期刊
JOURNAL OF HUMAN GENETICS
卷 63, 期 2, 页码 207-211出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s10038-017-0365-z
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资金
- Research on Measures for Intractable Diseases
- Comprehensive Research on Disability Health and Welfare
- Strategic Research Program for Brain Science (SRPBS)
- Practical Research Project for Rare/Intractable Diseases
- Initiative on Rare and Undiagnosed Diseases in Pediatrics
- Initiative on Rare and Undiagnosed Diseases in Adults from the Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Ministry of Health, Labor and Welfare
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [17K15630, 16H05357] Funding Source: KAKEN
Episodic ataxias (EAs) are rare channelopathies characterized by recurrent ataxia and vertigo, having eight subtypes. Mutated genes were found in four of these eight subtypes (EA1, EA2, EA5, and EA6). To date, only four missense mutations in the Solute Carrier Family 1 Member 3 gene (SLC1A3) have been reported to cause EA6. SLC1A3 encodes excitatory amino-acid transporter 1, which is a trimeric transmembrane protein responsible for glutamate transport in the synaptic cleft. In this study, we found a novel missense mutation, c. 383T>G (p. Met128Arg) in SLC1A3, in an EA patient by whole-exome sequencing. The modeled structural analysis suggested that p. Met128Arg may affect the hydrophobic transmembrane environment and protein function. Analysis of the pathogenicity of all mutations found in SLC1A3 to date using multiple prediction tools showed some advantage of using the Mendelian Clinically Applicable Pathogenicity (M-CAP) score. Various types of SLC1A3 variants, including nonsense mutations and indels, in the ExAC database suggest that the loss-of-function mechanism by SLC1A3 mutations is unlikely in EA6. The current mutation (p. Med128Arg) presumably has a gain-of-function effect as described in a previous report.
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