Affinage

FIG4

Polyphosphoinositide phosphatase · UniProt Q92562

Length
907 aa
Mass
103.6 kDa
Annotated
2026-04-28
79 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FIG4 is a SAC1-domain phosphoinositide phosphatase that hydrolyzes PI(3,5)P2 on late endosomal/lysosomal membranes and simultaneously serves as a scaffolding subunit of the PIKfyve–VAC14–FIG4 ternary complex required for PI(3,5)P2 biosynthesis. Within this complex, VAC14 forms a pentameric scaffold that recruits both PIKfyve (the lipid kinase) and FIG4; FIG4 binding to VAC14 protects FIG4 from rapid proteasomal degradation and is permissive for maximal PIKfyve kinase activity, explaining why FIG4 loss paradoxically reduces PI(3,5)P2 levels and causes lysosomal enlargement (PMID:14528018, PMID:18950639, PMID:20630877, PMID:26604144, PMID:40305106). PI(3,5)P2 generated by this complex activates the lysosomal Ca²⁺ channel TRPML1 to drive lysosomal fission and inhibits the chloride transporter ClC-7 to maintain lysosomal ion homeostasis; loss of these regulatory circuits underlies the vacuolar storage, spongiform neurodegeneration, and demyelination observed in FIG4-deficient neurons and Schwann cells, the basis of Charcot–Marie–Tooth disease type 4J (PMID:17572665, PMID:25926456, PMID:37363915, PMID:25187576). Neuronal FIG4 expression is both necessary and sufficient to prevent CNS neurodegeneration and supports non-cell-autonomous oligodendrocyte myelination, while adult-specific loss causes Wallerian degeneration of PNS axons, demonstrating a lifelong requirement (PMID:22581779, PMID:22131434, PMID:29688489).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2002 High

    Identification of FIG4 as the primary PI(3,5)P2 phosphatase resolved which enzyme turns over this signaling lipid in the Fab1 kinase pathway, establishing the first enzymatic function for FIG4.

    Evidence Genetic epistasis (fig4Δ suppressor of vac7Δ) with phosphoinositide measurement in yeast

    PMID:11950935

    Open questions at the time
    • No in vitro enzymatic characterization yet
    • Mammalian conservation undemonstrated
    • No structural information on FIG4
  2. 2003 High

    Demonstration that FIG4 is a Mg²⁺-dependent, PI(3,5)P2-selective phosphatase that physically associates with Vac14 at the vacuole membrane established the enzymatic specificity and placed FIG4 in a membrane-localized regulatory complex.

    Evidence In vitro phosphatase assay with purified yeast FIG4, GFP localization, co-immunoprecipitation with Vac14

    PMID:14528018

    Open questions at the time
    • Stoichiometry and architecture of the complex unknown
    • How Vac14 recruits FIG4 to the membrane unresolved
  3. 2007 High

    The discovery that mammalian FIG4 loss causes reduced PI(3,5)P2, LAMP2-positive vacuole accumulation, and neurodegeneration bridged the yeast enzymology to human disease and established FIG4 as a Charcot–Marie–Tooth 4J disease gene.

    Evidence Positional cloning of the pale tremor mouse, phosphoinositide measurement in mutant fibroblasts, nerve conduction studies

    PMID:17572665

    Open questions at the time
    • Paradox of PI(3,5)P2 reduction despite loss of its phosphatase unexplained
    • Cell-type requirements for FIG4 in neurodegeneration undefined
  4. 2008 High

    Mapping of the Fab1–Vac14–FIG4 ternary complex and the parallel mammalian PIKfyve–ArPIKfyve–Sac3 (PAS) complex revealed that the kinase and phosphatase are tethered by a shared scaffold, resolving the paradox that FIG4 loss reduces PI(3,5)P2 by showing FIG4 stabilizes kinase activity.

    Evidence Reciprocal co-immunoprecipitation and pull-down assays in yeast; co-IP plus in vitro PIKfyve kinase assay and GLUT4 translocation assay in mammalian cells

    PMID:18653468 PMID:18950639

    Open questions at the time
    • Quaternary structure of the complex unresolved
    • How FIG4 activates PIKfyve kinase mechanistically unclear
  5. 2009 High

    Showing that Sac3/FIG4 retains active phosphatase function within the assembled PAS complex and is regulated by insulin established that PI(3,5)P2 turnover and synthesis are coordinated within a single complex, with physiological input from insulin signaling.

