi.nlm.nih.gov/42044943","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40675,"output_tokens":6862,"usd":0.112477,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15770,"output_tokens":6285,"usd":0.117987,"stage2_stop_reason":"end_turn"},"total_usd":0.230464,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"FGF14 is required for normal neuronal signaling, axonal trafficking, and synaptosomal function; Fgf14-/- mice develop ataxia and paroxysmal hyperkinetic movement disorder with reduced dopamine agonist responses; an FGF14N-beta-gal fusion protein is efficiently transported into neuronal processes in basal ganglia and cerebellum, establishing FGF14's role in axonal trafficking.\",\n      \"method\": \"Targeted gene disruption (Fgf14-/- mice), beta-galactosidase fusion protein trafficking assay, neuropharmacological behavioral studies\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular/behavioral phenotypes, axonal transport assay, replicated across multiple readouts in single rigorous study\",\n      \"pmids\": [\"12123606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FGF14 interacts directly with the pore-forming alpha subunits of voltage-gated Na+ (Nav) channels; the disease-causing FGF14(F145S) mutant does not bind Nav alpha subunits directly but instead associates with wild-type FGF14 and disrupts FGF14-Nav interaction in a dominant-negative manner, reducing Nav expression at the axon initial segment, attenuating Nav currents, and reducing hippocampal neuron excitability.\",\n      \"method\": \"Co-immunoprecipitation, whole-cell patch-clamp electrophysiology, immunocytochemistry of axon initial segment Nav expression, dominant-negative expression in hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, electrophysiology, and localization experiments with multiple orthogonal methods in one study; replicated concept across multiple labs\",\n      \"pmids\": [\"17978045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FGF14 is required for normal Nav1.6 expression in cerebellar Purkinje neurons; loss of FGF14 in Fgf14-/- mice results in attenuated spontaneous firing and failure of repetitive firing in response to depolarization, associated with reduced Nav1.6 protein levels at Purkinje neurons.\",\n      \"method\": \"Current-clamp recordings from cerebellar slice preparations (Fgf14-/- vs. wild type), immunohistochemistry for Nav1.6\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined electrophysiological phenotype and protein localization readout, multiple orthogonal methods\",\n      \"pmids\": [\"18930825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The two N-terminal alternatively spliced FGF14 variants, FGF14-1a and FGF14-1b, differentially regulate Nav1.2 and Nav1.6 channel currents: FGF14-1b but not FGF14-1a attenuates Nav1.2 and Nav1.6 current densities, while an FGF14 mutant lacking the N-terminus increases Nav1.6 current density. Both FGF14-1a and FGF14-1b localize to the axon initial segment, and deletion of the N-terminus abolishes this localization.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in heterologous expression, confocal immunofluorescence localization in neurons, N-terminal deletion mutagenesis\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, imaging, mutagenesis) in one study with isoform-specific dissection\",\n      \"pmids\": [\"19465131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FGF14 localizes to the axon initial segment (AIS) of Purkinje neurons in a proximal-to-distal decreasing gradient; in Nav1.6-deficient (Scn8a med) mice, FGF14 immunoreactivity is markedly increased and expanded at the AIS in parallel with increased Nav1.1 and expanded βIV-spectrin; loss of FGF14 (Fgf14-/-) modestly but significantly reduces Nav1.1 and Nav1.6 alpha subunit levels at AIS sub-domains without affecting ankyrin G or βIV-spectrin localization.\",\n      \"method\": \"Immunohistochemistry and confocal imaging of AIS proteins in wild type, Scn8a med, and Fgf14-/- mice\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional genetic controls across multiple mouse models, multiple protein markers\",\n      \"pmids\": [\"23891806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FGF14 regulates presynaptic CaV2 Ca2+ channel function in cerebellar granule cells; knockdown of FGF14 reduces Ca2+ currents, diminishes vesicular recycling, and markedly reduces excitatory postsynaptic currents at the granule cell-to-Purkinje cell synapse; the SCA27-causing FGF14 mutant exerts a dominant-negative reduction in Ca2+ currents and EPSCs.