Project Overview

The human brain’s development relies on precisely coordinated genetic programs that ensure proper wiring and function. When these processes go awry, neurodevelopmental disorders, including severe epileptic encephalopathies, can arise. Lennox-Gastaut Syndrome (LGS) is a rare and severe childhood epilepsy that is often resistant to current treatments, suggesting the involvement of unknown disease mechanisms.

Recently, we identified a new gene, THAP12, in two patients with severe LGS. THAP12 belongs to a family of transcription factors —proteins that regulate gene activity— and has never been linked to any human disease before. Our initial studies revealed that mutations in THAP12 prevent its production, indicating a loss-of-function mechanism. In animal models, loss of THAP12 leads to early death in mice and severe brain development defects in zebrafish, confirming its essential role in neurodevelopment.

To further understand THAP12’s function, we now propose to study human-derived neural cells and brain organoids —tiny, lab-grown models of the brain— to determine which genes and biological processes THAP12 controls. Using complementary and sophisticated models and techniques, we will also investigate how THAP12 binds to DNA and identify potential molecular triggers regulating its activity. Finally, we will explore proteins that interact with THAP12 to better understand its role in brain cell development.

This research is highly innovative, as it explores a previously unknown molecular pathway in neurodevelopment, potentially uncovering new targets for treating drug-resistant epilepsy. Given that 30% of epilepsy patients do not respond to available treatments, identifying alternative therapeutic strategies is essential. Our interdisciplinary approach, combining genetics, neuroscience, and advanced biological models, positions us to make significant contributions to understanding brain development and disease. Ultimately, our findings could pave the way for novel treatments for epilepsy and other neurodevelopmental disorders.

Principal Investigator

Eric Samarut , Centre Hospitalier de L’Université de Montréal