By: Clare Logan
GATOR1 Complex and Epilepsy
What is the GATOR1 Gene?
The GATOR1 complex is made up of three genes (DEPDC5, NPRL2, and NPRL3) that work together to control how brain cells grow and communicate. These three genes make proteins that act as a “brake” for a key signaling system in our cells known as the mTOR pathway. This pathway helps brain cells grow, produce energy, and stay balanced. When the GATOR1 complex is working properly, it keeps the mTOR pathway from being overactive, helping neurons communicate smoothly.
If a change, or variant, occurs in one of the GATOR1 genes, that brake may not function correctly. In turn, the mTOR pathway may become too active, making brain cells more excitable, leading to seizures. In this way, variants in any one of the three genes can increase an individual’s risk of epilepsy. Variants in the GATOR1 complex can be inherited from a parent or happen for the first time in a child. Interestingly, not everyone with a GATOR1 variant will develop epilepsy, as some people carry the variant without ever experiencing seizures.
GATOR1-Related Epilepsy
Epilepsy caused by GATOR1 gene variants usually appears as focal epilepsy, meaning seizures begin in one specific area of the brain. Many people with this condition experience seizures during sleep, often involving sudden or intense movements, a pattern known as sleep-related hypermotor epilepsy (SHE). Seizures can begin at any age, from infancy through adulthood, and vary widely in severity. Additionally, responses to treatment differ from person to person with some individuals achieving seizure control with standard medications, and others having drug-resistant epilepsy. Research studies suggest that about half of those with GATOR1 variants continue to have seizures despite medication. Even within one family, some relatives may have frequent seizures while others with the same gene variant never develop epilepsy. Because a few studies have found a higher risk of sudden unexpected death in epilepsy (SUDEP) in families with GATOR1 variants, consistent seizure control and regular follow-up are especially important.
Research and Treatment
There is currently no cure for GATOR1-related epilepsy, and treatment focuses on managing seizures and supporting quality of life. Anti-seizure medications (ASMs) such as carbamazepine, levetiracetam, and lamotrigine are commonly used, though their success varies. When seizures start from a specific area of the brain (focal), epilepsy surgery may help. In fact, several studies have shown encouraging results for patients with GATOR1 variants who undergo surgery. Researchers are also studying medications that act directly on the mTOR pathway, such as everolimus, which is already used for other genetic epilepsies. While early results show possible benefits, more research is needed to confirm long-term safety and effectiveness.
Scientists continue to explore why some people with GATOR1 variants never develop epilepsy, with the goal of improving early diagnosis and developing targeted treatments. Families affected by GATOR1-related epilepsy often work with a team that includes neurologists, epileptologists, genetic counselors, and therapists. This multidisciplinary approach helps families understand more about inheritance, treatment options, and planning for the future.
Resources
“GATOR1-Related Epilepsies.” Epilepsy Foundation.
Baldassari, S., Picard, F., Verbeek, N.E. et al. The landscape of epilepsy-related GATOR1 variants. Genet Med 21, 398–408 (2019). https://doi.org/10.1038/s41436-018-0060-2
Baulac S, Baldassari S. DEPDC5-Related Epilepsy. 2016 Sep 29 [Updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK385626/
Dibbens, L., de Vries, B., Donatello, S. et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 45, 546–551 (2013). https://doi.org/10.1038/ng.2599
McGinley C, Teti S, Hofmann K, Schreiber JM, Cohen NT, Gaillard WD, Oluigbo CO. Seizure Control Outcomes following Resection of Cortical Dysplasia in Patients with DEPDC5 Variants: A Systematic Review and Individual Patient Data Analysis. Neuropediatrics. 2024 Feb;55(1):1-8. doi: 10.1055/a-2213-8584. Epub 2023 Nov 20. PMID: 37984419.