\",\n      \"method\": \"shRNA knockdown of FGF14 in granule cells, patch-clamp electrophysiology (Ca2+ currents and EPSCs), vesicular recycling assay, dominant-negative mutant expression\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with defined electrophysiological phenotypes, multiple readouts (Ca2+ current, vesicular recycling, EPSCs), dominant-negative validation\",\n      \"pmids\": [\"23831029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGF14 forms homodimers in cells; short peptide fragments (FLPK) targeting the β12-strand/β8-β9 loop of FGF14 reduce FGF14:FGF14 dimer interaction by ~25%; residues Y153/V155 at the β8-β9 loop modulate dimer strength; the dimer interface overlaps with the Nav channel binding surface.\",\n      \"method\": \"Split-luciferase complementation assay (LCA) for in-cell FGF14:FGF14 interaction, peptide competition, site-directed mutagenesis (Y153N/V155N)\",\n      \"journal\": \"CNS & neurological disorders drug targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in-cell reconstitution with LCA, single lab, single method for dimer measurement\",\n      \"pmids\": [\"25426956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Acute shRNA-mediated knockdown of FGF14 selectively in adult Purkinje neurons attenuates spontaneous and evoked action potential firing without altering Nav channel localization at the AIS; loss of FGF14 causes a hyperpolarizing shift in steady-state Nav current inactivation in adult Purkinje neurons; membrane hyperpolarization restores repetitive firing, indicating FGF14 regulates excitability in a membrane-potential-dependent manner; re-expression of FGF14 selectively in adult Fgf14-/- Purkinje neurons rescues spontaneous firing and improves motor performance.\",\n      \"method\": \"In vivo shRNA knockdown in adult mice, current-clamp and voltage-clamp recordings from cerebellar slices, immunohistochemistry, viral rescue experiment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, KO, rescue, electrophysiology, imaging), adult-specific manipulation ruling out developmental effects\",\n      \"pmids\": [\"25926453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PI3K/Akt pathway, Wee1 kinase, and PKC are identified as regulatory nodes of the FGF14:Nav1.6 complex; GSK3 is identified as a convergence point; GSK3 inhibition impairs excitability of hippocampal neurons.\",\n      \"method\": \"Split-luciferase complementation assay screening of 12 kinase pathway inhibitors, hierarchical clustering, patch-clamp electrophysiology in hippocampal neurons\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in-cell LCA with dose-dependent validation, single lab, functional electrophysiology confirmation of GSK3 node\",\n      \"pmids\": [\"25659151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FGF14 promotes axonal localization of voltage-gated sodium channels (VGSCs) at the axon initial segment; single-point mutations in FGF14 abrogating VGSC interaction abolish this axonal promotion function; concerted action with FGF13 (which limits somatodendritic VGSC surface expression) establishes polarized VGSC localization supporting efficient action potential initiation.\",\n      \"method\": \"shRNA knockdown of FGF14 and FGF13 in hippocampal neurons, site-directed mutagenesis of VGSC-interaction residues, confocal imaging of VGSC distribution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD plus interaction-abrogating mutagenesis, multiple orthogonal methods, functional mechanistic dissection\",\n      \"pmids\": [\"27044086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FGF14 regulates KCNQ2/3 (Kv7.2/7.3) channel function and AIS localization; FGF14 knockdown reduces KCNQ2 at the AIS and reduces whole-cell KCNQ currents; FGF14 interacts with KCNQ2 at a site distinct from the FGF14-VGSC interaction surface; FGF14 can simultaneously bridge NaV1.6 and KCNQ2.