    Evidence Active-site mutant (D488A) unable to rescue vacuolar phenotype; insulin suppresses Sac3 phosphatase activity in vitro; siRNA modulation of GLUT4 translocation

    PMID:19578118 PMID:19840946

    Open questions at the time
    • Mechanism of insulin-mediated Sac3 inhibition unknown
    • Post-translational modifications regulating Sac3 activity uncharacterized
  6. 2010 High

    Demonstrating that ArPIKfyve stabilizes Sac3/FIG4 by extending its half-life and that the CMT4J I41T mutation abolishes this protection identified the molecular basis of disease: loss of scaffold-mediated stabilization leading to proteasomal degradation of FIG4.

    Evidence Cycloheximide chase, MG-132 proteasome inhibitor rescue, co-IP in COS cells; patient fibroblast immunoblotting

    PMID:20630877 PMID:21655088

    Open questions at the time
    • Whether residual I41T protein retains any phosphatase activity unresolved
    • Therapeutic strategies to stabilize FIG4 protein unexplored
  7. 2012 High

    Cell-type-specific conditional knockouts established that neuronal FIG4 is necessary and sufficient to prevent CNS neurodegeneration and additionally supports oligodendrocyte myelination non-cell-autonomously, while Schwann-cell-autonomous FIG4 is required for PNS myelination.

    Evidence Synapsin-Cre conditional KO, NSE-promoter rescue, GFAP-promoter astrocyte rescue, motor-neuron and Schwann-cell Cre lines, electron microscopy, optic nerve electrophysiology

    PMID:22131434 PMID:22581779 PMID:25187576

    Open questions at the time
    • Non-cell-autonomous signal from neurons to oligodendrocytes unidentified
    • Relative contribution of autophagy vs. lysosomal fission defects to degeneration unclear
  8. 2015 High

    Linking FIG4-dependent PI(3,5)P2 to TRPML1 Ca²⁺ channel activation and dynamin-1-mediated lysosomal fission, and separately demonstrating a phosphatase-independent scaffolding function for FIG4 in vivo, bifurcated FIG4's role into enzymatic and structural contributions to lysosomal homeostasis.

    Evidence Intralysosomal Ca²⁺ measurement, ML-SA1 pharmacological rescue of Fig4−/− DRGs; catalytically dead C486S transgene partial rescue in Fig4 null mice; Drosophila phosphatase-dead rescue with Fab1/Rab7/HOPS epistasis

    PMID:25926456 PMID:26604144 PMID:26662798

    Open questions at the time
    • Quantitative contribution of scaffolding vs. phosphatase activity across tissues not defined
    • How FIG4 scaffolding stabilizes PIKfyve at the structural level unknown
  9. 2018 High

    Adult-onset conditional deletion revealed a lifelong requirement for FIG4 distinct from developmental roles, with PNS axons undergoing Wallerian degeneration and CNS remyelination being impaired after injury.

    Evidence Tamoxifen-inducible global KO in adult mice, sciatic nerve histology, compound action potential recording, chemical demyelination challenge

    PMID:29688489

    Open questions at the time
    • Whether adult neurodegeneration is reversible upon FIG4 restoration unknown
    • Temporal window for therapeutic intervention undefined
  10. 2023 High

    Genetic epistasis showing that ClC-7 knockout corrects lysosomal swelling in FIG4-null cells and extends lifespan in Fig4-null mice identified ClC-7 as a key downstream effector of PI(3,5)P2 deficiency, opening a therapeutic axis.

    Evidence CLCN7 KO in FIG4-null cells, dominant-negative CLCN7 in Fig4-null mice, lysosome size/pH measurement, survival analysis

    PMID:37363915

    Open questions at the time
    • Mechanism by which PI(3,5)P2 inhibits ClC-7 not structurally resolved
    • Whether ClC-7 inhibition rescues demyelination not tested
    • Relative contributions of ClC-7 vs. TRPML1 pathways to disease unclear
  11. 2025 High

    Cryo-EM and AlphaFold2 modeling of the VAC14 pentamer revealed the architectural basis for FIG4 and PIKfyve recruitment: two pentamer legs bind FIG4, with one also binding PIKfyve, explaining stoichiometry and linking disease mutations at VAC14–VAC14 interfaces to complex disassembly.

