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

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Title
Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination
Author(s)
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
Publication Date
2018-07
Journal
NEURON, v.99, no.1, pp.83 - 97.e7
Publisher
CELL PRESS
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. Park et al. demonstrate that brain somatic mutations in MTOR result in defective neuronal ciliogenesis in FMCDs. The aberrant accumulation of OFD1 by impaired autophagy is responsible for defective ciliogenesis. Moreover, defective ciliogenesis accounts for cortical dyslamination in FMCDs by compromising Wnt signals. © 2018 Elsevier Inc
URI
https://pr.ibs.re.kr/handle/8788114/5555
ISSN
0896-6273
Appears in Collections:
Center for Synaptic Brain Dysfunctions(시냅스 뇌질환 연구단) > Journal Papers (저널논문)
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