Affinage

FGF14

Fibroblast growth factor 14 · UniProt Q92915

Length
247 aa
Mass
27.7 kDa
Annotated
2026-06-09
74 papers in source corpus 24 papers cited in narrative 23 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2002 High

    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

    PMID:12123606

    Open questions at the time
    • No molecular target or binding partner identified
    • Cellular mechanism of trafficking defect unresolved
  2. 2007 High

    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

    PMID:17978045

    Open questions at the time
    • Binding interface residues not yet mapped
    • Did not address Purkinje-specific phenotype
  3. 2008 High

    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

    PMID:18930825

    Open questions at the time
    • Could not separate developmental from acute requirement
    • Mechanism of gating modulation not resolved
  4. 2009 High

    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

    PMID:19465131

    Open questions at the time
    • Physiological role of each isoform in vivo unclear
    • Structural basis of N-terminal targeting unknown
  5. 2013 High

    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

    PMID:23831029

    Open questions at the time
    • Direct FGF14-CaV2 binding not demonstrated
    • Mechanism of presynaptic regulation unresolved
  6. 2013 High

    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

    PMID:23891806

    Open questions at the time
    • Driver of the proximal-distal gradient unknown
    • Did not test gating consequences
  7. 2015 High

    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

    PMID:25926453

    Open questions at the time
    • Molecular trigger of inactivation shift not defined
    • AIS localization unchanged, decoupling localization from gating effect
  8. 2015 Medium

    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

    PMID:25659151

    Open questions at the time
    • LCA screen from single lab without orthogonal binding assay for most nodes
    • Direct phosphorylation sites not yet mapped
  9. 2016 Medium

    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

    PMID:25426956

    Open questions at the time
    • Dimer measured by single in-cell method
    • No high-resolution structure of the dimer
  10. 2016 High

    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

    PMID:26994141

    Open questions at the time
    • No co-crystal structure of FGF14:Nav complex
    • Contribution of each residue to in vivo firing untested
  11. 2016 High

    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

    PMID:27044086

    Open questions at the time
    • Trafficking machinery linking FGF14 to axonal delivery unknown
  12. 2016 High

    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

    PMID:27994149

    Open questions at the time
    • Stoichiometry of a tri-partite complex unresolved
    • Structural basis of the KCNQ2 interaction surface unknown
  13. 2016 High

    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

    PMID:26917740

    Open questions at the time
    • In vivo stoichiometry of phosphorylation unknown
    • Upstream regulators of CK2 in this context undefined
  14. 2017 High

    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

    PMID:28522250

    Open questions at the time
    • Causal link between S226 phosphorylation and disease behavior not fully established
    • Interplay with CK2 sites untested
  15. 2018 Medium

    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

    PMID:29359916

    Open questions at the time
    • Compound from single lab, two methods
    • Selectivity over other FHF-channel complexes not assessed
  16. 2019 High

    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

    PMID:31558566

    Open questions at the time
    • Identity of the residual open-channel blocker unknown
    • Structural basis of open-channel block unresolved
  17. 2020 High

    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

    PMID:32599005

    Open questions at the time
    • Physiological JAK2 activation context not defined in this study
    • Quantitative balance of dimer vs complex in neurons unknown
  18. 2020 Medium

    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

    PMID:32671946

    Open questions at the time
    • Single lab, no in vivo behavioral validation
    • Binding affinity quantification limited
  19. 2023 Medium

    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

    PMID:38115011

    Open questions at the time
    • Single lab, mechanism inferred from LCA and KD
    • Direct TNFR1-FGF14 phosphorylation coupling not biochemically isolated
  20. 2024 High

    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

    PMID:39484407 PMID:41558966

    Open questions at the time
    • Whether residual dominant-negative effects contribute alongside haploinsufficiency unresolved
    • Therapeutic correction not tested
  21. 2025 High

    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

    PMID:40323232

    Open questions at the time
    • Molecular basis of the Purkinje vs CA1 divergence unknown
    • Whether different Nav isoform composition explains the difference untested
  22. 2025 High

    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

    PMID:39747162

    Open questions at the time
    • Selectivity across FHF family not fully characterized
    • Long-term in vivo safety/efficacy untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005856 cytoskeleton 3
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 4
Partners
FGF13FGF14KCNQ2KCNQ3SCN2ASCN8A

