Affinage

DEPDC5

GATOR1 complex protein DEPDC5 · UniProt O75140

Length
1603 aa
Mass
181.3 kDa
Annotated
2026-06-09
83 papers in source corpus 36 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DEPDC5 is a component of the GATOR1 complex (with NPRL2 and NPRL3) that acts as a negative regulator of mTORC1 within the amino acid-sensing branch of the pathway (PMID:25366275, PMID:31174205). Mechanistically, DEPDC5 prevents constitutive mTOR retention at the lysosome under amino acid-poor conditions; its loss leaves mTOR lysosomally localized and signaling active even during amino acid withdrawal, distinguishing it from TSC2-dependent growth-factor sensing (PMID:32781001, PMID:29481864). Loss-of-function causes cell-autonomous mTORC1 (but not mTORC2) hyperactivation, neuronal soma enlargement, dysplastic and ectopic neurons, increased dendritic arborization, and a selective increase in excitatory synaptic transmission and intrinsic excitability (PMID:29481864, PMID:32113911, PMID:29274432); the excitatory synaptic phenotype is driven by an mTORC1-dependent rise in USP46, which deubiquitinates GluA1 and redistributes AMPA receptors to the neuronal surface, an effect reversed by USP46 knockdown or rapamycin (PMID:40467011). In neurons, DEPDC5 integrates amino acid availability (leucine, arginine, glutamine) into mTORC1 tone and mediates fasting-induced seizure protection (PMID:36044864). DEPDC5 inhibition of mTORC1 is released by Pim1/AKT phosphorylation (PMID:31548394), and DEPDC5 protein is degraded through chaperone-mediated autophagy via SNX10 or lactate-GPR81 signaling (PMID:41487148, PMID:38615493). Germline loss-of-function combined with a brain somatic second hit ('two-hit' model) in cortical progenitors causes focal cortical dysplasia with drug-resistant focal epilepsy (PMID:25623524, PMID:29708508, PMID:31353856), and excitatory-neuron-restricted loss drives generalized seizures and SUDEP that is preceded by ictal apnea rather than cardiac arrhythmia (PMID:37606181, PMID:34693554). Beyond the nervous system, DEPDC5 restrains mTORC1 in hepatocytes (via PPARα-regulated fatty acid oxidation), in CD8+ T cells (limiting ATF4-driven xanthine oxidase/lipid ROS and ferroptosis), and in tumor cells where its loss alters proliferation and drug sensitivity (PMID:34267188, PMID:38763950, PMID:31636198).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2013 Medium

    Established DEPDC5 as a disease gene before its molecular function was known, linking it to a neuronal signaling role through familial epilepsy genetics.

    Evidence Exome sequencing of affected families with immunostaining in human neurons

    PMID:23542697 PMID:23542701

    Open questions at the time
    • No molecular pathway assigned at this stage
    • Homology-based inference of G-protein signaling role not biochemically tested
  2. 2014 High

    Resolved DEPDC5's molecular identity by placing it in the GATOR1 complex as a negative regulator of mTORC1, explaining how epilepsy variants act mechanistically.

    Evidence Cell-based mTORC1 signaling assays and GATOR1 complex-formation assessment with epilepsy variants; patient-tissue mTOR activation markers

    PMID:24585383 PMID:25366275

    Open questions at the time
    • Did not define the amino acid sensing step DEPDC5 controls
    • Subcellular mechanism of mTORC1 inhibition unresolved
  3. 2015 Medium

    Demonstrated the two-hit mutational model for cortical lesion formation, connecting germline plus brain somatic DEPDC5 loss to focal cortical dysplasia with confirmed mTOR activation.

    Evidence Blood and brain DNA sequencing, histopathology, and mTOR activation immunostaining of resected tissue

    PMID:25623524 PMID:26000329

    Open questions at the time
    • Causality of somatic second hit not yet shown experimentally
    • DEP domain functional requirement inferred, not dissected
  4. 2016 High

    Provided in vivo proof that DEPDC5 loss causes constitutive mTORC1 hyperactivation and that the phenotype is rapamycin-reversible, establishing the mTORopathy mechanism organismally.

    Evidence TALEN knockout rat with S6K1/rpS6 phosphorylation assays, prenatal rapamycin rescue, and neuropathology

    PMID:26873552

    Open questions at the time
    • Embryonic lethality limited adult/neuronal analysis
    • Cell-autonomous vs systemic contributions not separated
  5. 2017 High

    Showed DEPDC5's mTORC1 repression is most critical during amino acid insufficiency and acts specifically in neurons to produce dysplasia and seizure susceptibility.

    Evidence Conditional (Synapsin1-Cre) and CRISPR germline knockout mice with phospho-S6, EEG, seizure threshold assays under nutrient deprivation; rapamycin rescue

    PMID:28974734 PMID:29274432

    Open questions at the time
    • Synaptic-level mechanism not yet defined
    • Amino acid specificity not quantified
  6. 2018 High

    Causally linked somatic DEPDC5 loss to FCD-related epilepsy via in vivo mosaic models and established the cellular and morphological consequences of inactivation.

