Affinage

DEPDC5

GATOR1 complex protein DEPDC5 · UniProt O75140

Length
1603 aa
Mass
181.3 kDa
Annotated
2026-04-28
83 papers in source corpus 31 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DEPDC5 is a core subunit of the GATOR1 complex that functions as the principal amino acid–sensing negative regulator of mTORC1, controlling lysosomal mTOR recruitment and activity via GTPase-activating protein function toward RagA/B GTPases. DEPDC5 loss abolishes mTORC1 suppression during amino acid withdrawal, causing constitutive mTORC1 hyperactivation that drives neuronal soma enlargement, dendritic dysmorphology, increased excitatory synaptic strength—including mTORC1-dependent USP46 upregulation leading to GluA1 deubiquitination and AMPA receptor surface accumulation—and excitation–inhibition imbalance (PMID:23542697, PMID:32781001, PMID:32113911, PMID:40467011). Germline heterozygous DEPDC5 loss-of-function mutations combined with somatic second-hit inactivation cause focal cortical dysplasia and mTORC1-dependent epilepsy with SUDEP, where excitatory neuron loss drives respiratory dysregulation preceding terminal cardiac events (PMID:29708508, PMID:31353856, PMID:37606181). Beyond neurons, DEPDC5 is phosphorylated by Pim1/AKT to release GATOR1-mediated mTORC1 inhibition in cancer cells, functions as a tumor suppressor in gastrointestinal stromal tumors, regulates hepatocyte PPARα-dependent lipid metabolism, and controls CD8+ T cell ferroptosis through an mTORC1–ATF4–xanthine oxidase axis (PMID:31548394, PMID:31636198, PMID:34267188, PMID:38763950).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2013 High

    Identifying DEPDC5 as a GATOR1 subunit and mTORC1 repressor answered what molecular complex mediates amino acid–dependent mTORC1 inhibition and linked its loss-of-function to familial focal epilepsy.

    Evidence Exome sequencing in epilepsy families combined with functional mTORC1 signaling assays

    PMID:23542697 PMID:23542701

    Open questions at the time
    • GAP activity toward Rag GTPases not yet directly demonstrated
    • structural basis of GATOR1 complex assembly unknown
    • mechanism linking mTORC1 hyperactivation to seizures uncharacterized
  2. 2014 High

    Systematic functional testing of epilepsy-associated DEPDC5 variants established that specific mutations disrupt GATOR1 complex integrity and/or mTORC1 inhibitory function, validating a loss-of-function mechanism for disease alleles.

    Evidence In vitro mTORC1 signaling and GATOR1 complex formation assays on 10 epilepsy-associated and 2 tumor-associated DEPDC5 variants

    PMID:25366275

    Open questions at the time
    • structural basis of variant-specific disruption unknown
    • genotype–phenotype correlation for seizure severity not established
  3. 2016 High

    In vivo genetic ablation in rodents demonstrated that DEPDC5 is essential for embryonic viability and that constitutive mTORC1 hyperactivation is the causal downstream mechanism, as rapamycin rescued embryonic lethality.

    Evidence TALEN-generated Depdc5 knockout rat with mTORC1 phosphorylation assays and prenatal rapamycin rescue

    PMID:26873552

    Open questions at the time
    • cell-type-specific requirements not yet dissected
    • whether mTORC1 is the sole effector of DEPDC5 loss not excluded
  4. 2017 High

    Neuron-specific conditional knockout resolved that DEPDC5 loss in neurons—not glia—drives mTORC1 hyperactivation, cortical dysplasia, and seizures, establishing cell-autonomous neuronal pathology.

    Evidence Syn1-Cre conditional Depdc5 knockout mouse with EEG, pS6 immunohistochemistry, and seizure threshold assays

    PMID:28974734 PMID:29274432

    Open questions at the time
    • which neuronal subtypes are most vulnerable not determined
    • downstream effectors mediating seizure generation unknown
  5. 2018 High

    Demonstration that biallelic (germline + somatic second-hit) DEPDC5 inactivation is required for focal cortical dysplasia, and that focal somatic deletion alone recapitulates FCD and SUDEP in rodents, established the two-hit model and cell-autonomous sufficiency of DEPDC5 loss for epileptogenesis.

