Brain Somatic Variant in Ras-Like Small GTPase Causes Focal Cortical Dysplasia Type II.

PURPOSE

In our group's previous study, we performed deep whole-exome sequencing and targeted amplicon sequencing in the postoperative brain tissue of epilepsy patients with focal cortical dysplasia type II (FCD II). We identified the first somatic variant of in the brain tissue of a child with FCD type IIb. encodes a small GTPase of the Ras superfamily. To date, the role of in brain development is not yet known. In this study, we reported that the somatic variant led to FCD type II through activation of the mammalian target of rapamycin (mTOR) pathways.

MATERIALS AND METHODS

HEK293T cells were transfected to analyze the expression of the RalA protein, as well as phosphorylated S6 (P-S6), one of the major markers of mTOR pathway activation, RalA GTPase activity, and the interaction between RalA and its downstream binding effectors. , wild-type, and mutant plasmids were transfected into the local cortex of mice using electroporation to evaluate the effect of c.G482A on neuronal migration.

RESULTS

The c.G482A mutation increased RalA protein expression, the abnormal activation of the mTOR pathways, RalA GTPase activity, and binding to downstream effectors. c.G482A local transfection in the embryonic brain induced abnormal cortical neuron migration in mice.

CONCLUSION

This study demonstrated for the first time that the somatic gain-of-function variant of activates the mTOR pathway and leads to neuronal migration disorders in the brain, facilitating the development of FCD II. Therefore, brain somatic mutation may be one of the pathogenic mechanisms leading to FCD II, which is always related to drug-resistant epilepsy in children. However, more somatic variations of this gene are required to be confirmed in more FCD II patient brain samples.