    Evidence Human tissue deep sequencing plus CRISPR-Cas9/in utero electroporation mosaic inactivation in mouse and rat; zebrafish loss-of-function with WT-but-not-mutant rescue; dendrite/spine morphology

    PMID:29708508 PMID:29761115 PMID:30080265

    Open questions at the time
    • Molecular driver of synaptic hyperexcitability not yet identified
    • SUDEP mechanism not dissected
  7. 2018 High

    Defined the subcellular mechanism: DEPDC5 loss locks mTOR at the lysosome and selectively hyperactivates mTORC1, producing soma enlargement and membrane process changes.

    Evidence shRNA knockdown in neuroblastoma and neural progenitor cells with confocal mTOR localization and rapamycin rescue

    PMID:29481864

    Open questions at the time
    • Direct biochemical interaction with Rag GTPases not shown here
    • Effect on inhibitory neurons untested
  8. 2018 Medium

    Extended DEPDC5-mTORC1 control beyond neurons to HIV-1 latency and hepatocellular carcinoma, broadening its role as a general mTORC1 restraint with metabolic/autophagic consequences.

    Evidence Genome-wide CRISPR screens and KO/overexpression in T-cell, monocyte, and HCC models with autophagy/ROS readouts and rapamycin antagonism

    PMID:29311600 PMID:30087333

    Open questions at the time
    • RagA-specific mechanism vs TSC1/Rheb branch only partially dissected
    • Physiological relevance outside cell lines uncertain
  9. 2019 High

    Identified an upstream regulatory input: Pim1/AKT phosphorylation of DEPDC5 releases its mTORC1 inhibition, providing a signaling node exploitable in tumor drug resistance.

    Evidence Phospho-specific antibodies, phospho-inactive and phospho-mimic (S1530E) mutants, kinase assays, and in vivo tumor experiments

    PMID:31548394

    Open questions at the time
    • Relevance of phosphorylation in neurons not tested
    • Structural basis of phospho-regulation unknown
  10. 2019 High

    Showed DEPDC5 loss destabilizes the GATOR1 complex (reduced NPRL2/NPRL3) and that downstream mTORC1, not GATOR1 levels, drives the rapamycin-rescuable phenotype.

    Evidence Conditional KO mice with video-EEG, behavior, and Western blot for NPRL2/NPRL3/phospho-S6; GIST tumor functional studies

    PMID:31174205 PMID:31353856 PMID:31636198

    Open questions at the time
    • Mechanism of GATOR1 partner destabilization unresolved
    • Link between morphology and seizures incomplete
  11. 2020 High

    Defined the synaptic and human-cell mechanisms: DEPDC5 loss selectively augments excitatory transmission and recapitulates mTORC1 haploinsufficiency in human iPSC neurons.

    Evidence RNAi in primary cortical cultures with mEPSC recordings and glutamate receptor analysis; patient iPSC-derived neurons with phospho-S6 and rapamycin rescue; CRISPR Neuro2a cells with FRET 4E-BP1 biosensor and mTOR localization

    PMID:32113911 PMID:32574724 PMID:32781001

    Open questions at the time
    • Molecular link from mTORC1 to glutamate receptors not yet established
    • Distinction from TSC2 mechanism mechanistically incomplete
  12. 2021 High

    Generalized DEPDC5-mTORC1 to peripheral metabolism, showing hepatocyte loss drives steatosis via PPARα suppression, and rigorously excluded a cardiac basis for SUDEP.

    Evidence Hepatocyte-specific KO with Torin1/fenofibrate intervention; HA-tagged Depdc5 knock-in showing brain/heart/lung expression and simultaneous EEG-ECG with human cardiac investigations

    PMID:34267188 PMID:34693554

    Open questions at the time
    • Tissue-specific determinants of mTORC1 output not defined
    • Non-cardiac SUDEP trigger not yet identified at this stage
  13. 2022 High

    Established DEPDC5 as the neuronal sensor of specific amino acids that underlies fasting-induced seizure protection, and revealed a non-cell-autonomous interneuron/PNN degradation route to hyperexcitability.

    Evidence Neuronal KO mice with brain amino acid metabolomics and fasting seizure assays; dorsal progenitor KO with PNN/PV+/microglia immunostaining and inhibitory synapse electrophysiology

    PMID:35580549 PMID:36044864

    Open questions at the time
    • Mechanism coupling microglia activation to PNN degradation not fully defined
    • Relative contribution of excitatory vs inhibitory deficits unresolved
  14. 2023 High

    Pinpointed the SUDEP mechanism to excitatory-neuron-driven seizures producing ictal apnea and respiratory dysregulation rather than cardiac arrhythmia.

    Evidence Excitatory- vs inhibitory-neuron-specific conditional KO mice with simultaneous EEG, cardiac, and respiratory recording and respiratory challenge

    PMID:37606181

    Open questions at the time
    • Brainstem circuit mediating apnea not mapped
    • Why excitatory but not inhibitory loss is fatal not fully explained
  15. 2024 High

    Revealed a ferroptosis-protective role in immune cells and confirmed human-organoid disease modeling, expanding the mTORC1-downstream consequences of DEPDC5 loss.