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Targeted gene disruption (Fgf14-/- mice), beta-galactosidase fusion protein trafficking assay, neuropharmacological behavioral studies Neuron High 12123606
2007 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. Co-immunoprecipitation, whole-cell patch-clamp electrophysiology, immunocytochemistry of axon initial segment Nav expression, dominant-negative expression in hippocampal neurons The Journal of neuroscience High 17978045
2008 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. Current-clamp recordings from cerebellar slice preparations (Fgf14-/- vs. wild type), immunohistochemistry for Nav1.6 Neurobiology of disease High 18930825
2009 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. Whole-cell patch-clamp electrophysiology in heterologous expression, confocal immunofluorescence localization in neurons, N-terminal deletion mutagenesis Molecular and cellular neurosciences High 19465131
2013 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. Immunohistochemistry and confocal imaging of AIS proteins in wild type, Scn8a med, and Fgf14-/- mice Molecular and cellular neurosciences High 23891806
2013 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. shRNA knockdown of FGF14 in granule cells, patch-clamp electrophysiology (Ca2+ currents and EPSCs), vesicular recycling assay, dominant-negative mutant expression Cell reports High 23831029
2014 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. Split-luciferase complementation assay (LCA) for in-cell FGF14:FGF14 interaction, peptide competition, site-directed mutagenesis (Y153N/V155N) CNS & neurological disorders drug targets Medium 25426956
2015 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. In vivo shRNA knockdown in adult mice, current-clamp and voltage-clamp recordings from cerebellar slices, immunohistochemistry, viral rescue experiment The Journal of neuroscience High 25926453
2015 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. Split-luciferase complementation assay screening of 12 kinase pathway inhibitors, hierarchical clustering, patch-clamp electrophysiology in hippocampal neurons PloS one Medium 25659151
2016 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. shRNA knockdown of FGF14 and FGF13 in hippocampal neurons, site-directed mutagenesis of VGSC-interaction residues, confocal imaging of VGSC distribution Proceedings of the National Academy of Sciences of the United States of America High 27044086
2016 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. shRNA knockdown of FGF14, whole-cell patch-clamp electrophysiology, co-immunoprecipitation, confocal imaging of KCNQ2 localization, heterologous expression system Proceedings of the National Academy of Sciences of the United States of America High 27994149
2016 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. Site-directed mutagenesis, split-luciferase complementation assay (LCA), whole-cell patch-clamp electrophysiology, intrinsic fluorescence spectroscopy of purified proteins The Journal of biological chemistry High 26994141
2016 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. Mass spectrometry (in vitro phosphorylation), split-LCA, whole-cell patch-clamp, confocal imaging, CK2 inhibitor (TBB) pharmacology in WT and Fgf14-/- mice FASEB journal High 26917740
2017 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. Nano-LC-MS/MS quantitative proteomics, in vitro kinase phosphorylation assay, mass spectrometry confirmation, split-LCA, confocal imaging, electrophysiology Experimental neurology High 28522250
2018 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. Split-LCA, whole-cell patch-clamp electrophysiology in HEK-Nav1.6 cells and medium spiny neurons, FGF14 knockdown dependency test ACS chemical neuroscience Medium 29359916
2019 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. Whole-cell voltage-clamp of Na+ currents in acutely dissociated Purkinje neurons from Fgf14-/-, NaVβ4-/-, and double-KO mice; TTX sensitivity analysis; ATX pharmacology The Journal of general physiology High 31558566
2020 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. High-throughput screening (>3000 compounds), in vitro phosphorylation, mass spectrometry, split-LCA, patch-clamp electrophysiology, FGF14-dependency test Biochimica et biophysica acta. Molecular cell research High 32599005
2020 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. In silico docking, split-LCA, surface plasmon resonance (SPR), whole-cell patch-clamp electrophysiology Physiological reports Medium 32671946
2023 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. 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 of neuroinflammation Medium 38115011
2024 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. Knock-in mouse model, Western blot (iFGF14 expression), current-clamp and voltage-clamp recordings from cerebellar slices, TTX pharmacology The Journal of neuroscience High 39484407 41558966
2025 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. Current-clamp and voltage-clamp in acute hippocampal slices from adult Fgf14-/- mice, immunohistochemistry with quantitative intensity analysis of AIS proteins The Journal of general physiology High 40323232
2025 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. Split-LCA, patch-clamp electrophysiology, in vivo neural recording, in vivo gene silencing, behavioral assays, in silico docking Nature communications High 39747162
2001 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. In situ hybridization, tissue grafting (ZPA, Shh-expressing cells), bead implantation (retinoic acid, FGF-2), analysis of chicken limb patterning mutants Mechanisms of development Low 10906454