\",\n      \"method\": \"shRNA knockdown of FGF14, whole-cell patch-clamp electrophysiology, co-immunoprecipitation, confocal imaging of KCNQ2 localization, heterologous expression system\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with electrophysiological phenotype, co-IP, imaging, and heterologous expression; multiple orthogonal methods\",\n      \"pmids\": [\"27994149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Identification of specific amino acid residues in FGF14 required for Nav1.6 interaction: Val-160 in the β-9 sheet is a hotspot for FGF14:Nav1.6 complex formation (V160A impairs Nav1.6 binding but not FGF14 homodimerization); Lys-74/Ile-76 at the N-terminal contribute to both Nav1.6 complex and FGF14:FGF14 dimer formation; Y158/V160 double mutation impedes FGF14-dependent modulation of Nav channel fast inactivation.\",\n      \"method\": \"Site-directed mutagenesis, split-luciferase complementation assay (LCA), whole-cell patch-clamp electrophysiology, intrinsic fluorescence spectroscopy of purified proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with purified proteins, mutagenesis, electrophysiology; multiple orthogonal methods in single study\",\n      \"pmids\": [\"26994141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CK2 (casein kinase 2) phosphorylates FGF14 directly at S228 and S230; CK2 inhibition reduces FGF14:Nav1.6 and FGF14:Nav1.2 interactions; S228A/S230A alanine mutations modify FGF14 modulation of Nav1.6-mediated currents; CK2 inhibition reduces FGF14 expression, attenuates transient Na+ currents, and shifts Nav channel steady-state inactivation in hippocampal neurons; CK2 inhibitor effects on excitability are occluded in Fgf14-/- mice, confirming on-target specificity.\",\n      \"method\": \"Mass spectrometry (in vitro phosphorylation), split-LCA, whole-cell patch-clamp, confocal imaging, CK2 inhibitor (TBB) pharmacology in WT and Fgf14-/- mice\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — MS-confirmed phosphorylation, mutagenesis, electrophysiology, and genetic epistasis (Fgf14-/- occlusion); multiple orthogonal methods\",\n      \"pmids\": [\"26917740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GSK-3β phosphorylates FGF14 at S226 in vitro, confirmed by mass spectrometry; phosphosilent S226A mutation impairs FGF14:Nav1.6 complex assembly and FGF14-dependent functional regulation of Nav1.6-mediated currents; PPARγ agonist rosiglitazone treatment of Tg2576 AD-model mice reduces S226 phosphorylation and rescues Nav channel expression at the AIS.\",\n      \"method\": \"Nano-LC-MS/MS quantitative proteomics, in vitro kinase phosphorylation assay, mass spectrometry confirmation, split-LCA, confocal imaging, electrophysiology\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-confirmed phosphorylation, in vitro kinase assay, functional mutagenesis (S226A), multiple orthogonal methods\",\n      \"pmids\": [\"28522250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A peptidomimetic (ZL181) targeting the FGF14:Nav1.6 protein-protein interaction interface binds to FGF14 and inhibits its interaction with the Nav1.6 C-tail; ZL181 acts synergistically with FGF14 to suppress Nav1.6 current density and slow fast inactivation kinetics but antagonizes FGF14 modulation of steady-state inactivation; ZL181 suppresses excitability of medium spiny neurons in the nucleus accumbens in an FGF14-expression-dependent manner.\",\n      \"method\": \"Split-LCA, whole-cell patch-clamp electrophysiology in HEK-Nav1.6 cells and medium spiny neurons, FGF14 knockdown dependency test\",\n      \"journal\": \"ACS chemical neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LCA and electrophysiology with FGF14-dependency confirmed by KD, single lab, two orthogonal methods\",\n      \"pmids\": [\"29359916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of FGF14 reduces resurgent Na+ current amplitude in cerebellar Purkinje neurons and leads to acceleration and stabilization of Na+ channel inactivation not reversed by site-3 toxin ATX; FGF14 preferentially modulates a highly TTX-sensitive (Nav1.6-containing) subset of Purkinje Na+ channels to facilitate open-channel block; however, deletion of FGF14 alone (or together with NaVβ4) does not eliminate resurgent current, indicating FGF14 is not the sole open-channel blocker.