    Evidence T cell-specific KO mice with ROS/xanthine oxidase/ATF4 readouts and tumor immunity assays; human cortical organoids with two-hit inactivation, single-cell transcriptomics, electrophysiology, and rapamycin rescue

    PMID:38763950 PMID:41789478

    Open questions at the time
    • ATF4/xanthine oxidase axis not tested in neurons
    • Notch/Wnt transcriptional changes not mechanistically connected to mTORC1
  16. 2024 Medium

    Identified chaperone-mediated autophagy as a route for DEPDC5 protein turnover, linking metabolic cues (lactate-GPR81) and SNX10 to mTORC1 activation.

    Evidence siRNA/Co-IP, lysosomal recruitment, glycolysis assays, and in vivo metastasis models defining GPR81/CMA and SNX10-DEPDC5 degradation

    PMID:38615493 PMID:41487148

    Open questions at the time
    • CMA degradation of DEPDC5 not demonstrated in neurons
    • SNX10-DEPDC5 interaction relies on single-lab Co-IP
  17. 2025 High

    Defined the molecular effector of excitatory synaptic hyperexcitability: mTORC1-dependent USP46 upregulation deubiquitinates GluA1 and redistributes AMPA receptors to the surface.

    Evidence Conditional KO mice with Co-IP interaction network (USP46/WDR48/WDR20), mEPSC, GluA1 ubiquitination, surface biotinylation, and USP46-knockdown/rapamycin rescue

    PMID:40467011

    Open questions at the time
    • Whether DEPDC5-USP46 binding is direct or mTORC1-mediated only partly resolved
    • WDR48/WDR20 functional role in this pathway untested
  18. 2025 High

    Separated developmental from postnatal disease mechanisms by showing postnatal focal DEPDC5 loss without lamination defects is sufficient for FCD pathology and seizures.

    Evidence AAV-Cre postnatal conditional KO mice with FCD-marker immunohistochemistry and seizure assays

    PMID:40996830

    Open questions at the time
    • Critical postnatal time window not bounded
    • Reversibility after lesion establishment untested
  19. 2026 Medium

    Identified a downstream effector contributing to seizures, with ectopic SLC6A5/GlyT2 overexpression in excitatory neurons whose co-deletion mitigates seizures.

    Evidence CRISPR in utero electroporation double Depdc5/Slc6a5 KO with seizure monitoring and rat/human expression profiling

    PMID:41587632

    Open questions at the time
    • Mechanism linking mTORC1 to Slc6a5 induction unknown
    • Single-lab functional rescue, mechanism not fully elucidated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DEPDC5/GATOR1 biochemically relays amino acid status to the Rag GTPases to control mTOR lysosomal localization, and how this is integrated with phosphorylation and CMA-mediated turnover across cell types, remains to be mechanistically unified.
  • No structural model of DEPDC5 within GATOR1 in the corpus
  • Direct enzymatic activity toward Rag GTPases not demonstrated
  • Cross-tissue regulation of DEPDC5 protein stability not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005764 lysosome 3 GO:0005634 nucleus 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
NPRL2NPRL3SNX10USP46WDR20WDR48
Complex memberships
GATOR1