    Evidence Deep sequencing of human surgical tissue; CRISPR/in utero electroporation in mouse and rat; neuromorphological and EEG analysis

    PMID:29708508 PMID:30080265 PMID:31353856

    Open questions at the time
    • timing of second-hit relative to cortical development not defined
    • whether migration defects are required for epileptogenesis unclear
  6. 2018 High

    Mechanistic dissection in neuronal cells showed DEPDC5 specifically controls amino acid–dependent lysosomal mTOR recruitment (distinct from TSC2/Rheb axis), explaining why DEPDC5 loss causes mTORC1 hyperactivation even during amino acid starvation.

    Evidence CRISPR Depdc5 vs Tsc2 knockout in Neuro2a cells; FRET biosensor for 4E-BP1 phosphorylation; confocal imaging of mTOR–lysosome colocalization

    PMID:29481864 PMID:32781001

    Open questions at the time
    • direct GAP activity measurement on Rag GTPases in neuronal context not performed
    • whether nutrient-independent functions of DEPDC5 exist in neurons not addressed
  7. 2019 High

    Discovery that Pim1 and AKT phosphorylate DEPDC5 to release GATOR1-mediated mTORC1 inhibition established DEPDC5 as a signal-regulated node integrating growth factor and amino acid sensing, with direct therapeutic implications for kinase inhibitor resistance in cancer.

    Evidence Phospho-specific antibodies; phospho-inactive and phospho-mimic DEPDC5 mutants; DEPDC5 knockout tumor cells; in vivo xenograft assays

    PMID:31548394

    Open questions at the time
    • phosphorylation sites not mapped at residue resolution beyond S1530
    • whether phosphorylation affects GATOR1 complex integrity or GAP activity not distinguished
  8. 2020 High

    Electrophysiological characterization revealed that DEPDC5 loss selectively increases excitatory but not inhibitory synaptic transmission, directly demonstrating that excitation–inhibition imbalance is a proximal mechanism of DEPDC5-associated epileptogenesis.

    Evidence Acute RNAi knockdown in primary cortical neurons; mEPSC/mIPSC recordings; synaptic marker immunocytochemistry

    PMID:32113911

    Open questions at the time
    • molecular identity of upregulated glutamate receptors not fully characterized
    • contribution of presynaptic vs postsynaptic mechanisms not resolved
  9. 2022 High

    Establishing that neuronal DEPDC5 is required for mTORC1 to sense amino acid fluctuations during fasting—and that this sensing mediates fasting-induced seizure protection—linked DEPDC5's metabolic function to a clinically relevant anticonvulsant mechanism.

    Evidence Neuronal Depdc5 conditional knockout mice; metabolomics; seizure threshold assays after fasting; specific amino acid deprivation experiments

    PMID:36044864

    Open questions at the time
    • which specific amino acid sensors upstream of GATOR1 are active in neurons not identified
    • whether dietary interventions can substitute for DEPDC5 function not tested
  10. 2023 High

    Cell-type-specific knockout showed that DEPDC5 loss in excitatory (but not inhibitory) neurons is sufficient for seizures and SUDEP, with ictal apnea preceding cardiac arrest, identifying respiratory circuit dysfunction as the proximal cause of SUDEP.

    Evidence Multiple Cre-driver Depdc5 knockout lines; simultaneous EEG-ECG-respiratory recordings; hypoxia challenge

    PMID:37606181

    Open questions at the time
    • specific brainstem circuits mediating respiratory failure not identified
    • whether interventions targeting respiratory drive can prevent SUDEP not tested
  11. 2024 High

    Identification of USP46 as a DEPDC5-interacting deubiquitinase revealed the molecular mechanism by which DEPDC5 loss increases excitatory synaptic strength: mTORC1-dependent USP46 upregulation reduces GluA1 ubiquitination, increasing surface AMPA receptors and glutamate quantal size.

