RAS pathway: The new frontier of brain mosaicism in epilepsy
Sahibjot Sran1, Tracy A Bedrosian2
1Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, United States of America.
Abstract:
As cells divide during development, errors in DNA replication and repair lead to somatic mosaicism - a phenomenon in which different cell lineages harbor unique constellations of genetic variants. Over the past decade, somatic variants that disrupt mTOR signaling, protein glycosylation, and other functions during brain development have been linked to cortical malformations and focal epilepsy. More recently, emerging evidence points to a role for Ras pathway mosaicism in epilepsy. The Ras family of proteins is a critical driver of MAPK signaling. Disruption of the Ras pathway is most known for its association with tumorigenesis; however, developmental disorders known as RASopathies commonly have a neurological component that sometimes includes epilepsy, offering evidence for Ras involvement in brain development and epileptogenesis. Brain somatic variants affecting the Ras pathway (e.g., KRAS, PTPN11, BRAF) are now strongly associated with focal epilepsy through genotype-phenotype association studies as well as mechanistic evidence. This review summarizes the Ras pathway and its involvement in epilepsy and neurodevelopmental disorders, focusing on new evidence regarding Ras pathway mosaicism and the potential future clinical implications.
Insights
Somatic mosaicism, genetic variants affecting the Ras pathway, and their link to focal epilepsy and neurodevelopmental disorders are increasingly recognized. This review explores Ras pathway involvement in brain development and epilepsy.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Somatic mosaicism arises from DNA errors during cell division, creating unique genetic variants in different cell lineages.
- Disruptions in signaling pathways like mTOR and Ras during brain development are linked to cortical malformations and epilepsy.
- Ras pathway dysregulation is known for tumorigenesis, but RASopathies also show neurological involvement, suggesting a role in brain development and epileptogenesis.
Approach:
- This review summarizes the Ras pathway's role in epilepsy and neurodevelopmental disorders.
- It focuses on emerging evidence linking Ras pathway mosaicism to focal epilepsy.
- The review also discusses genotype-phenotype associations and mechanistic studies.
Key Points:
- Brain somatic variants impacting the Ras pathway (KRAS, PTPN11, BRAF) are strongly associated with focal epilepsy.
- The Ras pathway is a critical regulator of MAPK signaling, crucial for cell proliferation and differentiation.
- Mosaicism in the Ras pathway during development contributes to neurological disorders.
Conclusions:
- Ras pathway mosaicism is a significant factor in focal epilepsy and neurodevelopmental disorders.
- Understanding these genetic variants offers insights into brain development and epileptogenesis.
- Future clinical implications may arise from targeting the Ras pathway in neurological conditions.