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 DEPDC5 loss-of-function mutations cause familial focal epilepsy with variable foci; the protein shares homology with G protein signaling molecules and localizes in human neurons, suggesting a role in neuronal signal transduction. Exome sequencing of affected families; localization by immunostaining in human neurons Nature genetics Medium 23542697 23542701
2014 DEPDC5 is a component of the GATOR1 complex and functions as a negative regulator of mTORC1 in the amino acid-sensing branch; variants disrupt DEPDC5-dependent inhibition of mTORC1 and GATOR1 complex formation. Functional assays of TORC1 signaling in cells transfected with epilepsy-associated DEPDC5 variants; assessment of GATOR1 complex formation Human mutation High 25366275
2014 DEPDC5 negatively regulates the mTOR pathway; loss-of-function mutations are associated with mTOR pathway hyperactivation (mTORopathy), and clinicoradiological phenotypes overlap with tuberous sclerosis. Genetic mutation analysis combined with mTOR pathway activation markers in patient tissue Annals of neurology Medium 24585383
2015 Germline, germline mosaic, and brain somatic DEPDC5 mutations can cause focal cortical dysplasia, with a 'two-hit' mutational model (similar to other mTORopathies) proposed for cortical lesion formation; mTOR activation confirmed by immunostaining of resected brain tissue. Sequencing of blood and brain DNA from patients; histopathological analysis; mTOR activation markers in brain tissue Annals of neurology Medium 25623524
2015 Germline nonsense DEPDC5 mutation (p.Arg555*) causes extensive focal cortical dysplasia IIa with mTOR activation confirmed by immunostaining of resected brain tissue; the DEP domain is critical for DEPDC5 function. Whole-exome sequencing; immunostaining of resected brain tissue for mTOR activation markers Annals of clinical and translational neurology Medium 26000329
2016 Homozygous Depdc5 knockout rat embryos die from embryonic day 14.5 with global growth delay and constitutive mTORC1 hyperactivation in brain and fibroblasts (measured by enhanced phosphorylation of S6K1 and rpS6); prenatal rapamycin treatment rescues the lethal phenotype. Heterozygous rats show cortical cytomegalic neurons and balloon-like cells with phosphorylated rpS6, abolished by prenatal rapamycin. TALEN-generated knockout rat; phosphorylation assays for S6K1/rpS6; rapamycin rescue experiment; neuropathological analysis Neurobiology of disease High 26873552
2017 Neuron-specific Depdc5 conditional knockout mice (Synapsin1-Cre) develop mTORC1 hyperactivation exclusively in neurons (increased phospho-S6), dysplastic and ectopic neurons, reactive astrogliosis, and seizure susceptibility; rapamycin inhibition rescues mTORC1 activity and partially rescues phenotype. Conditional KO mouse (Cre-lox); phospho-S6 immunostaining; EEG recording; chemoconvulsant seizure threshold assays; rapamycin treatment Neurobiology of disease High 29274432
2017 CRISPR-generated germline Depdc5 knockout mouse embryos show mTORC1 hyperactivity in brain and in fibroblasts/neurospheres under nutrient-deprived conditions, supporting DEPDC5 as a negative regulator of mTORC1 that is particularly important during amino acid insufficiency. CRISPR mutagenesis mouse model; mTORC1 activity assays in fibroblasts and neurospheres under nutrient deprivation Scientific reports High 28974734
2018 Biallelic two-hit (germline + brain somatic) DEPDC5 mutations cause focal cortical dysplasia with focal epilepsy; somatic second-hit mutation load is higher in seizure-onset zone than surrounding epileptogenic zone. CRISPR-Cas9 + in utero electroporation mosaic Depdc5 inactivation in mice recapitulates focal epilepsy with FCD and SUDEP-like events. Depdc5 inactivation shapes dendrite and spine morphology of excitatory neurons. Deep sequencing of postoperative human tissue; CRISPR-Cas9 + in utero electroporation mouse model; morphological analysis of dendrites and spines The Journal of clinical investigation High 29708508
2018 DEPDC5 knockdown in zebrafish causes mTOR-dependent motor hyperactivity and neuronal hyperexcitability; rescue by WT human DEPDC5 but not by epilepsy-associated mutants (p.Arg487* and p.Arg485Gln) confirms loss-of-function mechanism; rapamycin treatment rescues phenotype. Zebrafish Depdc5 knockdown model; behavioral assays; overexpression of WT and mutant DEPDC5; rapamycin treatment Annals of clinical and translational neurology High 29761115
2018 Somatic focal Depdc5 deletion via CRISPR + in utero electroporation in rat brain produces spontaneous seizures with electroclinical features of focal cortical dysplasia type IIA, establishing a causal link between somatic DEPDC5 loss and FCD-related epilepsy. In utero electroporation with CRISPR gene deletion in rat; EEG recording; histopathological analysis Annals of neurology High 30080265
2018 DEPDC5 knockdown in neural progenitor cells and neurons causes mTORC1 (but not mTORC2) hyperactivation, soma enlargement, increased filopodia, and inappropriate localization of mTOR at the lysosome during amino acid starvation; these effects are reversed by rapamycin. shRNA knockdown in neuroblastoma cells and mouse neural progenitor cells; mTOR subcellular localization by confocal imaging; rapamycin rescue Neurobiology of disease High 29481864
2018 DEPDC5 maintains HIV-1 latency by suppressing the mTORC1 pathway through RagA (distinct from TSC1 which acts via Rheb); knockout of DEPDC5 leads to enhanced HIV-1 reactivation antagonized by rapamycin. Genome-wide CRISPR screening; DEPDC5 KO in T-cell and monocyte latency models; rapamycin antagonism assay Emerging microbes & infections Medium 30087333
