Brain somatic mutations in MTOR leading to focal cortical dysplasia
نویسندگان
چکیده
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].
منابع مشابه
Germline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy
OBJECTIVE To assess the prevalence of somatic MTOR mutations in focal cortical dysplasia (FCD) and of germline MTOR mutations in a broad range of epilepsies. METHODS We collected 20 blood-brain paired samples from patients with FCD and searched for somatic variants using deep-targeted gene panel sequencing. Germline mutations in MTOR were assessed in a French research cohort of 93 probands wi...
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