A Taiwanese research study has uncovered links between genetic variants in the FOXJ3 gene and focal cortical dysplasia, which is a major cause of drug-resistant epilepsy.
There are about 3.4 million people in the U.S. living with epilepsy, and of these, around 60% have focal epilepsy. Focal cortical dysplasia occurs when neurons in one region of the cortex in the brain do not form normal layers or connections during fetal development. This condition affects up to 25% of patients with focal epilepsy and is linked to drug resistance.
“Focal cortical dysplasia is one of the most common causes of epilepsy that does not respond to medication, yet in many patients the underlying cause remains unknown,” said Jin-Wu Tsai, PhD, co-lead investigator and professor at National Yang Ming Chiao Tung University in Taipei, in a press statement. “Our findings identify FOXJ3 as the critical genetic and molecular link between abnormal brain development and epilepsy.”
FOXJ3 was previously known to play a role in in early neural development in the embryo and has been linked to regulation of some forms of cancer cells but was not previously linked to epilepsy or focal cortical dysplasia.
In this study, which is published in Nature Communications, Tsai and colleagues outline the discovery of rare pathogenic variants of FOXJ3 in a Taiwanese family where several members had focal epilepsy and focal cortical dysplasia. They also found similar FOXJ3 variants in other people with focal epilepsy.
The PTEN–mTOR pathway is a key regulation system inside cells that helps them decide how much they grow, divide, and make new proteins. Even small disruptions in this pathway can have big effects, leading to cancer, brain malformations, or abnormal cell signaling.
In the brain, overactive mTOR due to low PTEN can cause neurons and their supporting cells to grow abnormally, migrate incorrectly, and form disorganized circuits, which is strongly linked to epilepsies such as focal cortical dysplasia.
In this study, FOXJ3 was shown to target the PTEN gene and boost PTEN’s activity in developing brain cells. In a mouse model, overexpression of the mouse version of the PTEN gene rescued brain defects caused by low levels of FOXJ3. The pathogenic variants seen in the Taiwanese family effectively stopped production of the PTEN protein and resulted in the abnormal neural cell formation that leads to focal cortical dysplasia.
“Through the regulation of the PTEN-mTOR pathway, FOXJ3 controls the migration and differentiation of deeper-layer and Layer 4 neurons, and its dysfunction leads to cortical malformations that likely underlie the pathogenesis of focal cortical dysplasia,” write the authors. “These findings enhance our understanding of cortical development and offer potential avenues for the diagnosis and treatment of epilepsy and cortical malformations.”
This work adds FOXJ3 to the list of genes that can cause focal epilepsy and focal cortical dysplasia, which may improve genetic diagnosis in the future. It also suggests that targeting this growth‑control pathway could be a route to future therapies for this kind of epilepsy.
