Trial reportThe Journal of clinical investigation2018
Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy.
Trial report in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 139 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
139 citing papers in PubMed, 1 synthesis or guideline pooled it, 234 citations in OpenAlex.
- Genotype-phenotype correlations in focal malformations of cortical development: a pathway to integrated pathological diagnosis in epilepsy surgery.Brain pathology (Zurich, Switzerland) · 2019Pooled it
- Mosaic human cortical organoids model mTOR-related focal cortical dysplasia through DEPDC5 deletion.Brain : a journal of neurology · 2026Article
- Synergistic role of TFEB/TFE3 and mTORC1 in kidney cystogenesis and tumorigenesis.Cell death and differentiation · 2026Article
- Molecular Mechanisms of Seizure Gating in Sleep-Related Epilepsy: Genes, Channels, Sleep Stages and Circadian Rhythm.Current issues in molecular biology · 2026Review
- Focal Cortical Dysplasia Type II: Somatic Mutations, Molecular Mechanisms, and Integrative Multi-Omics Framework.CNS neuroscience & therapeutics · 2026Review
- Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.Progress in neuro-psychopharmacology & biological psychiatry · 2026Article
- DEPDC5: Modeling of the Two-Hit Wonder in Cortical Organoids.Epilepsy currents · 2026Article
- Neuroimaging spectrum of GATOR1-related epilepsy (GATORopathies).Neuroradiology · 2026Article
- Excitatory neurons and astrocytes-specific dysregulation and aberrant interactions are vulnerable to FCDI as suggested by single-cell spatial transcriptomics.Clinical and translational medicine · 2026Article
- Aberrant RNA splicing caused by variant in DEPDC5 identified in a patient with pharmacoresistant epilepsy.Neurogenetics · 2026Article
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Matched tissue-blood whole-exome sequencing improves detection of genetic etiologies in pediatric drug-resistant epilepsy.Frontiers in pediatrics · 2026Article
- Focal cortical dysplasias: modeling pediatric drug-resistant epilepsy using human brain organoids.Frontiers in cellular neuroscience · 2026Review
- Early death and neuronal abnormalities inbioRxiv : the preprint server for biology · 2025Article
- Seizure occurrence in FCD type II is predicted by lesion position and linked to cytoarchitectural alterations.Acta neuropathologica communications · 2025Article
- The role of genetic testing in evaluating surgical outcomes for pediatric focal cortical dysplasia associated with NPRL3 variant.Epilepsy & behavior reports · 2025Article
- α-hederin decreases the glycolysis level in intestinal epithelial cells via SNX10-mediated DEPDC5 degradation.Journal of pharmaceutical analysis · 2025Article
- Deep tissue sequencing improves genetic diagnostic yield in focal cortical dysplasia.medRxiv : the preprint server for health sciences · 2025Article
- Focal DEPDC5 loss without disruption to cerebral cortical neuron migration recapitulates DEPDC5-related focal epilepsy.JCI insight · 2025Article
- The transcriptomic signature of DEPDC5 KO induced mTOR hyperactivation in human neurons and its response to rapamycin treatment.Epilepsia · 2025Article
79 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP-like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.