    Evidence Co-immunoprecipitation; Depdc5 conditional knockout; GluA1 ubiquitination assay; electrophysiology; USP46 knockdown and rapamycin rescue

    PMID:40467011

    Open questions at the time
    • whether USP46 pathway is sufficient to explain all excitatory synaptic changes not established
    • reciprocal Co-IP for DEPDC5–USP46 not explicitly described
  12. 2024 High

    DEPDC5's role was extended beyond neurons: in CD8+ T cells, DEPDC5 loss causes hyper-mTORC1–driven ATF4 upregulation, xanthine oxidase production, lipid ROS accumulation, and spontaneous ferroptosis, establishing DEPDC5 as an immune cell survival factor.

    Evidence T cell–specific Depdc5 conditional knockout mice; ROS and xanthine oxidase assays; ATF4 expression; ferroptosis markers

    PMID:38763950

    Open questions at the time
    • whether DEPDC5-dependent ferroptosis occurs in other immune cell types unknown
    • therapeutic relevance of modulating this axis in immunotherapy not tested
  13. 2025 High

    Postnatal focal DEPDC5 deletion demonstrated that cortical dysplasia and epilepsy can arise independently of embryonic migration defects, and a patient-derived missense knock-in confirmed that subcellular mislocalization of mutant DEPDC5 is sufficient for mTOR hyperactivation and seizure susceptibility.

    Evidence Postnatal AAV-Cre in floxed Depdc5 mice; knock-in mouse of hDEPDC5-F685L; rapamycin rescue; EEG and histopathology

    PMID:39954744 PMID:40996830

    Open questions at the time
    • window of postnatal vulnerability not defined
    • structural basis of missense-induced mislocalization unknown
  14. 2026 High

    Human cortical organoids with mosaic biallelic DEPDC5 loss recapitulated dysmorphic neurons, hyperexcitability, and premature upper-layer neurogenesis with dysregulated Notch/Wnt signaling, establishing cell-autonomous human-specific developmental consequences of DEPDC5 loss.

    Evidence Patient-derived cortical organoids with mosaic two-hit DEPDC5 deletion; single-cell transcriptomics; electrophysiology; rapamycin rescue

    PMID:41789478

    Open questions at the time
    • whether Notch/Wnt dysregulation is mTORC1-dependent or independent not resolved
    • organoid model lacks circuit-level validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include the direct structural basis of DEPDC5's GAP activity toward Rag GTPases, identification of upstream amino acid sensors feeding into GATOR1 in neurons, whether non-mTORC1 functions of DEPDC5 contribute to disease, and whether targeting the USP46–GluA1 axis or ferroptosis pathway has therapeutic potential.
  • no reconstituted GAP assay for human DEPDC5 on Rag GTPases
  • upstream amino acid sensors in neurons not identified
  • therapeutic window for postnatal intervention not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0003924 GTPase activity 3
Localization
GO:0005764 lysosome 3 GO:0005829 cytosol 2
Pathway
R-HSA-112316 Neuronal System 6 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9612973 Autophagy 1
Partners
NPRL2NPRL3RRAGASNX10USP46WDR20WDR48
Complex memberships
GATOR1