    Evidence Cryo-EM structure, AlphaFold2 prediction, pull-downs in VAC14 KO human cells, fluorescence-detection size-exclusion chromatography, colocalization with VPS35-endosomes

    PMID:40305106

    Open questions at the time
    • High-resolution structure of the full PIKfyve–VAC14–FIG4 holo-complex not yet achieved
    • How VPS35-positive endosomal localization is specified structurally not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full structural basis for how FIG4 simultaneously promotes PI(3,5)P2 synthesis (scaffold) and turnover (phosphatase) within the assembled holo-complex, the identity of the non-cell-autonomous signal from neurons that supports oligodendrocyte myelination, and whether therapeutic modulation of ClC-7 or TRPML1 can substitute for FIG4 gene replacement remain open questions.
  • No atomic-resolution structure of the complete PIKfyve–VAC14–FIG4 ternary complex
  • Non-cell-autonomous neuronal signal for myelination unidentified
  • Relative therapeutic value of ClC-7 vs. TRPML1 modulation vs. gene therapy not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0005198 structural molecule activity 2 GO:0008289 lipid binding 2
Localization
GO:0005764 lysosome 5 GO:0005768 endosome 3 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1643685 Disease 2
Partners
ARF1CLCN7COPB1PIKFYVESNCAIPTRPML1VAC14
Complex memberships
PIKfyve-VAC14-FIG4 (PAS) complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 FIG4 (yeast ortholog) encodes a SAC1-domain polyphosphoinositide phosphatase responsible for turnover of PtdIns(3,5)P2; deletion of FIG4 in vac7Δ mutants dramatically restores PtdIns(3,5)P2 levels, placing FIG4 as the primary phosphatase for PtdIns(3,5)P2 degradation in the Fab1 kinase pathway Genetic epistasis (suppressor screen), yeast deletion mutants, phosphoinositide measurement Molecular biology of the cell High 11950935
2003 FIG4 (yeast ortholog) is a magnesium-activated, PtdIns(3,5)P2-selective phosphoinositide phosphatase in vitro; it localizes to the vacuole membrane and requires Vac14 for correct vacuolar localization; FIG4 physically associates with Vac14 in a membrane-associated complex In vitro phosphatase assay, GFP fusion live imaging, co-immunoprecipitation, genetic deletion Molecular biology of the cell High 14528018
2007 Mammalian FIG4 is functionally conserved as a PtdIns(3,5)P2 phosphatase; loss-of-function (ETn2β insertion in mouse Fig4) causes abnormal PtdIns(3,5)P2 concentration in fibroblasts, LAMP-2-positive vacuole accumulation, and neurodegeneration, establishing FIG4 as a PI(3,5)P2 5-phosphatase regulating the late endosome-lysosome axis Positional cloning, phosphoinositide measurement in patient/mutant fibroblasts, LAMP-2 immunostaining, nerve conduction studies Nature High 17572665
2008 FIG4 (yeast ortholog) forms a vacuole-associated signaling complex with Fab1 and Vac14; Fab1 binds Vac14 and FIG4 through its chaperonin-like domain; Vac14 and FIG4 bind each other directly and are mutually dependent for interaction with Fab1; this places the lipid kinase and phosphatase in a common functional unit that explains their dual roles in PtdIns(3,5)P2 synthesis and turnover Co-immunoprecipitation, pull-down assays, FYVE-domain PtdIns(3)P binding experiments, yeast genetics Molecular biology of the cell High 18653468
2008 The CMT4J-causing FIG4-I41T missense mutation impairs interaction of FIG4 with the scaffold protein VAC14, leading to proteasome-dependent degradation and severely reduced FIG4-I41T protein levels in vivo (only ~2% of transcript-predicted level) Yeast two-hybrid, mouse transgenic model (I41T cDNA on null background), immunoblotting of patient fibroblasts, proteasome inhibitor (MG-132) rescue PLoS genetics High 21655088
2008 ArPIKfyve (mammalian VAC14 ortholog) scaffolds the PIKfyve-ArPIKfyve-Sac3 (PAS) ternary complex; ArPIKfyve interacts with both Sac3 (FIG4) and PIKfyve; Sac3 is permissive for maximal PIKfyve-ArPIKfyve association; disruption of ArPIKfyve homomeric interactions via C-terminal peptide disassembles the PAS complex and reduces PIKfyve lipid kinase activity in vitro; complex disassembly also inhibits insulin-stimulated GLUT4 surface accumulation Co-immunoprecipitation in transfected mammalian cells, in vitro PIKfyve kinase assay, GLUT4 translocation assay in 3T3L1 adipocytes, dominant-negative peptide Journal of molecular biology High 18950639
