Pathogenesis of focal cortical dysplasia: possible mechanistic implification of somatic mutations

2014 Fiscal Year Final Research Report

• Project/Area Number: 25640027
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Niigata University
• Principal Investigator: KAKITA Akiyoshi 新潟大学, 脳研究所, 教授 (80281012)
• Co-Investigator(Kenkyū-buntansha): TAKEI Nobuyuki 新潟大学, 脳研究所, 准教授 (70221372)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Keywords: てんかん / 脳神経疾患 / 皮質異形成 / 体細胞変異 / 外科病理

Outline of Final Research Achievements

We explore the possible involvement of somatic mutations in focal cortical dysplasia (FCD) Type IIb. We performed whole exome sequencing using brain and blood samples from nine of the FCD Type IIb subjects. Somatic MTOR mutations were identified. The effect of MTOR mutations on mTOR kinase signaling was evaluated. We identified four lesion-specific somatic MTOR mutations in six of 13 (46%) individuals with FCD Type IIb showing mutant allele rates of 1.11 - 9.31%. Functional analyses showed that phosphorylation of ribosomal protein S6 in FCD Type IIb brain tissues with MTOR mutations was clearly elevated compared with control samples. Transfection of any of the four MTOR mutants into HEK293T cells led to elevated phosphorylation of 4EBP, the direct target of mTOR kinase. We found low-prevalence somatic mutations in MTOR in FCD Type IIb, indicating that activating somatic mutations in MTOR cause FCD Type IIb.

Free Research Field

神経病理学