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 DEPDC5 was identified as a component of the GATOR1 complex that functions as a repressor/negative regulator of the mTORC1 signaling pathway, specifically the amino acid-sensing branch; loss-of-function mutations cause hyperactivation of mTORC1. Exome sequencing identifying mutations; functional inference from shared homology and pathway context; subsequent in vitro TORC1 signaling assays Nature genetics High 23542697 23542701
2014 DEPDC5 variants disrupt GATOR1 complex formation and/or DEPDC5-dependent inhibition of TORC1 signaling, as assessed by functional assays of 10 epilepsy-associated variants and 2 ovarian tumor variants; three variants clearly disrupted mTORC1 inhibition. In vitro TORC1 signaling assays and GATOR1 complex formation assays on epilepsy-associated DEPDC5 variants Human mutation High 25366275
2015 DEPDC5 loss-of-function mutations lead to mTORC1 pathway activation (evidenced by mTOR activation marker immunostaining in resected brain tissue from patients with focal cortical dysplasia), establishing DEPDC5 as a negative regulator of mTOR in human brain tissue. Immunostaining of resected brain tissue for mTOR activation markers; germline and somatic sequencing Annals of clinical and translational neurology Medium 26000329
2016 Homozygous Depdc5 knockout in rats causes embryonic lethality with constitutive mTORC1 hyperactivation (enhanced phosphorylation of S6K1 and rpS6) in brain and cultured fibroblasts; rapamycin treatment rescues the embryonic lethal phenotype, confirming DEPDC5 acts upstream of mTORC1. TALEN-generated global Depdc5 knockout rat; phosphorylation assays for mTORC1 effectors; prenatal rapamycin rescue experiment Neurobiology of disease High 26873552
2017 Neuron-specific Depdc5 conditional knockout mice (Syn1-Cre) develop mTORC1 hyperactivation exclusively in neurons (increased pS6), dysplastic and ectopic neurons, reactive astrogliosis, and seizures; mTORC1 hyperactivation is not observed in astrocytes despite reactive gliosis. Cre-lox conditional knockout mouse; immunohistochemistry for pS6; EEG; chemoconvulsant seizure threshold assay Neurobiology of disease High 29274432
2017 DEPDC5 knockout in mice causes severe embryonic dysmorphology with mTORC1 hyperactivity observable in brain and in fibroblasts and neurospheres from knockout embryos cultured in nutrient-deprived conditions, confirming DEPDC5 role in nutrient-sensing mTORC1 regulation. CRISPR-generated null mouse; phosphorylation assays in primary fibroblasts and neurospheres under nutrient deprivation Scientific reports High 28974734
2018 Biallelic (germline + brain somatic second-hit) DEPDC5 inactivation causes focal cortical dysplasia with a mutation gradient—higher mosaicism in the seizure-onset zone; CRISPR-Cas9/in utero electroporation mosaic Depdc5 inactivation in mice recapitulates focal epilepsy with FCD and SUDEP-like events; Depdc5 loss shapes dendrite and spine morphology of excitatory neurons. Deep sequencing of postoperative human tissue; CRISPR-Cas9 with in utero electroporation mouse model; neuromorphological analysis The Journal of clinical investigation High 29708508
2018 Depdc5 knockdown in neural progenitor cells and neurons causes mTORC1 (but not mTORC2) hyperactivation, increased soma size, increased filopodial extension, and inappropriate lysosomal localization of mTOR during amino acid starvation; these effects are reversed by rapamycin. shRNA knockdown in mouse neuroblastoma (N2aC) and mouse neural progenitor cells; immunofluorescence for lysosomal mTOR localization; rapamycin rescue Neurobiology of disease High 29481864
2018 Depdc5 knockdown in zebrafish leads to motor hyperactivity and increased neuronal activity dependent on mTORC1; rescue by wild-type DEPDC5 but not by epilepsy-associated mutants (p.Arg487* and p.Arg485Gln), confirming these are loss-of-function alleles. Morpholino-based zebrafish knockdown model; behavioral assays; overexpression of WT vs. mutant DEPDC5; rapamycin treatment Annals of clinical and translational neurology High 29761115
2018 Somatic focal Depdc5 deletion (via in utero electroporation with CRISPR) in rat embryonic brain produces spontaneous seizures with electroclinical features of focal cortical dysplasia type IIA, establishing that focal loss of DEPDC5 is sufficient to generate FCD-like epilepsy. In utero electroporation + CRISPR-based somatic Depdc5 deletion in rat; EEG recording; histopathology Annals of neurology High 30080265
2018 DEPDC5 inhibits the AKT-mTORC1-S6 axis through RagA (distinct from TSC1, which acts via Rheb); knockout of DEPDC5 in T-cell and monocyte cell lines enhances HIV-1 reactivation reversible by rapamycin, placing DEPDC5 as a negative regulator of mTORC1 via the RagA GTPase. Genome-wide CRISPR screen; gene knockout in cell lines; rapamycin rescue; mechanistic dissection of TSC1 vs. DEPDC5 pathways Emerging microbes & infections Medium 30087333