2009 Sac3/FIG4 assembled in the PIKfyve-ArPIKfyve-Sac3 (PAS) core complex retains active PtdIns(3,5)P2 phosphatase activity; the Cpn60_TCP1 domain of PIKfyve is a major contact for the ArPIKfyve-Sac3 subcomplex; catalytically dead Sac3(D488A) fails to rescue vacuolar phenotype caused by kinase-deficient PIKfyve, demonstrating that Sac3 phosphatase activity within the PAS complex turns over PtdIns(3,5)P2 Domain mapping with truncation/point mutants, vacuole phenotype assay in COS cells, co-immunoprecipitation The Journal of biological chemistry High 19840946
2009 Sac3/FIG4 is an insulin-sensitive phosphatase; acute insulin markedly reduces the in vitro PtdIns(3,5)P2-hydrolyzing activity of Sac3; siRNA knockdown of Sac3 elevates PtdIns(3,5)P2 and increases GLUT4 translocation and glucose entry in response to insulin, while overexpression of catalytically active (but not phosphatase-dead Sac3-D488A) reduces GLUT4 surface abundance siRNA knockdown, in vitro phosphatase assay, GLUT4 translocation assay, HPLC phosphoinositide measurement The Journal of biological chemistry High 19578118
2010 ArPIKfyve stabilizes Sac3/FIG4 protein by attenuating its rapid proteasome-dependent degradation (t1/2 ~18.8 min for Sac3 alone, extended by ArPIKfyve coexpression); the CMT4J-causing Sac3-I41T mutant fails to have its half-life extended by ArPIKfyve, identifying a failure of ArPIKfyve-mediated stabilization as the primary molecular defect in CMT4J Cycloheximide chase, proteasome inhibitor (MG-132), co-immunoprecipitation, immunoblotting in COS cells The Journal of biological chemistry High 20630877
2012 Neuronal expression of FIG4 is both necessary and sufficient to prevent spongiform neurodegeneration in vivo; conditional inactivation of Fig4 specifically in neurons (synapsin-Cre) recapitulates the full spectrum of neurological abnormalities, while astrocytic expression of Fig4 prevents autophagy marker accumulation but not spongiform degeneration or lethality Conditional knockout (floxed allele × synapsin-Cre), neuron-specific transgenic rescue (NSE promoter), GFAP promoter-driven astrocyte rescue, histology Human molecular genetics High 22581779
2011 FIG4 is required for CNS myelination; Fig4 null mice show dramatic CNS myelin reduction and oligodendrocyte maturation defects; neuronal (non-cell-autonomous) expression of Fig4 rescues CNS myelination and tremor, demonstrating that FIG4 in neurons supports oligodendrocyte maturation Transgenic rescue with neuron-specific (NSE) promoter, optic nerve electrophysiology, electron microscopy, OL lineage cell counting The Journal of neuroscience High 22131434
2014 FIG4 has cell-autonomous roles in both motor neurons and Schwann cells for CMT4J pathogenesis; conditional Fig4 inactivation in motor neurons causes neuronal/axonal degeneration, while conditional inactivation in Schwann cells causes demyelination and defects in autophagy-mediated degradation and myelin biogenesis Cell-type-specific conditional knockout (motor neuron-Cre, Schwann cell-Cre), histology, electron microscopy, autophagy marker analysis Human molecular genetics High 25187576
2015 FIG4 deficiency impairs lysosomal Ca2+ efflux via the TRPML1 channel (whose endogenous ligand is PI(3,5)P2), causing elevated intralysosomal Ca2+, impaired lysosomal fission, and downstream downregulation of dynamin-1 GTPase; pharmacological reactivation of TRPML1 with synthetic ligand ML-SA1 rescues lysosomal storage in Fig4-/- cells and ex vivo DRGs Flow cytometry lysosome size assay, intralysosomal Ca2+ measurement, dynamin-1 immunoblotting, pharmacological rescue (ML-SA1), ex vivo DRG culture The Journal of neuroscience High 25926456
2015 A catalytically inactive FIG4 transgene (Cys486Ser active-site mutant) partially rescues neurodegeneration and juvenile lethality in Fig4 null mice, demonstrating a phosphatase-independent structural/scaffolding function of FIG4 in stabilizing the PI(3,5)P2 biosynthetic complex; however, late-onset defects (hydrocephalus, demyelination) confirm that phosphatase activity is also essential in vivo Active-site mutagenesis (Cys486Ser), in vivo transgenic rescue, vacuolization assay in fibroblasts, histology Human molecular genetics High 26604144
2015 The ArPIKfyve-Sac3/FIG4 complex interacts with synphilin-1 (Sph1) in brain; mass spectrometry identified Sph1 as a component of the ArPIKfyve-Sac3 complex; modulation of ArPIKfyve/Sac3 levels alters Sph1-GFP aggregation properties in a Sac3 phosphatase-dependent manner, promoting its cytosolic partitioning and removal by basal autophagy Mass spectrometry of brain-derived interactors, Co-immunoprecipitation, RNA silencing, overexpression in neuronal cell lines and primary cortical neurons, aggregation assay The Journal of biological chemistry Medium 26405034
