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

Authors
 Sang Min Park  ;  Jae Seok Lim  ;  Suresh Ramakrishina  ;  Se Hoon Kim  ;  Woo Kyeong Kim  ;  Junehawk Lee  ;  Hoon-Chul Kang  ;  Jeremy F. Reiter  ;  Dong Seok Kim  ;  Hyongbum (Henry) Kim  ;  Jeong Ho Lee 
Citation
 Neuron, Vol.99(1) : 83-97, 2018 
Journal Title
 Neuron 
ISSN
 0896-6273 
Issue Date
2018
Keywords
MTOR ; brain somatic mutation ; focal malformations of cortical development ; primary cilia
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.
Full Text
https://www.sciencedirect.com/science/article/pii/S0896627318304379
DOI
10.1016/j.neuron.2018.05.039
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
강훈철(Kang, Hoon Chul) ORCID logo https://orcid.org/0000-0002-3659-8847
김동석(Kim, Dong Seok)
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
김형범(Kim, Hyongbum) ORCID logo https://orcid.org/0000-0002-4693-738X
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/165425
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