2019 DEPDC5, as a component of GATOR1, is phosphorylated by Pim1 and AKT kinases at consensus sequences; this phosphorylation releases GATOR1-mediated inhibition of mTORC1. Phospho-inactive DEPDC5 mutants and DEPDC5 knockout partially block the ability of Pim/AKT inhibitors to suppress tumor growth and mTORC1 activity; knock-in of phospho-mimic S1530E confers resistance to Pim and AKT inhibitors. Phospho-specific antibodies; phospho-inactive mutant transfection; DEPDC5 knockout; phospho-mimic knock-in in tumor cells; in vitro and in vivo tumor growth assays Proceedings of the National Academy of Sciences of the United States of America High 31548394
2019 Depdc5 loss in neurons leads to mTORC1-dependent reduction in levels of the other GATOR1 subunits NPRL2 and NPRL3; rapamycin rescues mTORC1 hyperactivation (pS6) but not GATOR1 protein levels, indicating a downstream effect on complex stability. Western blotting of GATOR1 subunits in Depdc5cc+ knockout mouse brain; rapamycin treatment Human molecular genetics Medium 31174205
2019 DEPDC5 inactivation in GIST (gastrointestinal stromal tumor) cells reduces cell proliferation through the mTORC1 signaling pathway, induces cell-cycle arrest, and promotes tumor growth in vitro and in vivo; DEPDC5 is validated as a tumor suppressor. Whole-exome sequencing of GISTs; DEPDC5 inactivation in cell lines; DEPDC5 overexpression in vitro; nude mouse xenograft assay; mTORC1 pathway analysis Proceedings of the National Academy of Sciences of the United States of America High 31636198
2019 Second-hit DEPDC5 somatic mutations are restricted to dysmorphic neurons in focal cortical dysplasia IIA, and the somatic mutation load correlates with dysmorphic neuron density and the epileptogenic zone, confirming cell-autonomous mTORC1 hyperactivation drives the dysplastic phenotype. Deep sequencing of laser-captured dysmorphic neurons from human surgical tissue; correlation analysis Annals of clinical and translational neurology High 31353856
2020 Acute Depdc5 knockdown (~40–80%) in primary cortical neurons causes mTOR hyperactivation, increased soma size, dendritic arborization, increased excitatory synaptic transmission (mEPSC frequency and amplitude), increased density of excitatory synapses, and glutamate receptor expression, while inhibitory synapses are unaffected—demonstrating an excitation/inhibition imbalance causally linked to Depdc5 loss. RNAi-mediated acute Depdc5 knockdown in primary cortical cultures; electrophysiology (mEPSC/mIPSC recording); immunocytochemistry for synaptic markers Neurobiology of disease High 32113911
2020 Depdc5 knockout (but not Tsc2 knockout) cells fail to reduce mTOR lysosomal localization or S6/4E-BP1 phosphorylation in amino acid-free conditions, demonstrating that DEPDC5 specifically mediates amino acid-sensing-dependent lysosomal recruitment/inactivation of mTOR in neurons. CRISPR-edited Neuro2a cells and differentiated neurons; CFP/YFP FRET-biosensor for 4E-BP1 phosphorylation; confocal imaging of mTOR lysosomal localization during amino acid starvation Experimental neurology High 32781001
2021 Depdc5 deficiency in hepatocytes leads to mTORC1 hyperactivation and suppression of PPARα pathway, causing exacerbation of alcohol-induced hepatic steatosis; the steatotic phenotype is reversed by the mTORC1 inhibitor Torin1 or by fenofibrate (PPARα agonist), placing DEPDC5 upstream of mTORC1–PPARα axis in hepatocytes. Hepatocyte-specific Depdc5 conditional knockout mouse (Depdc5-LKO); ethanol feeding model; Torin1 and fenofibrate pharmacological rescue; liver histology and lipid measurements Cell death & disease High 34267188
2022 Brain mTORC1 signaling is reduced after acute fasting in mice; DEPDC5 (GATOR1 component) is required for neuronal mTORC1 to sense amino acid withdrawal (leucine, arginine, glutamine); neuronal Depdc5 knockout mice are resistant to amino acid fluctuations after fasting and to the seizure-protective effects of fasting, establishing DEPDC5 as the essential link between amino acid sensing and mTORC1 regulation in neurons mediating fasting-induced seizure protection. Neuronal Depdc5 conditional knockout mice; metabolomics; seizure threshold assays after fasting; leucine/arginine/glutamine deprivation assays Cell reports High 36044864
2023 Depdc5 deletion in excitatory neurons (cortical layer 5 and dentate gyrus) but not in cortical interneurons is sufficient to cause frequent generalized tonic-clonic seizures and SUDEP-like events; ictal apnea occurs before terminal cardiac asystole, and baseline respiratory dysfunction precedes SUDEP, implicating excitatory neuron-mediated respiratory dysregulation in SUDEP. Cell-type-specific Cre-lox Depdc5 knockout mice; EEG; simultaneous EEG-ECG; respiratory recordings; hypoxia challenge Annals of neurology High 37606181
