Activating Ras-MAPK pathway variants drive hippocampal clonal competition in human epilepsy

Area of Science:

• Neuroscience
• Genetics
• Epilepsy Research

Background:

• Mesial (medial) temporal lobe epilepsy (MTLE) is the most common focal epilepsy.
• Drug-resistant MTLE is treated with anterior temporal lobe resection, often revealing hippocampal sclerosis (HS).
• While germline genetics play a minor role, somatic variants in Ras-MAPK pathway genes are suspected contributors to MTLE.

Purpose of the Study:

• To investigate the prevalence, clinical relevance, and biological mechanisms of somatic Ras-MAPK variants in MTLE.
• To determine if somatic variants are enriched in MTLE surgical specimens compared to controls.
• To explore the association between somatic variant burden and surgical outcomes in MTLE.

Main Methods:

• Targeted duplex sequencing of hippocampal DNA from 462 MTLE surgical resections and controls.
• Analysis of somatic variants in Ras-MAPK pathway genes, including novel genes.
• Single-nucleus RNA sequencing and functional validation of identified variants in cellular models.

Main Results:

• Over 40% of MTLE specimens showed activating Ras-MAPK variants in known and novel genes, with significant enrichment versus controls.
• Eight Ras-MAPK genes exhibited positive clonal selection in MTLE.
• Increased somatic variant burden correlated with worse surgical outcomes and was linked to older seizure onset and HS pathology.

Conclusions:

• Somatic Ras-MAPK variants are prevalent in MTLE and may arise early in development.
• These variants are enriched in specific hippocampal cell types and influence gene expression, potentially driving hyperexcitability.
• Acquired risk factors and somatic Ras-MAPK variants may interact through clonal competition to increase epilepsy risk.