Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. 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, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.

Many abiotic and biotic stresses can reduce plant growth and development. Low temperature is one of the most harmful abiotic stresses, particularly for plants that are tropical or subtropical in origin. To elucidate the molecular mechanisms underlying the cold-stress response, components involved in the signal transduction of cold stress have been characterized. In this study, we characterized a basic helix-loop-helix (bHLH) transcription factor encoding gene, SlICE1, from tomato (Solanum lycopersicum), which shows similarity with Arabidopsis ICE1. e expression of SlICE1 was observed in younger leaves, owers, and green and red fruits. To characterize the function of SlICE1, overexpressing tomato lines were produced. SlICE1-overexpressing tomatoes exhibited chilling tolerance, and SlICE1 enhanced the expression of coldresponsive genes, such as SlCBF1 and SlDRCi7, as well as accumulation of ascorbic acid. e SlICE1 protein was degraded a er cold treatment. ese results indicate that SlICE1 enhances cold tolerance in tomatoes.

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