2024 DEPDC5 interacts with USP46 (ubiquitin-specific protease 46), WDR48, and WDR20 as binding partners; loss of DEPDC5 leads to mTORC1-dependent USP46 upregulation, decreased GluA1 ubiquitination, and increased surface GluA1-containing AMPA receptors—shifting glutamate quantal size upward and increasing excitatory synaptic strength. USP46 knockdown or rapamycin rescues this phenotype. Co-immunoprecipitation/protein interaction network analysis; Depdc5 conditional knockout mouse; electrophysiology (quantal size); ubiquitination assay; USP46 knockdown rescue; rapamycin rescue Neurobiology of disease High 40467011
2024 In T cell-specific Depdc5 knockout mice, DEPDC5-deficient CD8+ T cells produce high levels of xanthine oxidase and lipid ROS due to hyper-mTORC1-induced ATF4 expression, leading to spontaneous ferroptosis and reduced peripheral CD8+ T cell numbers. T cell-specific Depdc5 conditional knockout mice; ROS measurement; xanthine oxidase assay; ATF4 expression analysis; ferroptosis markers Cell discovery High 38763950
2024 Biallelic inactivation of Depdc5 in mouse medial prefrontal cortex leads to shared alterations in pyramidal neuron morphology, positioning, and membrane excitability compared with other mTORC1 pathway gene knockouts, but causes gene-specific differences in excitatory synaptic transmission. In utero electroporation for biallelic inactivation; patch-clamp electrophysiology; morphological analysis eLife High 38411613
2018 DEPDC5 down-regulation in hepatic stellate cells leads to increased β-catenin expression and production of MMP2 (matrix metallopeptidase 2), a secreted enzyme involved in fibrosis progression, identifying a DEPDC5–β-catenin–MMP2 pathway in hepatic stellate cells distinct from mTORC1. DEPDC5 siRNA knockdown in immortalized hepatic stellate cells (LX-2); β-catenin and MMP2 expression assays Hepatology (Baltimore, Md.) Medium 26517016
2018 DEPDC5 knockout in hepatocellular carcinoma cells leads to resistance to leucine starvation via impaired autophagy (reduced LC3-II, p62 accumulation, and ROS tolerance); DEPDC5 overexpression suppresses cell proliferation and tumorigenicity in immunocompromised mice, and promotes p62 degradation with increased ROS susceptibility. CRISPR/Cas9 DEPDC5 knockout in HCC cells; LC3-II/p62 western blotting; ROS assay; xenograft mouse model Scientific reports Medium 29311600
2019 Focal perineuronal net (PNN) degradation by proteolytic enzymes occurs in the malformed cortex of forebrain Depdc5-knockout mice prior to seizures, coincident with microglia inflammation, resulting in parvalbumin interneuron loss and impaired presynaptic inhibition. Forebrain-specific Depdc5 conditional knockout mouse; immunohistochemistry for PNNs (WFA staining), parvalbumin, and microglial markers; electrophysiology Developmental neuroscience Medium 35580549
2024 DEPDC5 protein degradation in colorectal cancer is mediated through chaperone-mediated autophagy (CMA) downstream of the GPR81/lactate signaling axis; SNX10 interacts with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation, activating mTORC1 and promoting EMT and metastasis. siRNA knockdown; Co-IP demonstrating SNX10-DEPDC5 interaction; western blotting for CMA markers; in vivo lung metastasis mouse model Phytomedicine : international journal of phytotherapy and phytopharmacology Medium 38615493
2025 A DEPDC5 missense variant (p.Phe685Leu) causes altered subcellular localization of the mutant protein in primary neurons and, when knocked into mice (hDEPDC5F685L), produces mTOR hyperactivation, enlarged neuronal soma, abnormal neurons, and heightened seizure susceptibility; rapamycin rescues neuronal size and mTOR activity and reduces seizure susceptibility. Mutant plasmid transfection for localization; nervous system-specific knock-in mouse; immunohistochemistry; seizure threshold assays; rapamycin rescue Neurobiology of disease High 39954744
2025 Postnatal focal cortical DEPDC5 loss (without disrupting embryonic cortical migration) is sufficient to cause mTOR hyperactivation, FCD pathological hallmarks (increased SMI-311 neurofilament, hypomyelination, astrogliosis, microglial activation), lowered seizure thresholds, increased focal seizures, and increased seizure-induced death, demonstrating a cell-autonomous postnatal role of DEPDC5. Postnatal AAV-Cre injection in floxed Depdc5 mice; histopathology; EEG; seizure threshold assays JCI insight High 40996830
2026 Mosaic biallelic DEPDC5 two-hit inactivation in human cortical organoids (hCOs) causes increased mTOR activity (rescued by rapamycin), dysmorphic-like neurons, enhanced neuronal excitability, premature upper-layer neuron generation, dysregulated Notch and Wnt signaling in neural progenitors, and altered metabolism and translation—establishing cell-autonomous effects of DEPDC5 biallelic loss during human corticogenesis. Patient-derived human cortical organoids with mosaic DEPDC5 two-hit deletion; single-cell transcriptomics; electrophysiology; rapamycin rescue; immunofluorescence Brain : a journal of neurology High 41789478