2019 DEPDC5 is phosphorylated by Pim1 and AKT kinases; phosphorylation of DEPDC5 releases inhibition of mTORC1. A phospho-mimic S1530E DEPDC5 confers resistance to Pim and AKT inhibitors in tumor cells in vitro and in vivo. Phospho-specific antibodies; transfection of phospho-inactive DEPDC5 mutants; kinase assays; knock-in phospho-mimic glutamic acid substitution; in vivo tumor experiments Proceedings of the National Academy of Sciences of the United States of America High 31548394
2019 DEPDC5 inactivation mutations in GISTs promote tumor growth via the mTORC1 signaling pathway, leading to cell-cycle arrest when DEPDC5 is present; DEPDC5 loss reduces cell proliferation and modulates sensitivity to KIT inhibitors. Whole exome sequencing; in vitro and nude mouse in vivo DEPDC5 inactivation experiments; mTORC1 pathway assays; cell proliferation assays Proceedings of the National Academy of Sciences of the United States of America High 31636198
2019 Neuronal Depdc5 knockout (Depdc5cc+) mice exhibit mTORC1 hyperactivation, hyperactivity, enlarged brain and neuronal soma, and rare seizures; rapamycin treatment prolongs survival, partially rescues hyperactivity, and reduces brain/neuronal size by suppressing downstream mTORC1 (phospho-S6) but not GATOR1 protein levels. Loss of Depdc5 leads to decreased levels of other GATOR1 proteins NPRL2 and NPRL3. Conditional KO mouse; video-EEG monitoring; open-field and elevated-plus maze testing; rapamycin treatment; Western blot for NPRL2, NPRL3, phospho-S6 Human molecular genetics High 31174205
2019 Second-hit DEPDC5 somatic mutation is limited to dysmorphic neurons in focal cortical dysplasia type IIA, and the somatic mutation load correlates with dysmorphic neuron density and the epileptogenic zone. Deep sequencing of surgical tissue; correlation of variant allele frequency with cell-type-specific histopathology Annals of clinical and translational neurology Medium 31353856
2020 Acute Depdc5 knockdown (~80%) in cortical neurons causes dose-dependent mTOR hyperactivation, soma enlargement, increased dendritic arborization, increased excitatory (but not inhibitory) synaptic transmission, and increased intrinsic excitability; the synaptic phenotype is driven specifically by excitatory synapses, with increased mEPSC frequency/amplitude, excitatory synapse density, and glutamate receptor expression. RNA interference in primary cortical cultures; mEPSC recording; synapse density analysis; glutamate receptor expression; comparison with heterozygous Depdc5+/- neurons Neurobiology of disease High 32113911
2020 Depdc5 KO (but not Tsc2 KO) cells fail to respond to amino acid withdrawal by moving mTOR off the lysosome; Depdc5 KO cells maintain mTOR lysosomal localization and 4E-BP1 phosphorylation even under amino acid-free conditions, whereas Tsc2 KO cells show partial reduction under amino acid starvation. CRISPR-edited Neuro2a cells; FRET-biosensor for 4E-BP1 phosphorylation in living cells; confocal imaging of mTOR lysosomal localization Experimental neurology High 32781001
2020 DEPDC5 haploinsufficiency in human iPSC-derived cortical neurons causes increased phosphorylation of ribosomal protein S6, increased iPSC proliferation rate, and enlarged soma in neurons; rapamycin rescues soma size, demonstrating mTORC1 haploinsufficiency in human cells. Patient iPSC-derived cortical neurons; phospho-S6 Western blot; soma size measurement; rapamycin rescue Neurobiology of disease Medium 32574724
2021 Hepatocyte-specific Depdc5 knockout activates mTORC1 constitutively; in ethanol-fed Depdc5-LKO mice, severe hepatic steatosis and inflammation develop via suppression of PPARα (master regulator of fatty acid oxidation); fenofibrate (PPARα agonist) reverses the steatosis, linking DEPDC5-mTORC1 to PPARα-mediated fatty acid oxidation. Hepatocyte-specific conditional KO mouse; Torin1 and fenofibrate pharmacological intervention; mTORC1 and PPARα pathway assays Cell death & disease High 34267188
2022 Brain mTORC1 signaling is reduced after acute fasting; neuronal mTORC1 integrates GATOR1 (amino acid sensing via DEPDC5) and TSC (growth factor sensing). Neuronal mTORC1 is most sensitive to withdrawal of leucine, arginine, and glutamine in a DEPDC5-dependent manner. Depdc5 neuronal-specific KO mice are resistant to changes in brain amino acid levels after fasting and do not benefit from fasting-induced seizure protection. Neuronal-specific Depdc5 KO mice; metabolomic analysis of brain amino acids; seizure susceptibility assays with fasting; comparison with amino acid withdrawal Cell reports High 36044864
2022 Long before seizure onset in a mouse model of DEPDC5-related epilepsy with cortical dysplasia (dorsal progenitor-specific Depdc5 deletion), microglia inflammation and proteolytic enzyme activity degrade perineuronal nets (PNNs) in malformed cortex, resulting in parvalbumin interneuron loss and impaired presynaptic inhibition. Forebrain dorsal progenitor-specific conditional KO mouse; immunostaining for PNNs, PV+ interneurons, microglia markers; electrophysiology of inhibitory synapses Developmental neuroscience Medium 35580549
2023 Depdc5 deletion in excitatory (but not inhibitory) cortical neurons causes frequent generalized tonic-clonic seizures and SUDEP; SUDEP is preceded by ictal apnea and respiratory dysregulation rather than cardiac arrhythmia, with EEG suppression at ictal offset and loss of theta activity only in fatal seizures. Neuron subtype-specific conditional KO mice (excitatory vs inhibitory); EEG, cardiac, and respiratory recording; respiratory challenge assays Annals of neurology High 37606181