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. The New England journal of medicine 202 36516086
2002 Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14. Neuron 151 12123606
2007 The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability. The Journal of neuroscience : the official journal of the Society for Neuroscience 138 17978045
2009 FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodium channels. Molecular and cellular neurosciences 113 19465131
2008 FGF14 regulates the intrinsic excitability of cerebellar Purkinje neurons. Neurobiology of disease 108 18930825
2006 Spinocerebellar ataxia associated with a mutation in the fibroblast growth factor 14 gene (SCA27): A new phenotype. Movement disorders : official journal of the Movement Disorder Society 92 16211615
2013 FGF14 regulates presynaptic Ca2+ channels and synaptic transmission. Cell reports 70 23831029
2015 Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 25926453
2016 Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action. Proceedings of the National Academy of Sciences of the United States of America 61 27044086
2013 FGF14 localization and organization of the axon initial segment. Molecular and cellular neurosciences 54 23891806
2015 Identifying a kinase network regulating FGF14:Nav1.6 complex assembly using split-luciferase complementation. PloS one 51 25659151
2023 Natural History and Phenotypic Spectrum of GAA-FGF14 Sporadic Late-Onset Cerebellar Ataxia (SCA27B). Movement disorders : official journal of the Movement Disorder Society 49 37470282
2016 FGF14 is a regulator of KCNQ2/3 channels. Proceedings of the National Academy of Sciences of the United States of America 49 27994149
2024 GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort. EBioMedicine 46 38507876
2013 A new variable phenotype in spinocerebellar ataxia 27 (SCA 27) caused by a deletion in the FGF14 gene. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 45 24252256
2024 Intronic FGF14 GAA repeat expansions are a common cause of ataxia syndromes with neuropathy and bilateral vestibulopathy. Journal of neurology, neurosurgery, and psychiatry 42 37399286
2017 PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease. Experimental neurology 40 28522250
2015 A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia. Neurogenetics 39 25566820
2009 SCA27 caused by a chromosome translocation: further delineation of the phenotype. Neurogenetics 38 19471976
2020 FGF14-related episodic ataxia: delineating the phenotype of Episodic Ataxia type 9. Annals of clinical and translational neurology 35 32162847
2019 Effects of FGF14 and NaVβ4 deletion on transient and resurgent Na current in cerebellar Purkinje neurons. The Journal of general physiology 34 31558566
2018 Functional Modulation of Voltage-Gated Sodium Channels by a FGF14-Based Peptidomimetic. ACS chemical neuroscience 34 29359916
2016 CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 26917740
2016 Identification of Amino Acid Residues in Fibroblast Growth Factor 14 (FGF14) Required for Structure-Function Interactions with Voltage-gated Sodium Channel Nav1.6. The Journal of biological chemistry 33 26994141
2022 YTHDF2-mediated FGF14-AS2 decay promotes osteolytic metastasis of breast cancer by enhancing RUNX2 mRNA translation. British journal of cancer 32 36216883
2024 The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clinical genetics 27 38221848
2020 Long noncoding RNA FGF14-AS2 inhibits breast cancer metastasis by regulating the miR-370-3p/FGF14 axis. Cell death discovery 26 33083023
2020 JAK2 regulates Nav1.6 channel function via FGF14Y158 phosphorylation. Biochimica et biophysica acta. Molecular cell research 25 32599005
2023 Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. Annals of clinical and translational neurology 24 37916889
2020 FGF14 Functions as a Tumor Suppressor through Inhibiting PI3K/AKT/mTOR Pathway in Colorectal Cancer. Journal of Cancer 24 31949485
2019 Long non-coding RNA FGF14-AS2 represses proliferation, migration, invasion, and induces apoptosis in breast cancer by sponging miR-205-5p. European review for medical and pharmacological sciences 24 31486497
2020 A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study. Cerebellum (London, England) 19 32157568
2019 Acetazolamide-Responsive Episodic Ataxia Linked to Novel Splice Site Variant in FGF14 Gene. Cerebellum (London, England) 19 30607796
2014 Modulation of the FGF14:FGF14 homodimer interaction through short peptide fragments. CNS & neurological disorders drug targets 19 25426956
2018 Emerging roles of Fgf14 in behavioral control. Behavioural brain research 18 30189289
2018 Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14. European journal of medical genetics 17 30017992
2025 Involvement of the Superior Cerebellar Peduncles in GAA-FGF14 Ataxia. Neurology. Genetics 15 39996128
2020 Overexpression of Long Non-Coding RNA FGF14-AS2 Inhibits Colorectal Cancer Proliferation Via the RERG/Ras/ERK Signaling by Sponging microRNA-1288-3p. Pathology oncology research : POR 14 32654025
2025 Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum. Brain : a journal of neurology 13 39378335
