Focal cortical dysplasia type II related to a new pathogenic gene-RAB6B

Objectives:Focal cortical dysplasia(FCD) type II constitutes the most common pathological finding in pediatric patients with epilepsy surgery. Currently, FCD II has been related to somatic variants narrowly restricted in mTOR pathway genes. Our research group reported a new pathogenic somatic mutation RAB6B (c.C383T; p.Thr128Met) in a children received FCD II lesions resected surgery in past study. Rab6B, a Rab family member that has not been reported to be link to FCD or mTOR pathway previously. Methods: We summarized the clinical features, and performed an in vitro functional study on this RAB6B variant. Results: Seizure onset time of the children harbored RAB6B mutation was 6 months. She reached seizure-free after lesion resected surgery at 1year and 2 months. Pathological finding of the lesion was FCD IIa. The variant is predicted damaging by SIFT, Polyphen2 and MutationTaster. Further in silico analysis predicted a reduction in protein stability, in association with a break in H-bonds in the GTP binding domain. This position is also strictly conserved in other species. In the transfected cell line of HEK293T, we demonstrated that the variant led to the RAB6B over-expression and mTOR pathway hyperactivation compared to cells that carried wild type RAB6B. CO-IP experiment exhibited loss of function(LOF) of this RAB6B mutation by decreased binding ability with downstream effector BICD-1. And in SH-SY5Y cell line, the variant transfected cells showed mTOR pathway hyperactivation and less trans-Golgi concentration. Conclusion: The outcomes provide evidence for novel pathogenic gene not involved in the mTOR pathway in the pathogenesis of FCDII.
Keywords: epilepsy; FCD II; somatic mutation; RAB6B gene; mTOR pathway