2015 Drosophila FIG4 (dFIG4) mutations predicted to inactivate phosphatase activity still rescue lysosomal expansion phenotypes in vivo, and Fab1 mutations causing the same phenotype are epistatic, establishing a phosphatase-independent biosynthetic/scaffolding function of FIG4 in lysosomal membrane homeostasis; lysosomal phenotypes are suppressed by genetic inhibition of Rab7 or the HOPS complex, placing FIG4 function after endosome-to-lysosome fusion Drosophila genetics (null mutants, phosphatase-dead transgene, Fab1 epistasis, Rab7/HOPS double mutants), LysoTracker staining, flight ability assay Human molecular genetics High 26662798
2017 FIG4 deficiency causes accumulation of TRPV4 at the plasma membrane of patient fibroblasts due to impaired endosomal trafficking/turnover; knockdown of Fig4 in murine motor neurons causes vacuolation and cell death, and inhibition of TRPV4 activity significantly preserves viability Patient fibroblast analysis, Fig4 siRNA knockdown in motor neurons, TRPV4 inhibitor treatment, immunofluorescence of membrane proteins Journal of neuropathology and experimental neurology Medium 28859335
2017 Sac3/FIG4 knockdown in RAW264.7 macrophages decreases cell surface scavenger receptor A (SR-A) protein levels and suppresses foam cell formation; ArPIKfyve knockdown similarly decreases Sac3 and SR-A; PIKfyve knockdown has no effect on SR-A, demonstrating that the ArPIKfyve-Sac3 complex regulates SR-A protein levels independently of PIKfyve kinase activity shRNA knockdown, flow cytometry for SR-A surface levels, foam cell assay (acetylated LDL uptake) Experimental cell research Medium 28552585
2018 Adult-specific inactivation of Fig4 (tamoxifen-inducible global KO) causes wasting, tremor, motor impairment and death within 2 months, demonstrating a life-long requirement; PNS myelinated axons undergo Wallerian degeneration while CNS myelin is intact; FIG4 is additionally required for timely CNS remyelination after chemical lesion Tamoxifen-inducible Cre-mediated KO (CAG-creER), histology of sciatic and optic nerves, compound action potential recording, chemical demyelination challenge Human molecular genetics High 29688489
2019 CMT4J patient fibroblasts show significant reductions in both PtdIns(3,5)P2 (−36%) and PtdIns5P (−43%) compared to controls, measured by HPLC, demonstrating that FIG4 loss reduces PI(3,5)P2 despite FIG4's known role in activating PIKfyve; patients without aberrant vacuoles have especially low PtdIns3P, linking PtdIns3P levels to vacuolization phenotype HPLC phosphoinositide profiling of myo-[2-3H]inositol-labeled primary patient fibroblasts, immunoblotting Molecular neurobiology High 31313076
2021 AAV9-mediated delivery of a codon-optimized FIG4 sequence into Fig4 null mice rescues lethality and peripheral neuropathy when administered neonatally (P1 or P4), with dose-dependent efficacy, providing preclinical proof of concept for gene therapy AAV9 gene delivery in mouse model, survival analysis, neurophysiology, histopathology The Journal of clinical investigation High 33878035
2021 BioID proximity mapping of Vac14 and FIG4 identified 89 high-confidence shared interactors including COPI subunit COPB1 and the GTPase Arf1; proximity ligation assays validated Vac14-COPB1 and Vac14-Arf1 interactions, linking the PIKfyve-VAC14-FIG4 complex to COPI-mediated endosomal dynamics BioID proximity labeling, mass spectrometry, proximity ligation assay Journal of proteome research Medium 34554760
2023 FIG4 and VAC14 function in PI(3,5)P2 biosynthesis, which inhibits the lysosomal chloride transporter ClC-7; knockout of CLCN7 in FIG4 null cells corrects lysosomal swelling and partially corrects lysosomal hyperacidification; in Fig4 null mice, reduction of ClC-7 via dominant-negative CLCN7 improved growth, neurological function, and increased lifespan by 20% CLCN7 knockout in FIG4 null cells, dominant-negative CLCN7 mouse model, lysosome size and pH measurement, survival analysis PLoS genetics High 37363915
2025 VAC14 forms a star-shaped pentamer scaffold; two legs bind FIG4, with one also binding PIKfyve; VAC14 oligomerization is critical for Fab1/PIKfyve function, PI(3,5)P2 generation, VAC14 localization to VPS35-containing endosomes, and PIKfyve-VAC14-FIG4 complex formation; pediatric disease mutations at VAC14-VAC14 interfaces disrupt complex assembly AlphaFold2 structural prediction, cryo-EM, pull-down assays in VAC14 KO human cells, fluorescence-detection size-exclusion chromatography, yeast genetics, colocalization with VPS35-endosomes Molecular biology of the cell High 40305106