2021 Cardiac investigations in DEPDC5/NPRL2/NPRL3 patients and novel Depdc5 mouse strains reveal no structural or functional cardiac damage; HA-tagged Depdc5 mouse shows Depdc5 expression in brain, heart, and lungs; simultaneous EEG-ECG in Depdc5c/- mice shows seizure-induced SUDEP-like events are not preceded by cardiac arrhythmia. HA-tagged Depdc5 knock-in mouse; neuron-specific second-allele deletion mouse; simultaneous EEG-ECG recording; human cardiac investigations (Holter, Echo, ECG); autopsy Annals of neurology High 34693554
2024 DEPDC5 deficiency in CD8+ T cells causes hyper-mTORC1-induced ATF4 expression, leading to elevated xanthine oxidase and lipid ROS production, spontaneous ferroptosis, and reduced peripheral CD8+ T cell numbers; T cell-specific Depdc5 KO mice confirm impaired anti-tumor immunity. T cell-specific Depdc5 conditional KO mouse; ROS measurement; xanthine oxidase assay; ATF4 expression analysis; tumor immunity assay Cell discovery High 38763950
2024 Biallelic inactivation of DEPDC5 in mosaic human cortical organoids (two-hit model) increases mTOR activity rescued by rapamycin, produces dysmorphic-like neurons and enhanced neuronal excitability, disrupts neuronal differentiation, and alters expression of Notch/Wnt signaling pathway genes and synaptic/epilepsy-associated genes. Patient-derived human cortical organoids with CRISPR-based two-hit DEPDC5 inactivation; single-cell transcriptomics; mTOR activity assays; electrophysiology; rapamycin rescue Brain : a journal of neurology High 41789478
2024 Biallelic inactivation of Depdc5 in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability with other mTORC1 repressor gene knockouts, but different changes in excitatory synaptic transmission compared to Tsc1 or Pten loss, indicating gene-specific synaptic mechanisms. In utero electroporation-based biallelic inactivation; electrophysiology; morphological analysis; comparison across mTORC1 pathway genes eLife Medium 38411613
2025 DEPDC5 interacts with USP46 (ubiquitin-specific protease that regulates GluA1), WDR48, and WDR20 as binding partners. In Depdc5 cKO neurons, loss of DEPDC5 leads to mTORC1-dependent USP46 upregulation, decreased ubiquitination of GluA1, and surface redistribution of GluA1-containing AMPA receptors, increasing excitatory quantal size. USP46 knockdown or rapamycin rescues the increased glutamate quantal size and USP46 elevation. Conditional KO mouse; co-immunoprecipitation/protein interaction network; electrophysiology (mEPSC); GluA1 ubiquitination assay; surface biotinylation; USP46 knockdown; rapamycin rescue Neurobiology of disease High 40467011
2025 Postnatal focal cortical DEPDC5 loss (AAV-Cre injection in postnatal day 0-1 mice) without disruption to cortical lamination is sufficient to cause mTOR hyperactivation, FCD pathological hallmarks (SMI-311 neurofilament staining, hypomyelination, astrogliosis, microglial activation), lower seizure thresholds, increased focal seizures, and seizure-induced death. AAV-Cre postnatal conditional KO mouse; immunohistochemistry for FCD markers; seizure threshold assays; seizure monitoring JCI insight High 40996830
2018 DEPDC5 knockout in hepatocellular carcinoma cells causes resistance to leucine starvation; DEPDC5-KO reduces LC3-II and accumulates p62, inducing ROS tolerance. DEPDC5 overexpression suppresses cell proliferation and tumorigenicity in immunocompromised mice and triggers p62 degradation with increased ROS susceptibility. CRISPR/Cas9 DEPDC5 KO in HCC cells; overexpression in immunocompromised mice; autophagy markers (LC3-II, p62); ROS measurement Scientific reports High 29311600
2015 DEPDC5 downregulation in hepatic stellate cells (LX-2) increases β-catenin expression and production of MMP2 (matrix metallopeptidase 2), a secreted enzyme involved in fibrosis progression, linking DEPDC5 to the β-catenin pathway in liver fibrosis. In vitro DEPDC5 downregulation in LX-2 cells; β-catenin and MMP2 expression assays Hepatology (Baltimore, Md.) Medium 26517016
2024 GPR81 activation by lactate promotes chaperone-mediated autophagy (CMA)-mediated degradation of DEPDC5 protein, activating mTOR signaling and promoting EMT/metastasis in colorectal cancer; gentisic acid inhibits GPR81 and blocks DEPDC5 degradation. siRNA knockdown; Western blotting; immunofluorescence; in vivo lung metastasis mouse model; CMA pathway analysis Phytomedicine Medium 38615493
2025 SNX10 interacts directly with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation; SNX10 knockdown accelerates DEPDC5 degradation, activates mTORC1, and elevates glycolysis; α-hederin binds the SNX10-DEPDC5 complex and impairs the SNX10-DEPDC5 interaction to inhibit CMA-mediated DEPDC5 degradation. Co-immunoprecipitation (SNX10-DEPDC5 interaction); lysosomal recruitment assay; siRNA knockdown; Western blotting; glycolysis measurement Journal of pharmaceutical analysis Medium 41487148
2026 In excitatory neurons of the malformed cortex of a DEPDC5-related epilepsy rat model and human patient tissue, Slc6a5 (glycine transporter GlyT2) is ectopically overexpressed. Simultaneous CRISPR KO of Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. CRISPR in utero electroporation for simultaneous Depdc5/Slc6a5 KO; seizure monitoring; expression profiling in rat and human tissue Experimental neurology Medium 41587632