\",\n      \"method\": \"Whole-cell voltage-clamp of Na+ currents in acutely dissociated Purkinje neurons from Fgf14-/-, NaVβ4-/-, and double-KO mice; TTX sensitivity analysis; ATX pharmacology\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined electrophysiological phenotype across multiple genetic backgrounds, pharmacological dissection\",\n      \"pmids\": [\"31558566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"JAK2 phosphorylates FGF14 at Y158, a residue that mediates both FGF14 homodimerization and FGF14:Nav1.6 complex formation; JAK2 inhibition increases FGF14 homodimerization inversely to FGF14:Nav1.6 complex formation; this effect is abolished by the FGF14Y158A mutation; JAK2 controls FGF14-dependent modulation of Nav1.6 channels; JAK2 inhibitor (Fedratinib) reduces firing in hippocampal CA1 neurons by an FGF14-dependent mechanism.\",\n      \"method\": \"High-throughput screening (>3000 compounds), in vitro phosphorylation, mass spectrometry, split-LCA, patch-clamp electrophysiology, FGF14-dependency test\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — MS-confirmed phosphorylation, in vitro kinase assay, mutagenesis, electrophysiology with genetic dependency; multiple orthogonal methods\",\n      \"pmids\": [\"32599005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The FGF14 V160 residue within the FGF14 core domain is a hotspot for FGF14:Nav1.6 complex formation; the FLPK peptide (mapping around V160) disrupts FGF14:Nav1.6 interaction, confirmed by split-LCA and surface plasmon resonance; FLPK activity requires the FGF14 N-terminal tail; in nucleus accumbens medium spiny neurons, FLPK increases firing frequency by interfering with Nav1.6 inactivation.\",\n      \"method\": \"In silico docking, split-LCA, surface plasmon resonance (SPR), whole-cell patch-clamp electrophysiology\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SPR (direct binding), LCA, electrophysiology; multiple methods but single lab\",\n      \"pmids\": [\"32671946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNFR1 stimulation via JAK2 increases FGF14:Nav1.6 complex assembly; in experimental cerebral malaria (eCM), Plasmodium chabaudi infection augments Nav1.6 channel conductance of CA1 pyramidal neurons through the TNFR1-JAK2-FGF14-Nav1.6 signaling network, leading to neuronal hyperexcitability; genetic silencing of FGF14 in CA1 mitigated infection-induced hyperexcitability and reduced sickness behavior.\",\n      \"method\": \"Split-LCA for TNFR1 signaling effects on FGF14:Nav1.6 complex, whole-cell patch-clamp in eCM brain slices, FGF14 genetic knockdown in vivo, anti-TNF antibody treatment\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — LCA, electrophysiology, in vivo genetic knockdown; multiple methods in single lab\",\n      \"pmids\": [\"38115011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The FGF14(F145S) SCA27A knock-in mouse (Fgf14^F145S) shows haploinsufficiency: heterozygous Fgf14^F145S mice display reduced iFGF14 protein expression and impaired Purkinje neuron firing (shift from tonic to burst firing), mirroring heterozygous Fgf14 KO mice; homozygous Fgf14^F145S mice show undetectable iFGF14 and more severe firing deficits; the firing change reflects a hyperpolarizing shift in Nav channel closed-state inactivation; TTX mimics the burst firing phenotype in WT neurons.\",\n      \"method\": \"Knock-in mouse model, Western blot (iFGF14 expression), current-clamp and voltage-clamp recordings from cerebellar slices, TTX pharmacology\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in model with genetic controls, Western blot, electrophysiology, pharmacological validation; multiple orthogonal methods\",\n      \"pmids\": [\"41558966\", \"39484407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of iFGF14 in adult hippocampal CA1 pyramidal neurons increases (rather than decreases) evoked repetitive firing; unlike Purkinje neurons, Nav current steady-state inactivation voltage dependence is not shifted in CA1 neurons; Nav1.6 protein levels along the AIS are significantly higher in Fgf14-/- CA1 neurons compared to wild type, without disruption of Nav1.6 or ankyrin G localization pattern, indicating cell-type-specific FGF14 regulation of Nav channels.