Alternative titles; symbols
HGNC Approved Gene Symbol: SLC1A3
SNOMEDCT: 718753002;
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38): 5:36,606,606-36,688,334 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | Episodic ataxia, type 6 | 612656 | Autosomal dominant | 3 |
Glutamate and aspartate are excitatory neurotransmitters that have been implicated in a number of pathologic states of the nervous system. Accumulation of extracellular excitatory amino acids can be cytotoxic and may also lower the seizure threshold in epilepsy. EAAT1 (SLC1A3) is a member of a family of high-affinity sodium-dependent transporter molecules that regulate neurotransmitter concentrations at the excitatory glutamatergic synapses of the mammalian central nervous system (Kirschner et al., 1994). SLC1A3 also functions as a glutamate-activated anion channel (summary by Winter et al., 2012).
Shashidharan et al. (1994) isolated a novel cDNA from a human brain cDNA library. The cDNA encoded a deduced protein that was 95% homologous to a previously reported rabbit glutamate/aspartate transporter. Northern blot analysis demonstrated expression of the corresponding mRNA in human brain, liver, muscle, ovary, testis, and in retinoblastoma cell lines. The highest expression was found in the substantia nigra, red nucleus, and hippocampus, and in cerebral cortical layers. Shashidharan et al. (1994) referred to this as human glutamate transporter III and showed that it is structurally distinct from the previously described brain-specific glutamate transporters SLC1A1 (133550) and SLC1A2 (600300). The novel cDNA likely corresponded to the SLC1A3 gene.
Stoffel et al. (1996) isolated the human sodium-dependent L-glutamate/L-aspartate transporter gene, which they referred to as GLAST1, and found that it encodes a putative 542-amino acid protein. They stated that the gene is unrelated to any previously described neurotransmitter transporter gene family, but its exon/intron structure corresponds largely to that of the sodium-dependent neutral amino acid transporter ASCT1 (SLC1A4; 600229). GLAST1, ASCT1, and the glutamate transporters GLT1 (SLC1A2) and EAAC1 (SLC1A1) have similar amino acid sequences.
Stoffel et al. (1996) determined that the human GLAST1 gene contains 10 exons spanning at least 85 kb.
Hagiwara et al. (1996) showed that the mouse Slcla3 gene contains 10 exons spanning more than 56 kb.
Crystal Structure
Canul-Tec et al. (2017) presented the crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter-1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures revealed architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids, and posttranslational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry revealed a mechanism of inhibition in which the transporter is locked in the outward-facing states of the transport cycle.
Kirschner et al. (1994) mapped the human EAAT1 gene to chromosome 5p13 by fluorescence in situ hybridization (FISH). They used interspecific backcross analysis to map the mouse homolog to chromosome 15 in a region of homology to human 5p13. They commented that the EAAT1 locus may be related to the syndrome of microcephaly and mental retardation observed by Keppen et al. (1992) in association with interstitial deletion of distal band 5p13.
By FISH, Takai et al. (1995) also mapped the SLC1A3 gene to chromosome 5p13. Stoffel et al. (1996) mapped the GLAST1 gene to 5p12-p11.
Hagiwara et al. (1996) mapped the mouse Slc1a3 gene to chromosome 15A2 by FISH.
In a 10-year-old boy with episodic ataxia, seizures, migraine, and alternating hemiplegia consistent with episodic ataxia type 6 (EA6; 612656), Jen et al. (2005) identified a heterozygous mutation in the SLC1A3 gene (600111.0001).
In 3 affected members of a family with EA6, de Vries et al. (2009) identified a heterozygous mutation in the SLC1A3 gene (600111.0002). There was 1 unaffected carrier of the mutation, indicating reduced penetrance. Functional expression studies showed that the mutation resulted in an 18% decrease in glutamate uptake.
In the retina, the glutamate transporter GLAST is expressed in Muller cells, whereas the glutamate transporter GLT1 is found only in cones and various types of bipolar cells. To investigate the functional role of this differential distribution of glutamate transporters, Harada et al. (1998) analyzed Glast and Glt1 mutant mice. In Glast-deficient mice, the electroretinogram b-wave and oscillatory potentials were reduced and retinal damage after ischemia was exacerbated, whereas Glt1-deficient mice showed almost normal electroretinograms and mildly increased retinal damage after ischemia. These results demonstrated that Glast is required for normal signal transmission between photoreceptors and bipolar cells and that both Glast and Glt1 play a neuroprotective role during ischemia in the retina.
Watase et al. (1998) found that mouse Glast was most abundantly expressed in the Bergmann glia in the cerebellum. Glast-deficient mice developed normally and could manage simple coordinated tasks, such as staying on a stationary or a slowly rotating rod, but failed more challenging tests, such as staying on a quickly rotating rod. Electrophysiologic studies showed that Purkinje cells in the mutant mice remained multiply innervated by climbing fibers, even at the adult stage. After cold-induced injury, the mutant mice had significantly more cerebellar edema compared to wildtype mice, indicating that Glast is essential for preventing neuronal injury after traumatic cerebellar injury.
Matsugami et al. (2006) found that the brains of mice lacking Glast or Glt1 developed normally but that Glast/Glt1 double-knockout mice died around embryonic days 17 to 18 and exhibited cortical, hippocampal, and olfactory bulb disorganization. Several essential aspects of neuronal development, such as stem cell proliferation, radial migration, neuronal differentiation, and survival of subplate neurons, were impaired. Matsugami et al. (2006) concluded that the regulation of extracellular glutamate concentration and the maintenance of glutamate-mediated synaptic transmission is necessary for normal brain development.