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature 413 17572665
2003 Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase. Molecular biology of the cell 162 14528018
2002 Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4, a polyphosphoinositide phosphatase family member. Molecular biology of the cell 134 11950935
2008 The THP1-SAC3-SUS1-CDC31 complex works in transcription elongation-mRNA export preventing RNA-mediated genome instability. Molecular biology of the cell 123 18667528
2009 Sus1, Cdc31, and the Sac3 CID region form a conserved interaction platform that promotes nuclear pore association and mRNA export. Molecular cell 118 19328066
2008 Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain : a journal of neurology 115 18556664
2008 Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase. Molecular biology of the cell 109 18653468
2011 Pathogenic mechanism of the FIG4 mutation responsible for Charcot-Marie-Tooth disease CMT4J. PLoS genetics 90 21655088
2014 Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology 72 24598713
1999 Sac3, an Snf1-like serine/threonine kinase that positively and negatively regulates the responses of Chlamydomonas to sulfur limitation. The Plant cell 68 10368187
2008 ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. Journal of molecular biology 62 18950639
2003 Sac3 is an mRNA export factor that localizes to cytoplasmic fibrils of nuclear pore complex. Molecular biology of the cell 62 12631707
2017 FIG4 variants in central European patients with amyotrophic lateral sclerosis: a whole-exome and targeted sequencing study. European journal of human genetics : EJHG 56 28051077
2009 PIKfyve-ArPIKfyve-Sac3 core complex: contact sites and their consequence for Sac3 phosphatase activity and endocytic membrane homeostasis. The Journal of biological chemistry 55 19840946
2012 Neuronal expression of Fig4 is both necessary and sufficient to prevent spongiform neurodegeneration. Human molecular genetics 53 22581779
2007 Sus1, Sac3, and Thp1 mediate post-transcriptional tethering of active genes to the nuclear rim as well as to non-nascent mRNP. RNA (New York, N.Y.) 51 18003937
2015 Reactivation of Lysosomal Ca2+ Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 25926456
2015 FIG4 regulates lysosome membrane homeostasis independent of phosphatase function. Human molecular genetics 43 26662798
2014 Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Human molecular genetics 43 25187576
2011 Congenital CNS hypomyelination in the Fig4 null mouse is rescued by neuronal expression of the PI(3,5)P(2) phosphatase Fig4. The Journal of neuroscience : the official journal of the Society for Neuroscience 42 22131434
2010 ArPIKfyve regulates Sac3 protein abundance and turnover: disruption of the mechanism by Sac3I41T mutation causing Charcot-Marie-Tooth 4J disorder. The Journal of biological chemistry 41 20630877
2000 SAC3 may link nuclear protein export to cell cycle progression. Proceedings of the National Academy of Sciences of the United States of America 41 10716708
2011 Distinct pathogenic processes between Fig4-deficient motor and sensory neurons. The European journal of neuroscience 38 21410794
2009 Sac3 is an insulin-regulated phosphatidylinositol 3,5-bisphosphate phosphatase: gain in insulin responsiveness through Sac3 down-regulation in adipocytes. The Journal of biological chemistry 34 19578118
2021 AAV9-mediated FIG4 delivery prolongs life span in Charcot-Marie-Tooth disease type 4J mouse model. The Journal of clinical investigation 33 33878035
1982 Identification of a new genetic site (sac-3+) in Neisseria gonorrhoeae that affects sensitivity to normal human serum. Infection and immunity 33 6802757
2012 Fig4 deficiency: a newly emerged lysosomal storage disorder? Progress in neurobiology 30 23165282