\",\n      \"method\": \"Current-clamp and voltage-clamp in acute hippocampal slices from adult Fgf14-/- mice, immunohistochemistry with quantitative intensity analysis of AIS proteins\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined electrophysiological and localization phenotypes, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"40323232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Compound 1028 targets FGF14 residue R117 at the FGF14/Nav1.6 protein-protein interaction interface; it modulates FGF14/Nav1.6 complex assembly, depolarizes the voltage-dependence of Nav1.6 channel inactivation (nanomolar potency), enhances medium spiny neuron excitability ex vivo and accumbal neuron firing rate in vivo; behavioral motivational effects are abrogated by in vivo Fgf14 gene silencing in the NAc, confirming on-target mechanism.\",\n      \"method\": \"Split-LCA, patch-clamp electrophysiology, in vivo neural recording, in vivo gene silencing, behavioral assays, in silico docking\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (LCA, electrophysiology, in vivo recording, genetic dependency test, behavior), single lab but rigorous design\",\n      \"pmids\": [\"39747162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Chicken FHF-4 (ortholog of FGF14) is expressed in paraxial mesoderm, lateral ridge, and posterior-dorsal limb base; its expression is correlated with early limb innervation patterns and is regulated by retinoic acid; ectopic FHF-4 expression correlates with local induction of limb-like innervation, suggesting a role in regulating early innervation events at the base of the limbs.\",\n      \"method\": \"In situ hybridization, tissue grafting (ZPA, Shh-expressing cells), bead implantation (retinoic acid, FGF-2), analysis of chicken limb patterning mutants\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression/localization correlation in chicken model, no direct functional assay for FHF-4 protein mechanism\",\n      \"pmids\": [\"10906454\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGF14 (iFGF14) is an intracellular, non-secreted FGF that functions as a multivalent regulator of neuronal excitability by directly binding the C-terminal tail of voltage-gated Na+ (Nav) channel alpha subunits (particularly Nav1.6 and Nav1.2) at the axon initial segment (AIS), where it promotes Nav channel localization, modulates channel gating (shifting steady-state inactivation), and sustains high-frequency repetitive firing in cerebellar Purkinje neurons; it also regulates presynaptic CaV2 Ca2+ channels and KCNQ2/3 K+ channels at the AIS; its interactions with Nav channels are regulated by post-translational phosphorylation via CK2 (at S228/S230), GSK-3β (at S226), and JAK2 (at Y158), and by the dimerization state of FGF14 itself; loss-of-function (Fgf14-/- mice or SCA27A knock-in) causes Purkinje neuron hypoexcitability through a hyperpolarizing shift in Nav channel inactivation, ataxia, and paroxysmal movement disorder, while loss of FGF14 paradoxically increases excitability in hippocampal CA1 neurons, revealing cell-type-specific functional roles.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FGF14 (iFGF14) is an intracellular fibroblast growth factor that functions as a multivalent scaffold controlling neuronal excitability at the axon initial segment (AIS), where it directly binds the pore-forming alpha subunits of voltage-gated Na+ (Nav) channels to govern their localization, gating, and the repetitive firing of cerebellar Purkinje neurons [#1, #2, #7]. The interaction is mediated by a defined core-domain surface — notably Val-160 and Tyr-158 in the beta-9 sheet plus N-terminal residues (Lys-74/Ile-76) — that partially overlaps the FGF14 homodimerization interface, so that dimerization and Nav binding are competing, mutually regulated states [#6, #11]. Through this interface FGF14 promotes axonal Nav (Nav1.6, Nav1.2) accumulation at the AIS and sustains high-frequency firing, acting in concert with FGF13 to establish polarized channel distribution, while its N-terminal splice variants (FGF14-1a/1b) confer isoform-specific modulation of Nav current density [#3, #9, #4]. Beyond Nav channels, FGF14 binds KCNQ2/3 (Kv7) K+ channels at a distinct surface and can simultaneously bridge Nav1.6 and KCNQ2, and it supports presynaptic CaV2 Ca2+ channel function and synaptic transmission at the granule-to-Purkinje synapse [#10, #5]. The FGF14:Nav complex is dynamically tuned by phosphorylation of FGF14 — CK2 at S228/S230, GSK-3beta at S226, and JAK2 at Y158 — linking the channel scaffold to PI3K/Akt, GSK3, and cytokine (TNFR1) signaling nodes [#12, #13, #16, #8, #18]. FGF14 modulates Nav steady-state