Brain somatic mutations in MTOR leading to focal cortical dysplasia

Abstract

Focal cortical dysplasia type II (FCDII) is a focal malformation of the developing cerebral cortex and the major cause of intractable epilepsy. However, since the molecular genetic etiology of FCD has remained enigmatic, the effective therapeutic target for this condition has remained poorly understood. Our recent study on FCD utilizing various deep sequencing platforms identified somatic mutations in MTOR (existing as low as 1% allelic frequency) only in the affected brain tissues. We observed that these mutations induced hyperactivation of the mTOR kinase. In addition, focal cortical expression of mutant MTOR using in utero electroporation in mice, recapitulated the neuropathological features of FCDII, such as migration defect, cytomegalic neuron and spontaneous seizures. Furthermore, seizures and dysmorphic neurons were rescued by the administration of mTOR inhibitor, rapamycin. This study provides the first evidence that brain somatic activating mutations in MTOR cause FCD, and suggests the potential drug target for intractable epilepsy in FCD patients. [BMB Reports 2016; 49(2): 71-72].

Fig. 1.. Schematic presentation of the experimental design. Deep whole exome sequencing (WES) was performed in four FCDII patients, and the raw sequencing data were analyzed to discover an alternative allele. Overlapping mutations in both Virmid and MuTect algorithms were selected as candidate single nucleotide variants (SNVs). Subsequently, we performed deep sequencing of the MTOR gene with various sequencing platforms in a large FCDII cohort comprising an additional 73 patients. Finally, the validated MTOR mutations were subjected to in vitro and in vivo functional analysis.