Brain somatic mutations in MTOR leading to focal cortical dysplasia.

Jae Seok Lim, Jeong Ho Lee,

BMB reports, January 18, 2016

Focal cortical dysplasia type II (FCDII) is a focal malformation of developing cerebral cortex and the major cause of intractable epilepsy. However, since molecular genetic etiology of FCD has remained mysterious, effective therapeutic target for this condition is poorly understood. Our recent study on FCD utilizing various deep sequencing platform identified somatic mutations in MTOR existing as low as 1% allelic frequency only in affected brain tissues. We observed that identified mutations induced hyperactivation of mTOR kinase. In addition, focal cortical expression of mutant MTOR using in utero electroporation in mice recapitulated neuropathological features of FCDII, such as migration defect, cytomegalic neuron and spontaneous seizure. Furthermore, seizures and dysmorphic neurons were rescued by 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.

Pubmed Link: 26779999