Researchers at Baylor College of Medicine and Texas Children’s Hospital have identified a previously underappreciated genetic route to seizures, reframing how epilepsy can arise when gene variants disrupt not just single targets but entire biological networks. The work also aims to narrow the gap in epilepsy genetics: about half of patients with a suspected heritable cause still have no diagnosis.
The study, published in the Journal of Clinical Investigation, argues that epilepsy may emerge from specific combinations of two—and possibly more—defective genes. While more than 1,000 individual epilepsy genes are known, the clinical yield remains limited, motivating deeper exploration of pathways beyond the “usual suspects” tied to heightened synaptic signaling.
Rather than focusing only on synaptic activity, the team investigated seizure-associated genes involved in actin biology, the cellular system that builds and remodels filaments forming the cytoskeleton. Actin regulatory factors help shape how cells maintain structure and coordinate intracellular transport—processes essential for proper neuronal function.
In earlier work, the Baylor lab linked variants in the human gene TIAM1 to a seizure disorder. In the new study, researchers used fruit fly models carrying a TIAM1 equivalent disruption (sif) to determine how actin defects translate into epileptic behavior.
Flies with the sif mutation developed seizures and showed abnormal actin filament organization: filaments were shorter and accumulated in neuronal clusters. Importantly, neuronal vulnerability was not uniform; glutamatergic “excitatory” neurons—those that release the neurotransmitter glutamate—were most affected, pointing to a pathway-specific effect on seizure-driving circuits.
Unexpectedly, affected neurons did not display obvious structural wiring differences. Instead, the team identified a functional shift consistent with mitochondrial involvement: neurons showed increased mitochondrial numbers, reduced mitochondrial size, and signs of heightened oxidative stress.
The researchers propose an actin–mitochondria–glutamate (AMG) pathway. Excess reactive oxygen species (ROS) were linked to enhanced glutamatergic transmission, creating a setting that increases seizure susceptibility.
Crucially, interfering with steps in this pathway reduced seizures in the fly model. Blocking mitochondrial fragmentation with the drug Mdivi-1 suppressed seizure activity, while an anti-ROS treatment (NACA) reduced both seizures and the heightened glutamatergic signaling.
Finally, the study demonstrated that combining two defective genes within the AMG pathway can amplify seizure risk in ways consistent with patient genetics. This “digenic” framework could improve genetic testing strategies and suggest new therapeutic targets for drug-resistant or genetically unsolved cases.
Subject of Research:
Animals
Article Title:
Epilepsy-associated digenic variants affecting an actin–mitochondria–glutamate pathway promote seizure susceptibility
News Publication Date:
16-Jul-2026
Web References:
https://www.jci.org/articles/view/198696
http://dx.doi.org/10.1172/JCI198696
References:
10.1172/JCI198696
Image Credits:
Not provided.
Keywords
epilepsy; genetics; digenic variants; actin; mitochondria; ROS; glutamate; neuronal excitability; seizure susceptibility; JCI
Tags: complex genetic basis of epilepsyepilepsy and actin cytoskeletonepilepsy gene variantsfruit fly models of epilepsygene interactions in epilepsygenetic network disruptions in epilepsygenetic pathways to epilepsymolecular mechanisms of epilepsyneuronal cell structure and seizure riskpathways beyond synaptic signaling in epilepsyrole of actin in neuronal functionTIAM1 gene and seizure disorders
