Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy
Epilepsy is a brain disorder which afflicts more than 50 million people worldwide. Many epilepsy patients can control their symptoms through medication, but about 30% suffer from intractable epilepsy and are unable to manage the disease with drugs. Intractable epilepsy causes multiple seizures, permanent mental, physical, and developmental disabilities, and even death. Therefore, surgical removal of the affected area from the brain has been practiced as a treatment for patients with medically refractory seizures, but this too fails to provide a complete solution because only 60% of the patients who undergo surgery are rendered free of seizures. The research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering at the Korea Advanced Institute of Science and Technology (KAIST) has identified brain somatic mutations in the gene of mechanistic target of rapamycin (MTOR) as the cause of focal cortical dysplasia type II (FCDII), one of the most important and common inducers to intractable epilepsy, particularly in children. They propose a targeted therapy to lessen epileptic seizures by suppressing the activation of mTOR kinase, a signaling protein in the brain. Their research results were published online in Nature Medicine on March 23, 2015.
Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of cerebral cortex characterized by dysmorphic neurons, disrupted lamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in the affected regions. Here, the research used deep whole exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from 4 FCDII patients to uncover a de novo brain somatic mutation, MTOR c.7280T>C (p.Leu2427Pro) in 2 patients. Deep sequencing of the MTOR gene in an additional 73 FCDII patients using hybrid capture and PCR amplicon sequencing identified 9 different somatic missense mutations found in multiple brain tissue samples of 12 FCDII patients. The identified mutations accounted for 15.6% of all of the FCDII participants (12 of 77) and the prevalence of the mutant allele in affected brain tissues ranged from 1.26% to 12.6%. The identified mutations induced the constitutive activation of mTOR kinase and cytomegalic neurons in the affected brains carrying mutations. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides the first evidence that brain somatic activating mutations in MTOR cause FCD and identify mTOR as a treatment target for intractable epilepsy in FCD patients.
Lim JS et al. Nature Medicine 2015 Apr;21(4):395-400
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