Source papers

Stage 0 corpus · 83 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nature genetics 276 23542697
2015 Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Annals of neurology 220 25623524
2013 Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nature genetics 192 23542701
2018 Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. The Journal of clinical investigation 186 29708508
2014 Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Annals of neurology 173 24585383
2011 Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers. Nature genetics 137 21725309
2014 DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology 107 24814846
2017 A mouse model of DEPDC5-related epilepsy: Neuronal loss of Depdc5 causes dysplastic and ectopic neurons, increased mTOR signaling, and seizure susceptibility. Neurobiology of disease 89 29274432
2015 Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5. Annals of clinical and translational neurology 79 26000329
2016 Depdc5 knockout rat: A novel model of mTORopathy. Neurobiology of disease 78 26873552
2019 Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA. Annals of clinical and translational neurology 60 31353856
2017 Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling. Scientific reports 49 28974734
2015 Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation. Neurology. Genetics 46 27066565
2022 DEPDC5-related epilepsy: A comprehensive review. Epilepsy & behavior : E&B 42 35429726
2019 Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice. Human molecular genetics 42 31174205
2018 Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. Annals of clinical and translational neurology 40 29761115
2018 Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA. Annals of neurology 40 30080265
2019 Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors. Proceedings of the National Academy of Sciences of the United States of America 37 31636198
2015 DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy. Epilepsia 35 26216793
2017 DEPDC5 mutations in familial and sporadic focal epilepsy. Clinical genetics 34 28170089
2013 A recurrent mutation in DEPDC5 predisposes to focal epilepsies in the French-Canadian population. Clinical genetics 33 24283814
2017 DEPDC5 as a potential therapeutic target for epilepsy. Expert opinion on therapeutic targets 32 28406046
2018 DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons. Neurobiology of disease 31 29481864
2024 The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife 29 38411613
2020 Acute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis. Neurobiology of disease 29 32113911
2015 DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. Hepatology (Baltimore, Md.) 29 26517016
2020 DEPDC5 Variants Associated Malformations of Cortical Development and Focal Epilepsy With Febrile Seizure Plus/Febrile Seizures: The Role of Molecular Sub-Regional Effect. Frontiers in neuroscience 27 32848577
2021 Cardiac Investigations in Sudden Unexpected Death in DEPDC5-Related Epilepsy. Annals of neurology 26 34693554
2018 TSC1 and DEPDC5 regulate HIV-1 latency through the mTOR signaling pathway. Emerging microbes & infections 26 30087333
2014 Genetics advances in autosomal dominant focal epilepsies: focus on DEPDC5. Progress in brain research 26 25194487
2017 Polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with chronic hepatitis C-related hepatocellular carcinoma. Scientific reports 25 28928439
2024 DEPDC5 protects CD8+ T cells from ferroptosis by limiting mTORC1-mediated purine catabolism. Cell discovery 23 38763950
2014 Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy. Human mutation 23 25366275
2023 Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy. Annals of neurology 20 37606181
2022 DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting. Cell reports 19 36044864
2019 Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth. Proceedings of the National Academy of Sciences of the United States of America 19 31548394
2022 Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy. Developmental neuroscience 18 35580549
2024 Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation. Phytomedicine : international journal of phytotherapy and phytopharmacology 17 38615493
2018 DEPDC5 deficiency contributes to resistance to leucine starvation via p62 accumulation in hepatocellular carcinoma. Scientific reports 17 29311600
2021 Phenotypic and Genotypic Characterization of DEPDC5-Related Familial Focal Epilepsy: Case Series and Literature Review. Frontiers in neurology 15 34239491
2020 DEPDC5 haploinsufficiency drives increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons. Neurobiology of disease 15 32574724
2021 Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway. Cell death & disease 12 34267188
2023 Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria. Human molecular genetics 11 36067010
2021 Simultaneous loss of TSC1 and DEPDC5 in skeletal and cardiac muscles produces early-onset myopathy and cardiac dysfunction associated with oxidative damage and SQSTM1/p62 accumulation. Autophagy 11 34964695
2014 Role of IFN-ks, IFN-ks related genes and the DEPDC5 gene in Hepatitis B virus-related liver disease. Journal of viral hepatitis 11 25032264
2017 A stereo EEG study in a patient with sleep-related hypermotor epilepsy due to DEPDC5 mutation. Seizure 10 29125946
