A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain
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 disabilit...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2019-09-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/12/9/dmm038828 |
| _version_ | 1819163713855291392 |
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| author | Tamio Furuse Hiroshi Mizuma Yuuki Hirose Tomoko Kushida Ikuko Yamada Ikuo Miura Hiroshi Masuya Hiromasa Funato Masashi Yanagisawa Hirotaka Onoe Shigeharu Wakana |
| author_facet | Tamio Furuse Hiroshi Mizuma Yuuki Hirose Tomoko Kushida Ikuko Yamada Ikuo Miura Hiroshi Masuya Hiromasa Funato Masashi Yanagisawa Hirotaka Onoe Shigeharu Wakana |
| author_sort | Tamio Furuse |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T17:48:31Z |
| format | Article |
| id | doaj.art-cc49a2714ee7442fb81f77b38aa7c057 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-22T17:48:31Z |
| publishDate | 2019-09-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-cc49a2714ee7442fb81f77b38aa7c0572022-12-21T18:18:14ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-09-0112910.1242/dmm.038828038828A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brainTamio Furuse0Hiroshi Mizuma1Yuuki Hirose2Tomoko Kushida3Ikuko Yamada4Ikuo Miura5Hiroshi Masuya6Hiromasa Funato7Masashi Yanagisawa8Hirotaka Onoe9Shigeharu Wakana10 Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan Laboratory for Pathophysiological and Health Science, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan Resource Advancement Unit, Integrated Bioresource Information Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan Human Brain Research Center, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan Japan Mouse Clinic, RIKEN BioResource Research Center, Tsukuba, Ibaraki 305-0074, Japan 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.http://dmm.biologists.org/content/12/9/dmm038828ENU mutagenesisEpilepsyGLUT1DSGlucose transporter 1 |
| spellingShingle | Tamio Furuse Hiroshi Mizuma Yuuki Hirose Tomoko Kushida Ikuko Yamada Ikuo Miura Hiroshi Masuya Hiromasa Funato Masashi Yanagisawa Hirotaka Onoe Shigeharu Wakana A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain Disease Models & Mechanisms ENU mutagenesis Epilepsy GLUT1DS Glucose transporter 1 |
| title | A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain |
| title_full | A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain |
| title_fullStr | A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain |
| title_full_unstemmed | A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain |
| title_short | A new mouse model of GLUT1 deficiency syndrome exhibits abnormal sleep-wake patterns and alterations of glucose kinetics in the brain |
| title_sort | new mouse model of glut1 deficiency syndrome exhibits abnormal sleep wake patterns and alterations of glucose kinetics in the brain |
| topic | ENU mutagenesis Epilepsy GLUT1DS Glucose transporter 1 |
| url | http://dmm.biologists.org/content/12/9/dmm038828 |
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