and resurgent current, and its loss produces a hyperpolarizing shift in Nav inactivation that drives Purkinje hypoexcitability and a switch from tonic to burst firing, whereas in hippocampal CA1 neurons loss of FGF14 paradoxically raises Nav1.6 levels and increases firing — establishing cell-type-specific regulatory roles [#7, #15, #20]. The disease-causing F145S mutation acts dominant-negatively and as a haploinsufficiency allele in SCA27A knock-in mice, recapitulating impaired Purkinje firing [#1, #19], and the FGF14:Nav1.6 interface is a druggable target modulated by interface-binding peptides and small molecules (ZL181, FLPK, compound 1028) [#14, #17, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that FGF14 is required in vivo for normal neuronal signaling and axonal trafficking, defining its broad role before any molecular partner was known.\",\n      \"evidence\": \"Targeted Fgf14-/- mouse with behavioral, synaptosomal, and beta-galactosidase fusion trafficking readouts\",\n      \"pmids\": [\"12123606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No molecular target or binding partner identified\", \"Cellular mechanism of trafficking defect unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Nav channel alpha subunits as direct FGF14 binding partners and showed the F145S mutant disrupts the complex dominant-negatively, providing the first molecular mechanism for FGF14 control of excitability.\",\n      \"evidence\": \"Co-immunoprecipitation, patch-clamp, AIS immunocytochemistry, and dominant-negative expression in hippocampal neurons\",\n      \"pmids\": [\"17978045\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface residues not yet mapped\", \"Did not address Purkinje-specific phenotype\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected FGF14 loss to reduced Nav1.6 in cerebellar Purkinje neurons and failure of repetitive firing, tying the molecular interaction to the ataxia phenotype.\",\n      \"evidence\": \"Current-clamp of Fgf14-/- cerebellar slices with Nav1.6 immunohistochemistry\",\n      \"pmids\": [\"18930825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Could not separate developmental from acute requirement\", \"Mechanism of gating modulation not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed N-terminal splice variants differentially regulate Nav1.2/Nav1.6 currents and that the N-terminus is required for AIS targeting, establishing isoform-specific functional outputs.\",\n      \"evidence\": \"Patch-clamp in heterologous cells, confocal localization, N-terminal deletion mutagenesis\",\n      \"pmids\": [\"19465131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of each isoform in vivo unclear\", \"Structural basis of N-terminal targeting unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended FGF14 function beyond Nav channels to presynaptic CaV2 Ca2+ channels and synaptic transmission, broadening its role to neurotransmitter release.\",\n      \"evidence\": \"shRNA knockdown in granule cells with Ca2+ current, vesicular recycling, and EPSC recordings plus dominant-negative mutant\",\n      \"pmids\": [\"23831029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FGF14-CaV2 binding not demonstrated\", \"Mechanism of presynaptic regulation unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapped FGF14 to a graded AIS distribution and showed reciprocal regulation with Nav channel availability, clarifying how FGF14 partitions across AIS sub-domains.\",\n      \"evidence\": \"Confocal immunohistochemistry of AIS proteins in wild type, Scn8a med, and Fgf14-/- mice\",\n      \"pmids\": [\"23891806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Driver of the proximal-distal gradient unknown\", \"Did not test gating consequences\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated FGF14 acts acutely in adult Purkinje neurons by modulating Nav inactivation in a membrane-potential-dependent manner, separating its role from developmental wiring.\",\n      \"evidence\": \"In vivo adult shRNA knockdown, current/voltage-clamp, and viral rescue in Fgf14-/- mice\",\n      \"pmids\": [\"25926453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of inactivation shift not defined\", \"AIS localization unchanged, decoupling localization from gating effect\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified kinase signaling nodes (PI3K/Akt, Wee1, PKC, GSK3) that regulate the FGF14:Nav1.6 complex, framing the scaffold as a signaling-responsive hub.