Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A novel mutation in SLC1A3 causes episodic ataxia


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

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2


  1. 1.

    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.

    Article  PubMed  Google Scholar 

  2. 2.

    Jen JC. Hereditary episodic ataxias. Ann N Y Acad Sci. 2008;1142:250–3.

    CAS  Article  PubMed  Google Scholar 

  3. 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.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    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.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    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.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    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.

    Article  PubMed  Google Scholar 

  9. 9.

    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.

    Article  PubMed  Google Scholar 

  10. 10.

    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.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    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.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yernool D, Boudker O, Jin Y, Gouaux E. Structure of a glutamate transporter homologue from Pyrococcus horikoshii. Nature. 2004;431:811–8.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    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.

    Article  PubMed  Google Scholar 

  15. 15.

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    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.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Winter N, Kovermann P, Fahlke C. A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. Brain. 2012;135:3416–25.

    Article  PubMed  Google Scholar 

  18. 18.

    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.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Lomize MA, Lomize AL, Pogozheva ID, Mosberg HI. OPM: orientations of proteins in membranes database. Bioinformatics. 2006;22:623–5.

    CAS  Article  PubMed  Google Scholar 

Download references


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 ( 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.

Author information



Corresponding author

Correspondence to Naomichi Matsumoto.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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).

Download citation

Further reading


Quick links