Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy

J Clin Invest. 2018 Jun 1;128(6):2452-2458. doi: 10.1172/JCI99384. Epub 2018 Apr 30.


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.

Keywords: Epilepsy; Genetics; Molecular genetics; Neurodevelopment; Neuroscience.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Dendrites / metabolism
  • Dendrites / pathology
  • Epilepsies, Partial* / genetics
  • Epilepsies, Partial* / metabolism
  • Epilepsies, Partial* / pathology
  • Female
  • GTPase-Activating Proteins* / genetics
  • GTPase-Activating Proteins* / metabolism
  • Germ-Line Mutation*
  • Humans
  • Male
  • Malformations of Cortical Development* / genetics
  • Malformations of Cortical Development* / metabolism
  • Malformations of Cortical Development* / pathology
  • Mechanistic Target of Rapamycin Complex 1* / genetics
  • Mechanistic Target of Rapamycin Complex 1* / metabolism
  • Mice
  • Mice, Mutant Strains
  • Neurons / metabolism
  • Neurons / pathology
  • Repressor Proteins* / genetics
  • Repressor Proteins* / metabolism
  • Spine / metabolism
  • Spine / pathology


  • DEPDC5 protein, human
  • Depdc5 protein, mouse
  • GTPase-Activating Proteins
  • Repressor Proteins
  • Mechanistic Target of Rapamycin Complex 1