\",\n      \"evidence\": \"Split-luciferase complementation screen of kinase inhibitors with hippocampal electrophysiology\",\n      \"pmids\": [\"25659151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LCA screen from single lab without orthogonal binding assay for most nodes\", \"Direct phosphorylation sites not yet mapped\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved the FGF14 dimer interface and showed it overlaps the Nav binding surface, explaining how dimerization state gates channel engagement.\",\n      \"evidence\": \"Split-luciferase complementation, peptide competition, and Y153N/V155N mutagenesis\",\n      \"pmids\": [\"25426956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dimer measured by single in-cell method\", \"No high-resolution structure of the dimer\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pinpointed Val-160 and N-terminal Lys-74/Ile-76 as binding hotspots distinguishing Nav engagement from homodimerization, providing residue-level control of the complex.\",\n      \"evidence\": \"Site-directed mutagenesis, split-LCA, patch-clamp, and intrinsic fluorescence of purified proteins\",\n      \"pmids\": [\"26994141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of FGF14:Nav complex\", \"Contribution of each residue to in vivo firing untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed FGF14 establishes polarized VGSC localization in concert with FGF13, defining a division of labor between FHF paralogs for action potential initiation.\",\n      \"evidence\": \"shRNA knockdown of FGF14/FGF13, interaction-abrogating mutagenesis, confocal imaging\",\n      \"pmids\": [\"27044086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery linking FGF14 to axonal delivery unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended FGF14 to KCNQ2/3 K+ channels via a distinct surface, showing it can simultaneously bridge Nav1.6 and KCNQ2 as a multivalent AIS organizer.\",\n      \"evidence\": \"shRNA knockdown, patch-clamp, co-IP, confocal imaging, heterologous expression\",\n      \"pmids\": [\"27994149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of a tri-partite complex unresolved\", \"Structural basis of the KCNQ2 interaction surface unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified CK2 as a direct FGF14 kinase (S228/S230) controlling Nav complex assembly and excitability, with Fgf14-/- occlusion confirming on-target action.\",\n      \"evidence\": \"In vitro phosphorylation with MS, split-LCA, patch-clamp, and CK2 inhibitor pharmacology in WT and Fgf14-/- mice\",\n      \"pmids\": [\"26917740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo stoichiometry of phosphorylation unknown\", \"Upstream regulators of CK2 in this context undefined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established GSK-3beta phosphorylation of FGF14 at S226 as a regulator of complex assembly, with PPARgamma agonism rescuing AIS Nav expression in an AD model.\",\n      \"evidence\": \"Quantitative MS, in vitro kinase assay, S226A mutagenesis, confocal imaging, electrophysiology in Tg2576 mice\",\n      \"pmids\": [\"28522250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal link between S226 phosphorylation and disease behavior not fully established\", \"Interplay with CK2 sites untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated the FGF14:Nav1.6 interface is druggable, with a peptidomimetic modulating channel gating in an FGF14-dependent manner in medium spiny neurons.\",\n      \"evidence\": \"Split-LCA, patch-clamp in HEK-Nav1.6 and medium spiny neurons, FGF14 knockdown dependency test\",\n      \"pmids\": [\"29359916\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Compound from single lab, two methods\", \"Selectivity over other FHF-channel complexes not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed FGF14 shapes resurgent Na+ current by promoting open-channel block of TTX-sensitive Nav1.6 channels but is not the sole blocking factor, refining its biophysical role.