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Behavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy
Published on: October 19, 2021
DEPDC5 mutations in familial and sporadic focal epilepsy
M-H Tsai1,2, C-K Chan3, Y-C Chang4
1Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
Background And Aims:
Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
Materials And Methods:
We studied a kindred of familial focal epilepsy with variable foci using whole-exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
Results:
We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the DEPDC5 gene.
Discussion And Conclusions:
Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.
Insights
Mutations in the DEPDC5 gene are a common cause of familial focal epilepsy. This study found DEPDC5 mutations also play a role in sporadic focal epilepsy, suggesting new therapeutic targets.
Area of Science:
- Genetics
- Neurology
- Epilepsy Research
Background:
- Mutations in the disheveled, Egl-10 and pleckstrin domain-containing protein 5 (DEPDC5) gene are linked to familial focal epilepsy.
- The role of DEPDC5 mutations in sporadic focal epilepsy remains unclear.
Purpose of the Study:
- To investigate the significance of DEPDC5 gene mutations in patients with sporadic focal epilepsy.
- To identify novel mutations and their functional consequences in epilepsy.
Main Methods:
- Whole-exome sequencing was performed on a family with familial focal epilepsy.
- Targeted resequencing of DEPDC5 exons was conducted in 293 patients with focal epilepsy.
Main Results:
- A novel splice site mutation in DEPDC5 was identified in a Taiwanese family, activating the mTOR pathway.
- Two (0.9%) patients with sporadic focal epilepsy harbored probable pathogenic DEPDC5 mutations.
Conclusions:
- DEPDC5 is a significant genetic cause of both familial and sporadic focal epilepsy.
- Targeting the mTOR pathway may be a future therapeutic strategy for focal epilepsy patients with DEPDC5 mutations.
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