1996 The SAC3 gene encodes a nuclear protein required for normal progression of mitosis. Journal of cell science 30 8799844
2018 Genetic screening of the genes interacting with Drosophila FIG4 identified a novel link between CMT-causing gene and long noncoding RNAs. Experimental neurology 28 30165075
2015 Knockdown of the Drosophila FIG4 induces deficient locomotive behavior, shortening of motor neuron, axonal targeting aberration, reduction of life span and defects in eye development. Experimental neurology 28 26708557
2020 FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome. Parkinsonism & related disorders 26 32268254
2019 Cerebral hypomyelination associated with biallelic variants of FIG4. Human mutation 25 30740813
2013 ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases. Neuropathology : official journal of the Japanese Society of Neuropathology 25 23888880
1987 Evidence that the serum resistance genetic locus sac-3 of Neisseria gonorrhoeae is involved in lipopolysaccharide structure. Journal of general microbiology 21 3129537
2018 Protective role of the lipid phosphatase Fig4 in the adult nervous system. Human molecular genetics 20 29688489
2009 Transcription at the proximity of the nuclear pore: a role for the THP1-SAC3-SUS1-CDC31 (THSC) complex. RNA biology 19 19229139
2013 Novel FIG4 mutations in Yunis-Varon syndrome. Journal of human genetics 18 24088667
2006 The sulfur acclimation SAC3 kinase is required for chloroplast transcriptional repression under sulfur limitation in Chlamydomonas reinhardtii. Proceedings of the National Academy of Sciences of the United States of America 18 16672369
2004 The Sac3 homologue shd1 is involved in mitotic progression in mammalian cells. The Journal of biological chemistry 17 15322101
2015 Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene. Human molecular genetics 16 26604144
2014 Whole exome sequencing identifies three recessive FIG4 mutations in an apparently dominant pedigree with Charcot-Marie-Tooth disease. Neuromuscular disorders : NMD 15 24878229
1996 Characterization of the SAC3 gene of Saccharomyces cerevisiae. Yeast (Chichester, England) 15 8873450
2023 The chloride antiporter CLCN7 is a modifier of lysosome dysfunction in FIG4 and VAC14 mutants. PLoS genetics 14 37363915
2017 Structure of the Sac3 RNA-binding M-region in the Saccharomyces cerevisiae TREX-2 complex. Nucleic acids research 13 28334829
2020 Clinical and radiological characterization of novel FIG4-related combined system disease with neuropathy. Clinical genetics 12 32385905
2017 A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade. Journal of neuropathology and experimental neurology 12 28859335
2013 The PIKfyve-ArPIKfyve-Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines. Biochemical and biophysical research communications 12 24070605
2012 Fig4 expression in the rodent nervous system and its potential role in preventing abnormal lysosomal accumulation. Journal of neuropathology and experimental neurology 12 22157617
2023 Clinical and genetic features of patients suffering from CMT4J. Journal of neurology 11 37950760
2022 Novel Variants in the FIG4 Gene Associated With Chinese Sporadic Amyotrophic Lateral Sclerosis With Slow Progression. Journal of clinical neurology (Seoul, Korea) 10 35021275
2019 Severe Consequences of SAC3/FIG4 Phosphatase Deficiency to Phosphoinositides in Patients with Charcot-Marie-Tooth Disease Type-4J. Molecular neurobiology 10 31313076
2022 Case report: A variant of the FIG4 gene with rapidly progressive amyotrophic lateral sclerosis. Frontiers in neurology 9 36090855
2021 FIG4-Associated Yunis-Varon Syndrome: Identification of a Novel Missense Variant. Molecular syndromology 9 34899148
2022 Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice. Molecular genetics and metabolism 8 36434903