\",\n      \"evidence\": \"Voltage-clamp of dissociated Purkinje neurons across Fgf14-/-, NaVbeta4-/-, and double-KO mice with TTX/ATX pharmacology\",\n      \"pmids\": [\"31558566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the residual open-channel blocker unknown\", \"Structural basis of open-channel block unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified JAK2 phosphorylation of FGF14 at Y158 as a switch reciprocally controlling homodimerization versus Nav1.6 binding, mechanistically coupling cytokine signaling to channel modulation.\",\n      \"evidence\": \"HTS, in vitro phosphorylation with MS, split-LCA, patch-clamp, and Y158A dependency test\",\n      \"pmids\": [\"32599005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological JAK2 activation context not defined in this study\", \"Quantitative balance of dimer vs complex in neurons unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed V160 as a binding hotspot by direct SPR and showed the FLPK peptide disrupts the complex to enhance excitability, validating the interface biophysically.\",\n      \"evidence\": \"In silico docking, split-LCA, surface plasmon resonance, patch-clamp in nucleus accumbens neurons\",\n      \"pmids\": [\"32671946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no in vivo behavioral validation\", \"Binding affinity quantification limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed FGF14 within a TNFR1-JAK2-FGF14-Nav1.6 axis driving hippocampal hyperexcitability in cerebral malaria, linking inflammation to channel scaffolding in disease.\",\n      \"evidence\": \"Split-LCA for TNFR1 effects, patch-clamp in eCM slices, in vivo FGF14 knockdown, anti-TNF treatment\",\n      \"pmids\": [\"38115011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, mechanism inferred from LCA and KD\", \"Direct TNFR1-FGF14 phosphorylation coupling not biochemically isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed the SCA27A F145S allele acts through haploinsufficiency with reduced iFGF14 and a hyperpolarizing shift in Nav closed-state inactivation, clarifying the disease mechanism in a knock-in model.\",\n      \"evidence\": \"Fgf14^F145S knock-in mice with Western blot, current/voltage-clamp, and TTX pharmacology\",\n      \"pmids\": [\"41558966\", \"39484407\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether residual dominant-negative effects contribute alongside haploinsufficiency unresolved\", \"Therapeutic correction not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed opposite, cell-type-specific FGF14 function in CA1 neurons, where loss raises Nav1.6 levels and increases firing without an inactivation shift, demonstrating context-dependent regulation.\",\n      \"evidence\": \"Current/voltage-clamp in adult Fgf14-/- hippocampal slices with quantitative AIS immunohistochemistry\",\n      \"pmids\": [\"40323232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the Purkinje vs CA1 divergence unknown\", \"Whether different Nav isoform composition explains the difference untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a small molecule (compound 1028) targeting FGF14 R117 that depolarizes Nav1.6 inactivation with nanomolar potency and drives accumbal firing and motivational behavior in an FGF14-dependent manner, advancing the interface as a CNS drug target.\",\n      \"evidence\": \"Split-LCA, patch-clamp, in vivo recording, in vivo gene silencing, behavior, in silico docking\",\n      \"pmids\": [\"39747162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity across FHF family not fully characterized\", \"Long-term in vivo safety/efficacy untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural and regulatory logic that determines why FGF14 loss hypo-excites Purkinje neurons but hyper-excites CA1 neurons, and how dimerization, phosphorylation, and channel-isoform context are integrated in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of an FGF14:Nav or FGF14:KCNQ complex in the corpus\", \"Cell-type determinants of opposite excitability outcomes unknown\", \"Integrated quantitative model of dimer/phospho/complex equilibrium absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 5, 7, 10, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 4, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 7, 15, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 13, 16, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SCN8A\", \"SCN2A\", \"KCNQ2\", \"KCNQ3\", \"FGF13\", \"FGF14\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}