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Updated: May 2, 2026
Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy
Published on: October 19, 2021
Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations
Ingrid E Scheffer1, Sarah E Heron, Brigid M Regan
1Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia; Florey Institute of Neuroscience and Mental Health, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia.
Abstract:
We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.
Insights
Mutations in the DEPDC5 gene are linked to various forms of focal epilepsy, including those with and without brain lesions. These findings suggest potential mTOR pathway-targeted therapies for epilepsy.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Familial focal epilepsy with variable foci was recently linked to DEPDC5 gene mutations.
- Mutations in DEPDC5 were found in over 10% of small families with nonlesional focal epilepsy.
Purpose of the Study:
- To investigate the association of DEPDC5 mutations with both lesional and nonlesional epilepsies.
- To characterize the malformations associated with DEPDC5 mutations.
- To explore potential therapeutic strategies targeting the mTOR pathway.
Main Methods:
- Genetic analysis of families with epilepsy.
- Clinical and radiological evaluation of affected individuals.
- Investigation of DEPDC5's role in the mTOR pathway.
Main Results:
- DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family.
- DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia and focal band heterotopia.
- DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway.
Conclusions:
- DEPDC5 mutations represent a significant cause of focal epilepsy with diverse clinicoradiological phenotypes.
- The clinicoradiological features of DEPDC5-associated epilepsy resemble mTORopathies like tuberous sclerosis.
- Targeting the mTOR pathway may offer a potential therapeutic approach for DEPDC5-related epilepsies.
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