2019 Correlation between the DEPDC5 rs1012068 polymorphism and the risk of HBV-related hepatocellular carcinoma. Clinics and research in hepatology and gastroenterology 9 30683632
2020 Dynamic analysis of 4E-BP1 phosphorylation in neurons with Tsc2 or Depdc5 knockout. Experimental neurology 7 32781001
2018 DEPDC5 takes a second hit in familial focal epilepsy. The Journal of clinical investigation 7 29708509
2023 Observation of a Possible Successful Treatment of DEPDC5-Related Epilepsy with mTOR Inhibitor. Neuropediatrics 6 37263295
2014 Variations in DEPDC5 gene and its association with chronic hepatitis C virus infection in Saudi Arabia. BMC infectious diseases 6 25551790
2021 Persistent mTORC1 activation via Depdc5 deletion results in spontaneous hepatocellular carcinoma but does not exacerbate carcinogen- and high-fat diet-induced hepatic carcinogenesis in mice. Biochemical and biophysical research communications 5 34562654
2019 DEPDC5 mutation and familial focal epilepsy with variable foci: genotype and phenotype of a family. Epileptic disorders : international epilepsy journal with videotape 5 30767899
2024 The mTOR pathway genes mTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. bioRxiv : the preprint server for biology 4 37609221
2024 Ictal and Postictal Central Apnea in DEPDC5-Related Epilepsy. Neurology. Genetics 4 39376210
2023 Seizure Control Outcomes following Resection of Cortical Dysplasia in Patients with DEPDC5 Variants: A Systematic Review and Individual Patient Data Analysis. Neuropediatrics 4 37984419
2019 Magnetoencephalogram-assisted diagnosis of familial focal epilepsy with variable foci in a Chinese family with a novel DEPDC5 mutation. Epileptic disorders : international epilepsy journal with videotape 4 31225799
2025 The transcriptomic signature of DEPDC5 KO induced mTOR hyperactivation in human neurons and its response to rapamycin treatment. Epilepsia 3 40704780
2024 A novel variation in DEPDC5 causing familial focal epilepsy with variable foci. Frontiers in genetics 3 38974383
2025 A missense variant in DEPDC5 resulted in abnormal morphology and increased seizure susceptibility and mortality through regulating mTOR signaling. Neurobiology of disease 2 39954744
2025 Case Report: Unraveling clinical heterogeneity in DEPDC5-related epilepsy: a genotype-phenotype correlation study in eight pediatric cases. Frontiers in neuroscience 2 41141423
2021 DEPDC5 variant in focal cortical dysplasia: a case report and review of the literature. Oxford medical case reports 2 34055363
2021 [Genotype and phenotype of children with DEPDC5 gene variants related epilepsy]. Zhonghua er ke za zhi = Chinese journal of pediatrics 2 34587683
2018 [DEPDC5, a new key to understand various epilepsies]. Nihon yakurigaku zasshi. Folia pharmacologica Japonica 2 30531098
2025 Explosive onset focal epilepsies without cortical malformation: A review of a pediatric cohort with pathogenic variations in the GATOR1 complex (DEPDC5, NPRL3 and NPRL2). Seizure 1 40188669
2025 Dual Diagnosis of Fragile X Syndrome and DEPDC5-Related Disorder Emphasizes DEPDC5's Role Beyond Familial Epilepsy: A Case Report and Literature Review. Case reports in genetics 1 40206130
2025 DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46. Neurobiology of disease 1 40467011
2025 α-hederin decreases the glycolysis level in intestinal epithelial cells via SNX10-mediated DEPDC5 degradation. Journal of pharmaceutical analysis 1 41487148
2024 Nonsense mutation in DEPDC5 gene in a patient with carbamazepine-responsive focal epilepsy. Epilepsy & behavior reports 1 38983576
2023 Neurophysiological assessment of cortical activity in DEPDC5- and NPRL3-related epileptic mTORopathies. Orphanet journal of rare diseases 1 36639812
2023 Correlation of DEPDC5 rs1012068 and rs5998152 Polymorphisms with Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Journal of oncology 1 36733671
2022 What is the impact of a novel DEPDC5 variant on an infant with focal epilepsy: a case report. BMC pediatrics 1 35907814
2016 Partial deletion of DEPDC5 in a child with focal epilepsy. Epilepsia open 1 29588938
2026 Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy. Experimental neurology 0 41587632
2026 Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion. Brain : a journal of neurology 0 41789478
2026 Cardiac remodeling and arrhythmia in a mouse model of Depdc5 haploinsufficiency. Epilepsia 0 41954126
2025 Genotypic and clinical phenotypic analysis of DEPDC5 gene mutations. Neurogenetics 0 40100487
2025 Splicing variants in DEPDC5-related epilepsies: From functional characterization to correction. Epilepsia 0 40543030
2025 DEPDC5-Related Familial Focal Epilepsy With Variable Foci-1: A Report of a Rare Case. Cureus 0 40546503
2025 Identification of a Second-Hit Brain Somatic DEPDC5 Variant Supports Causality of a DEPDC5 Germline Variant of Uncertain Significance. Time for a Classification Update? American journal of medical genetics. Part A 0 40742146
2025 Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal epilepsy. JCI insight 0 40996830
2025 Early death and neuronal abnormalities in depdc5 loss-of-function mosaic zebrafish models. bioRxiv : the preprint server for biology 0 41427333
2023 Generation of a human iPSC line CIPi003-A from a patient with focal epilepsy harboring a heterozygous mutation in DEPDC5 gene. Stem cell research 0 37722146

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