2021 Clinical features of homozygous FIG4-p.Ile41Thr Charcot-Marie-Tooth 4J patients. Annals of clinical and translational neurology 8 33405357
2019 Epigallocatechin gallate enhances the motor neuron survival and functional recovery after brachial plexus root avulsion by regulating FIG4. Folia neuropathologica 8 32337947
2015 The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation. The Journal of biological chemistry 8 26405034
2024 FIG4-Related Parkinsonism and the Particularities of the I41T Mutation: A Review of the Literature. Genes 7 39457468
2021 Proximity Interactome Map of the Vac14-Fig4 Complex Using BioID. Journal of proteome research 6 34554760
2016 The Sac3 TPR-like region in the Saccharomyces cerevisiae TREX-2 complex is more extensive but independent of the CID region. Journal of structural biology 6 27422657
2013 Murine Fig4 is dispensable for muscle development but required for muscle function. Skeletal muscle 6 24004519
2023 Altered phenotypes due to genetic interaction between the mouse phosphoinositide biosynthesis genes Fig4 and Pip4k2c. G3 (Bethesda, Md.) 5 36691351
2015 FIG4 is a hepatitis C virus particle-bound protein implicated in virion morphogenesis and infectivity with cholesteryl ester modulation potential. The Journal of general virology 5 26519381
2022 T2 olivary nuclei hyperintensities: A characteristic neuroimaging finding in FIG4-related leukoencephalopathy. American journal of medical genetics. Part A 4 36529678
2020 Case Report: Association of a Variant of Unknown Significance in the FIG4 Gene With Frontotemporal Dementia and Slowly Progressing Motoneuron Disease: A Case Report Depicting Common Challenges in Clinical and Genetic Diagnostics of Rare Neuropsychiatric and Neurologic Disorders. Frontiers in neuroscience 4 33424531
2017 Phosphoinositide phosphatase Sac3 regulates the cell surface expression of scavenger receptor A and formation of lipid droplets in macrophages. Experimental cell research 4 28552585
2009 Getting to the gate: crystallization of a Sac3(CID):Sus1:Cdc31 complex. Molecular cell 4 19328059
2025 VAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex. Molecular biology of the cell 3 40305106
2022 Clinical and Genetic Analysis of a Patient with CMT4J. Neurology international 3 35225887
2022 Case report and literature review: Novel compound heterozygous FIG4 variants causing both of peripheral and central nervous system defects. Frontiers in pediatrics 3 36340727
2025 Role of cell cycle-related gene SAC3 domain containing 1 as a potential target of nitidine chloride in hepatocellular carcinoma progression. World journal of clinical oncology 2 40503414
2026 FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer. Cancer letters 1 41577074
2025 Homeostatic Influence of Fig4 Outside of the Fab1-Vac14-Fig4 Complex in Saccharomyces cerevisiae. Molecular microbiology 1 40741910
1999 The Saccharomyces cerevisiae LEP1/SAC3 gene is associated with leucine transport. Molecular & general genetics : MGG 1 10517330
2026 TREX2 component PCID2 scaffolds alternative SAC3-based subcomplexes with distinct RNA processing and export function. bioRxiv : the preprint server for biology 0 42039562
2025 SAC3 domain containing 1 intervention in energy metabolism reprogramming assists in the progression of hepatocellular carcinoma. World journal of gastrointestinal oncology 0 40697225
2025 Identification and splicing analysis of the first deep intronic FIG4 variant causing Yunis-Varon syndrome. Frontiers in genetics 0 40860339
2025 Phenotypic spectrum of variants in the FIG4 gene: variants associated with Charcot-Marie-Tooth 4J and parkinsonism. European journal of medical genetics 0 41177402
2018 The mRNA export factor Sac3 maintains nuclear homeostasis and regulates cytoskeleton organization in Candida albicans. Future microbiology 0 29436239