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

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

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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.

Original languageEnglish
Pages (from-to)83-97.e7
JournalNeuron
Volume99
Issue number1
DOIs
Publication statusPublished - 2018 Jul 11

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Malformations of Cortical Development
Mutation
Brain
Autophagy
Genome
Pediatrics

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Cite this

Park, Sang Min ; Lim, Jae Seok ; Ramakrishina, Suresh ; Kim, Se Hoon ; Kim, Woo Kyeong ; Lee, Junehawk ; Kang, Hoon Chul ; Reiter, Jeremy F. ; Kim, Dong Seok ; Kim, Hyongbum (Henry) ; Lee, Jeong Ho. / Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination. In: Neuron. 2018 ; Vol. 99, No. 1. pp. 83-97.e7.
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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.",
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Park, SM, Lim, JS, Ramakrishina, S, Kim, SH, Kim, WK, Lee, J, Kang, HC, Reiter, JF, Kim, DS, Kim, HH & Lee, JH 2018, 'Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination', Neuron, vol. 99, no. 1, pp. 83-97.e7. https://doi.org/10.1016/j.neuron.2018.05.039

Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination. / Park, Sang Min; Lim, Jae Seok; Ramakrishina, Suresh; Kim, Se Hoon; Kim, Woo Kyeong; Lee, Junehawk; Kang, Hoon Chul; Reiter, Jeremy F.; Kim, Dong Seok; Kim, Hyongbum (Henry); Lee, Jeong Ho.

In: Neuron, Vol. 99, No. 1, 11.07.2018, p. 83-97.e7.

Research output: Contribution to journalArticle

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AU - Kim, Se Hoon

AU - Kim, Woo Kyeong

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AU - Kang, Hoon Chul

AU - Reiter, Jeremy F.

AU - Kim, Dong Seok

AU - Kim, Hyongbum (Henry)

AU - Lee, Jeong Ho

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AB - 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.

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