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RESEARCH ARTICLE
A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain
Tamio Furuse, Hiroshi Mizuma, Yuuki Hirose, Tomoko Kushida, Ikuko Yamada, Ikuo Miura, Hiroshi Masuya, Hiromasa Funato, Masashi Yanagisawa, Hirotaka Onoe, Shigeharu Wakana
Disease Models & Mechanisms 2019 12: dmm038828 doi: 10.1242/dmm.038828 Published 12 September 2019
Tamio Furuse
1Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan
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  • ORCID record for Tamio Furuse
  • For correspondence: tamio.furuse@riken.jp
Hiroshi Mizuma
2Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan
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Yuuki Hirose
3International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan
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Tomoko Kushida
1Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan
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Ikuko Yamada
1Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan
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Ikuo Miura
1Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan
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Hiroshi Masuya
4Resource Advancement Unit, Integrated Bioresource Information Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan
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Hiromasa Funato
3International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan
5Department of Anatomy, School of Medicine, Faculty of Medicine, Toho University, Tokyo 143-8540, Japan
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Masashi Yanagisawa
3International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan
6Life Science Center for Survival Dynamics (TARA), University of Tsukuba, Ibaraki 305-8575, Japan
7Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Hirotaka Onoe
8Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
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Shigeharu Wakana
1Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan
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ABSTRACT

Dysfunction of glucose transporter 1 (GLUT1) proteins causes infantile epilepsy, which is designated as a GLUT1 deficiency syndrome (GLUT1DS; OMIM #606777). Patients with GLUT1DS display varied clinical phenotypes, such as infantile seizures, ataxia, severe mental retardation with learning disabilities, delayed development, hypoglycorrhachia, and other varied symptoms. Glut1Rgsc200 mutant mice mutagenized with N-ethyl-N-nitrosourea (ENU) carry a missense mutation in the Glut1 gene that results in amino acid substitution at the 324th residue of the GLUT1 protein. In this study, these mutants exhibited various phenotypes, including embryonic lethality of homozygotes, a decreased cerebrospinal-fluid glucose value, deficits in contextual learning, a reduction in body size, seizure-like behavior and abnormal electroencephalogram (EEG) patterns. During EEG recording, the abnormality occurred spontaneously, whereas the seizure-like phenotypes were not observed at the same time. In sleep-wake analysis using EEG recording, heterozygotes exhibited a longer duration of wake times and shorter duration of non-rapid eye movement (NREM) sleep time. The shortened period of NREM sleep and prolonged duration of the wake period may resemble the sleep disturbances commonly observed in patients with GLUT1DS and other epilepsy disorders. Interestingly, an in vivo kinetic analysis of glucose utilization by positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose imaging revealed that glucose transportation was reduced, whereas hexokinase activity and glucose metabolism were enhanced. These results indicate that a Glut1Rgsc200 mutant is a useful tool for elucidating the molecular mechanisms of GLUT1DS.

This article has an associated First Person interview with the joint first authors of the paper.

Footnotes

  • Competing interests

    The authors declare no competing or financial interests.

  • Author contributions

    Conceptualization: T.F., H. Mizuma, H. Masuya, H.O., S.W.; Methodology: T.F., H. Mizuma, Y.H., T.K., I.Y., I.M.; Software: H. Masuya; Validation: T.F., H. Mizuma, Y.H., H.F.; Formal analysis: T.F., H. Mizuma, Y.H., T.K., I.Y., I.M.; Investigation: H.O., S.W.; Data curation: T.F., H. Mizuma, Y.H.; Writing - original draft: T.F., H. Mizuma, Y.H.; Writing - review & editing: T.F., H. Mizuma, Y.H.; Visualization: H. Mizuma, Y.H.; Supervision: H. Masuya, H.F., M.Y., H.O., S.W.; Project administration: H. Masuya, M.Y., H.O., S.W.; Funding acquisition: T.F., M.Y.

  • Funding

    This study was supported by the KAKENHI from the Japan Society for the Promotion of Science (JSPS) (grant numbers 17H06095 to M.Y.; 17K07144 to T.F.), the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from the Cabinet Office and the JSPS, Japan (to M.Y.), and the World Premier International Research Center Initiative (WPI) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (to M.Y.).

  • Data availability

    The mutant mouse used in this study (RBRC No.: RBRC-GSC0242) is available from Experimental Animal Division, RIKEN BioResource Research Center (https://mus.brc.riken.jp/en/).

  • Supplementary information

    Supplementary information available online at http://dmm.biologists.org/lookup/doi/10.1242/dmm.038828.supplemental

  • Received January 9, 2019.
  • Accepted July 30, 2019.
  • © 2019. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • ENU mutagenesis
  • Epilepsy
  • GLUT1DS
  • Glucose transporter 1

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RESEARCH ARTICLE
A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain
Tamio Furuse, Hiroshi Mizuma, Yuuki Hirose, Tomoko Kushida, Ikuko Yamada, Ikuo Miura, Hiroshi Masuya, Hiromasa Funato, Masashi Yanagisawa, Hirotaka Onoe, Shigeharu Wakana
Disease Models & Mechanisms 2019 12: dmm038828 doi: 10.1242/dmm.038828 Published 12 September 2019
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RESEARCH ARTICLE
A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain
Tamio Furuse, Hiroshi Mizuma, Yuuki Hirose, Tomoko Kushida, Ikuko Yamada, Ikuo Miura, Hiroshi Masuya, Hiromasa Funato, Masashi Yanagisawa, Hirotaka Onoe, Shigeharu Wakana
Disease Models & Mechanisms 2019 12: dmm038828 doi: 10.1242/dmm.038828 Published 12 September 2019

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