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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Caffarelli M, Kimia AA, Torres AR. Acute ataxia in children: a review of the differential diagnosis and evaluation in the emergency department. Pediatr Neurol. 2016;65:14–30.
Jen JC. Hereditary episodic ataxias. Ann N Y Acad Sci. 2008;1142:250–3.
Conroy J, McGettigan P, Murphy R, Webb D, Murphy SM, McCoy B, et al. A novel locus for episodic ataxia: UBR4 the likely candidate. EJHG. 2014;22:505–10.
Mestre TA, Manole A, MacDonald H, Riazi S, Kraeva N, Hanna MG, et al. A novel KCNA1 mutation in a family with episodic ataxia and malignant hyperthermia. Neurogenetics. 2016;17:245–9.
Maksemous N, Roy B, Smith RA, Griffiths LR. Next-generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2. Mol Genet Genomic Med. 2016;4:211–22.
Escayg A, De Waard M, Lee DD, Bichet D, Wolf P, Mayer T, et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet. 2000;66:1531–9.
Jen JC, Wan J, Palos TP, Howard BD, Baloh RW. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology. 2005;65:529–34.
de Vries B, Mamsa H, Stam AH, Wan JJ, Bakker SLM, Vanmolkot KRJ, et al. Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. Arch Neurol. 2009;66:97–101.
Pyle A, Smertenko T, Bargiela D, Griffin H, Duff J, Appleton M, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 2015;138:276–83.
Choi KD, Jen JC, Choi SY, Shin JH, Kim HS, Kim HJ, et al. Late-onset episodic ataxia associated with SLC1A3 mutation. J Hum Genet. 2017;62:443–6.
Iwama K, Sasaki M, Hirabayashi S, Ohba C, Iwabuchi E, Miyatake S, et al. Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations. J Hum Genet. 2016;61:527–31.
Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845–58.
Yernool D, Boudker O, Jin Y, Gouaux E. Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature. 2004;431:811–8.
Adamczyk A, Gause CD, Sattler R, Vidensky S, Rothstein JD, Singer H, et al. Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome. Psychiatr Genet. 2011;21:90–97.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
Jagadeesh KA, Wenger AM, Berger MJ, Guturu H, Stenson PD, Cooper DN, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet. 2016;48:1581–6.
Winter N, Kovermann P, Fahlke C. A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. Brain. 2012;135:3416–25.
Jensen S, Guskov A, Rempel S, Hanelt I, Slotboom DJ. Crystal structure of a substrate-free aspartate transporter. Nat Struct Mol Biol. 2013;20:1224–6.
Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI. OPM: orientations of proteins in membranes database. Bioinformatics. 2006;22:623–5.
We thank the individuals and their families for their participation in this study. We also thank Nobuko Watanabe and Mai Sato for technical assistance. We are also grateful to Tom Buckle, MSc, from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript. This work was supported by grants from Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare; the Strategic Research Program for Brain Science (SRPBS); the Practical Research Project for Rare/Intractable Diseases; the Initiative on Rare and Undiagnosed Diseases in Pediatrics; the Initiative on Rare and Undiagnosed Diseases in Adults from the Japan Agency for Medical Research and Development; a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid for Scientific Research (A and B); Grant-in-Aid for Young Scientists (B); Challenging Exploratory Research from the Japan Society for the Promotion of Science; the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; grants from the Ministry of Health, Labor and Welfare; and the Takeda Science Foundation.
Conflict of interest
The authors declare no conflict of interest.
Electronic supplementary material
About this article
Cite this article
Iwama, K., Iwata, A., Shiina, M. et al. A novel mutation in SLC1A3 causes episodic ataxia. J Hum Genet 63, 207–211 (2018). https://doi.org/10.1038/s10038-017-0365-z
Sex-Stratified Single-Cell RNA-Seq Analysis Identifies Sex-Specific and Cell Type-Specific Transcriptional Responses in Alzheimer’s Disease Across Two Brain Regions
Molecular Neurobiology (2021)
Scientific Reports (2020)
Haploinsufficiency of A20 caused by a novel nonsense variant or entire deletion of TNFAIP3 is clinically distinct from Behçet’s disease
Arthritis Research & Therapy (2019)
Communications Biology (2018)