2023 TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria. Journal of neuroinflammation 13 38115011
2000 Expression and regulation of chicken fibroblast growth factor homologous factor (FHF)-4 at the base of the developing limbs. Mechanisms of development 13 10906454
2023 MiR-1246b, a novel miRNA molecule of extracellular vesicles in bronchoalveolar lavage fluid, promotes nodule growth through FGF14 in patients with lung cancer. Cell death & disease 12 38040694
2020 Mapping of the FGF14:Nav1.6 complex interface reveals FLPK as a functionally active peptide modulating excitability. Physiological reports 12 32671946
2018 Identification of peptidomimetics as novel chemical probes modulating fibroblast growth factor 14 (FGF14) and voltage-gated sodium channel 1.6 (Nav1.6) protein-protein interactions. Bioorganic & medicinal chemistry letters 12 30587448
2022 Analysis of Fibroblast Growth Factor 14 (FGF14) structural variants reveals the genetic basis of the early onset nystagmus locus NYS4 and variable ataxia. European journal of human genetics : EJHG 11 36207621
2021 LncRNA FGF14-AS2 represses growth of prostate carcinoma cells via modulating miR-96-5p/AJAP1 axis. Journal of clinical laboratory analysis 11 34655124
2019 Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels. Proteomes 11 30678040
2001 Expression and regulation of chicken fibroblast growth factor homologous factor (FHF)-4 during craniofacial morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 11 11241832
2025 Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons. Nature communications 10 39747162
2012 Spinocerebellar ataxia type 27 (SCA27) is an uncommon cause of dominant ataxia among Chinese Han population. Neuroscience letters 9 22579694
2023 Paroxysmal Ataxia: A Characteristic Feature of FGF14 Repeat Expansion (SCA27B). Neurology. Genetics 8 38170134
2025 The FGF14 GAA repeat expansion is a major cause of ataxia in the Cypriot population. Brain communications 7 39801711
2024 Neuroradiological findings in GAA-FGF14 ataxia (SCA27B): more than cerebellar atrophy. medRxiv : the preprint server for health sciences 7 38405699
2021 FGF14-AS2 accelerates tumorigenesis in glioma by forming a feedback loop with miR-320a/E2F1 axis. Journal of Cancer 6 34659533
2020 MEX3C promotes osteosarcoma malignant progression through negatively regulating FGF14. Journal of B.U.ON. : official journal of the Balkan Union of Oncology 6 32862604
2025 High Prevalence of the Intronic GAA-FGF14 Repeat Expansion in Dutch Patients With Late-Onset Ataxia. Neurology. Genetics 5 40017559
2025 Neuropathy in GAA-FGF14 Late-Onset Cerebellar Ataxia (SCA27B): Prevalence and Characteristics. European journal of neurology 4 40579842
2024 Assessment of the Clinical Interactions of GAA Repeat Expansions in FGF14 and FXN. Neurology. Genetics 4 39574782
2017 Familial episodic ataxia in lambs is potentially associated with a mutation in the fibroblast growth factor 14 (FGF14) gene. PloS one 4 29253853
2025 Deletion of Fgf14 confers resilience to basal and stress-induced depressive-like behavior and reduces anxiety in mice. Translational psychiatry 3 40204701
2024 In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons. bioRxiv : the preprint server for biology 3 39484407
2026 In Vivo Expression of an SCA27A-Linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2 41558966
2025 FGF14 (GAA∙TTC) repeat expansion-related ataxia SCA27B is common in Northern Finland. Parkinsonism & related disorders 2 40623333
2025 Uncovering molecular determinants of potency and binding affinity in hit compounds targeting FGF14/Nav1.6 complex. Journal of cheminformatics 2 41366810
2024 The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient. Movement disorders : official journal of the Movement Disorder Society 2 39704271
2023 Pearls & Oy-sters: ATX-FGF14 Mimicking Autoimmune Pathology. Neurology 2 37460234
2025 Loss of intracellular FGF14 (iFGF14) increases excitability of mature hippocampal pyramidal neurons. The Journal of general physiology 1 40323232
2025 Increased expression of FGF14 and SCN2A/SCN11A is associated with better survival of HCC patients. Tumori 1 40329566
2025 Unstable FGF14 GAA repeat expansions in Indian ataxia patients: a broader phenotype and involvement of modifier loci? Journal of human genetics 1 40835733
2025 Spinocerebellar Ataxia 27 A with Episodic Ataxia: Case Series of Fibroblast Growth Factor 14 (FGF14) Microdeletions. Cerebellum (London, England) 1 41099962
2024 Somatic instability of the FGF14 -SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum. medRxiv : the preprint server for health sciences 1 39006414
2026 Long-term response to aminopyridines in a cohort of patients with ataxia associated with downbeat nystagmus due to the FGF14 GAA expansion. Neurologia 0 42044943
2026 Identification of FGF14 GAA Expansions in Polish Patients with Undiagnosed Cerebellar Ataxia - A Preliminary Study. Cerebellum (London, England) 0 42096001
2025 FGF14 Peptide Derivative Differentially Regulates Nav1.2 and Nav1.6 Function. Life (Basel, Switzerland) 0 41010287

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