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Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders

CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To addre...

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Autores principales: Ishizuka, K, Fujita, Y, Kawabata, T, Kimura, H, Iwayama, Y, Inada, T, Okahisa, Y, Egawa, J, Usami, M, Kushima, I, Uno, Y, Okada, T, Ikeda, M, Aleksic, B, Mori, D, Someya, To, Yoshikawa, T, Iwata, N, Nakamura, H, Yamashita, T, Ozaki, N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611740/
https://www.ncbi.nlm.nih.gov/pubmed/28763059
http://dx.doi.org/10.1038/tp.2017.173
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author Ishizuka, K
Fujita, Y
Kawabata, T
Kimura, H
Iwayama, Y
Inada, T
Okahisa, Y
Egawa, J
Usami, M
Kushima, I
Uno, Y
Okada, T
Ikeda, M
Aleksic, B
Mori, D
Someya, To
Yoshikawa, T
Iwata, N
Nakamura, H
Yamashita, T
Ozaki, N
author_facet Ishizuka, K
Fujita, Y
Kawabata, T
Kimura, H
Iwayama, Y
Inada, T
Okahisa, Y
Egawa, J
Usami, M
Kushima, I
Uno, Y
Okada, T
Ikeda, M
Aleksic, B
Mori, D
Someya, To
Yoshikawa, T
Iwata, N
Nakamura, H
Yamashita, T
Ozaki, N
author_sort Ishizuka, K
collection PubMed
description CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders.
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spelling pubmed-56117402017-09-27 Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders Ishizuka, K Fujita, Y Kawabata, T Kimura, H Iwayama, Y Inada, T Okahisa, Y Egawa, J Usami, M Kushima, I Uno, Y Okada, T Ikeda, M Aleksic, B Mori, D Someya, To Yoshikawa, T Iwata, N Nakamura, H Yamashita, T Ozaki, N Transl Psychiatry Original Article CX3CR1, a G protein-coupled receptor solely expressed by microglia in the brain, has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in transcriptomic and animal studies but not in genetic studies. To address the impacts of variants in CX3CR1 on neurodevelopmental disorders, we conducted coding exon-targeted resequencing of CX3CR1 in 370 Japanese SCZ and 192 ASD patients using next-generation sequencing technology, followed by a genetic association study in a sample comprising 7054 unrelated individuals (2653 SCZ, 574 ASD and 3827 controls). We then performed in silico three-dimensional (3D) structural modeling and in vivo disruption of Akt phosphorylation to determine the impact of the detected variant on CX3CR1-dependent signal transduction. We detected a statistically significant association between the variant Ala55Thr in CX3CR1 with SCZ and ASD phenotypes (odds ratio=8.3, P=0.020). A 3D structural model indicated that Ala55Thr could destabilize the conformation of the CX3CR1 helix 8 and affect its interaction with a heterotrimeric G protein. In vitro functional analysis showed that the CX3CR1-Ala55Thr mutation inhibited cell signaling induced by fractalkine, the ligand for CX3CR1. The combined data suggested that the variant Ala55Thr in CX3CR1 might result in the disruption of CX3CR1 signaling. Our results strengthen the association between microglia-specific genes and neurodevelopmental disorders. Nature Publishing Group 2017-08 2017-08-01 /pmc/articles/PMC5611740/ /pubmed/28763059 http://dx.doi.org/10.1038/tp.2017.173 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Ishizuka, K
Fujita, Y
Kawabata, T
Kimura, H
Iwayama, Y
Inada, T
Okahisa, Y
Egawa, J
Usami, M
Kushima, I
Uno, Y
Okada, T
Ikeda, M
Aleksic, B
Mori, D
Someya, To
Yoshikawa, T
Iwata, N
Nakamura, H
Yamashita, T
Ozaki, N
Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
title Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
title_full Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
title_fullStr Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
title_full_unstemmed Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
title_short Rare genetic variants in CX3CR1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
title_sort rare genetic variants in cx3cr1 and their contribution to the increased risk of schizophrenia and autism spectrum disorders
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611740/
https://www.ncbi.nlm.nih.gov/pubmed/28763059
http://dx.doi.org/10.1038/tp.2017.173
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