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Neuron. 2018 Jul 11;99(1):83-97.e7. doi: 10.1016/j.neuron.2018.05.039. Epub 2018 Jun 21.

Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination.

Author information

1
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
2
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea.
3
Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, Republic of Korea.
4
Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
5
Biomedical HPC Technology Research Center, KISTI, Daejeon 34141, Republic of Korea.
6
Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children's Hospital, Epilepsy Research Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
7
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
8
Pediatric Neurosurgery, Severance Children's Hospital, Department of Neurosurgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
9
Department of Pharmacology, Brain Korea 21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
10
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea; Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Republic of Korea. Electronic address: jhlee4246@kaist.ac.kr.

Abstract

Focal malformations of cortical development (FMCDs), including focal cortical dysplasia (FCD) and hemimegalencephaly (HME), are major etiologies of pediatric intractable epilepsies exhibiting cortical dyslamination. Brain somatic mutations in MTOR have recently been identified as a major genetic cause of FMCDs. However, the molecular mechanism by which these mutations lead to cortical dyslamination remains poorly understood. Here, using patient tissue, genome-edited cells, and mouse models with brain somatic mutations in MTOR, we discovered that disruption of neuronal ciliogenesis by the mutations underlies cortical dyslamination in FMCDs. We found that abnormal accumulation of OFD1 at centriolar satellites due to perturbed autophagy was responsible for the defective neuronal ciliogenesis. Additionally, we found that disrupted neuronal ciliogenesis accounted for cortical dyslamination in FMCDs by compromising Wnt signals essential for neuronal polarization. Altogether, this study describes a molecular mechanism by which brain somatic mutations in MTOR contribute to the pathogenesis of cortical dyslamination in FMCDs.

KEYWORDS:

MTOR; brain somatic mutation; focal malformations of cortical development; primary cilia

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