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 272 23542697
2015 Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations. Annals of neurology 218 25623524
2013 Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nature genetics 190 23542701
2018 Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. The Journal of clinical investigation 180 29708508
2014 Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Annals of neurology 171 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 87 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 76 26873552
2019 Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA. Annals of clinical and translational neurology 59 31353856
2017 Knockout of the epilepsy gene Depdc5 in mice causes severe embryonic dysmorphology with hyperactivity of mTORC1 signalling. Scientific reports 48 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 41 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 39 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
2015 DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection. Hepatology (Baltimore, Md.) 29 26517016
2020 Acute knockdown of Depdc5 leads to synaptic defects in mTOR-related epileptogenesis. Neurobiology of disease 28 32113911
2024 The mTOR pathway genes MTOR, Rheb, Depdc5, Pten, and Tsc1 have convergent and divergent impacts on cortical neuron development and function. eLife 27 38411613
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
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
2023 Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy. Annals of neurology 18 37606181
2022 DEPDC5-dependent mTORC1 signaling mechanisms are critical for the anti-seizure effects of acute fasting. Cell reports 18 36044864
2022 Perineuronal Nets Degradation and Parvalbumin Interneuron Loss in a Mouse Model of DEPDC5-Related Epilepsy. Developmental neuroscience 17 35580549
2018 DEPDC5 deficiency contributes to resistance to leucine starvation via p62 accumulation in hepatocellular carcinoma. Scientific reports 17 29311600
2024 Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation. Phytomedicine : international journal of phytotherapy and phytopharmacology 16 38615493
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
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
2023 Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria. Human molecular genetics 10 36067010
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
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 The transcriptomic signature of DEPDC5 KO induced mTOR hyperactivation in human neurons and its response to rapamycin treatment. Epilepsia 2 40704780
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 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 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 0 40206130
2025 DEPDC5 regulates the strength of excitatory synaptic transmission by interacting with ubiquitin-specific protease 46. Neurobiology of disease 0 40467011
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