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Review
. 2023 May:180:106074.
doi: 10.1016/j.nbd.2023.106074. Epub 2023 Mar 11.

RAS pathway: The new frontier of brain mosaicism in epilepsy

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Free article
Review

RAS pathway: The new frontier of brain mosaicism in epilepsy

Sahibjot Sran et al. Neurobiol Dis. 2023 May.
Free article

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.

Keywords: Epilepsy; Neurodevelopment; RAS signaling; Somatic mosaicism.

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Conflict of interest statement

Declaration of Competing Interest The authors report no declaration of interest.

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