In a 10-year-old boy with episodic ataxia, seizures, migraine, and alternating hemiplegia (EA6; 612656), Jen et al. (2005) identified a heterozygous 1047C-G transversion in the SLC1A3 gene, resulting in a pro290-to-arg substitution in a highly conserved residue within the fifth transmembrane domain. The mutation was not identified in either unaffected parent or in 232 control chromosomes. From birth, the child had experienced 4 discrete episodes of ataxia and slurred speech, seemingly triggered by a febrile illness. At age 6 years, he developed a severe right-sided headache followed by hemiparesis and decreased consciousness lasting 5 days. MRI showed cerebellar atrophy, and neurologic examination showed mild interictal truncal ataxia. Functional expression studies showed decreased expression of the mutant protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant transporter multimerized with the wildtype transporter to exert a dominant-negative effect. Jen et al. (2005) postulated a role for abnormal glutamate transmission in the neurologic features seen in this patient.
In in vitro electrophysiologic studies, Winter et al. (2012) found that the P290R mutation increased SLC1A3 anion currents compared to wildtype in both the presence and the absence of glutamate. These changes were observed in addition to the reduction of glutamate transport. Winter et al. (2012) suggested that the relatively severe phenotype of the patient reported by Jen et al. (2005) resulted from a gain-of-function effect of the P290R mutation on the anion channel function of SLC1A3, perhaps by altering the anion current in glial cells and GABAergic synaptic transmission.
Because the P290R substitution reduces expression of human SLC1A3 in Xenopus oocytes, Hotzy et al. (2013) studied the homologous mutation (P259R) in SLC1A1 (133550), which is robustly expressed in Xenopus oocytes. They found that, compared with wildtype, the substitution decelerated a conformational change that accompanies binding of sodium to the glutamate-free form of the transporter.
In 3 affected members of a Dutch family with episodic ataxia-6 (EA6; 612656), de Vries et al. (2009) identified a heterozygous 556T-A transversion in the SLC1A3 gene, resulting in a cys186-to-ser (C186S) substitution in a highly conserved residue in transmembrane segment 4b. In vitro functional expression studies in COS-7 cells showed that the mutant EAAT1 resulted in an 18% decrease in glutamate uptake compared to the wildtype channel. De Vries et al. (2009) noted that the phenotype was less severe than that reported by Jen et al. (2005), as the P290R mutation (600111.0001) resulted in markedly decreased glutamate uptake. The C186S mutation was not identified in 200 Dutch controls.
In 2 first cousins of European descent with a variant of episodic ataxia-6 (EA6; 612656), Pyle et al. (2015) identified a heterozygous c.1361G-A transition in the SLC1A3 gene, resulting in an arg454-to-gln (R454Q) substitution. The mutation, which was found by exome sequencing, was filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Sequencing Project databases, as well as 286 in-house controls. The mutation segregated with the disorder in the family. Functional studies of the variant were not performed. The patients had onset of gait ataxia and dysarthria in their thirties; the disorder was not described as episodic.
Canul-Tec, J. C., Assal, R., Cirri, E., Legrand, P., Brier, S., Chamot-Rooke, J., Reyes, N. Structure and allosteric inhibition of excitatory amino acid transporter 1. Nature 544: 446-451, 2017. [PubMed: 28424515] [Full Text: https://doi.org/10.1038/nature22064]
de Vries, B., Mamsa, H., Stam, A. H., Wan, J., Bakker, S. L. M., Vanmolkot, K. R. J., Haan, J., Terwindt, G. M., Boon, E. M. J., Howard, B. D., Frants, R. R., Baloh, R. W., Ferrari, M. D., Jen, J. C., van den Maagdenberg, A. M. J. M. Episodic ataxia associated with EAAT1 mutation C186S affecting glutamate reuptake. Arch. Neurol. 66: 97-101, 2009. Note: Erratum: Arch. Neurol. 66: 497 only, 2009; Erratum: Arch. Neurol. 66: 772 only, 2009. [PubMed: 19139306] [Full Text: https://doi.org/10.1001/archneurol.2008.535]
Hagiwara, T., Tanaka, K., Takai, S., Maeno-Hikichi, Y., Mukainaka, Y., Wada, K. Genomic organization, promoter analysis, and chromosomal localization of the gene for the mouse glial high-affinity glutamate transporter Slc1a3. Genomics 33: 508-515, 1996. [PubMed: 8661010] [Full Text: https://doi.org/10.1006/geno.1996.0226]
Harada, T., Harada, C., Watanabe, M., Inoue, Y., Sakagawa, T., Nakayama, N., Sasaki, S., Okuyama, S., Watase, K., Wada, K., Tanaka, K. Functions of the two glutamate transporters GLAST and GLT-1 in the retina. Proc. Nat. Acad. Sci. 95: 4663-4666, 1998. [PubMed: 9539795] [Full Text: https://doi.org/10.1073/pnas.95.8.4663]
Hotzy, J., Schneider, N., Kovermann, P., Fahlke, C. Muting a conserved proline residue within the trimerization domain modifies Na+ binding to excitatory amino acid transporters and associated conformational changes. J. Biol. Chem. 288: 36492-36501, 2013. [PubMed: 24214974] [Full Text: https://doi.org/10.1074/jbc.M113.489385]
Jen, J. C., Wan, J., Palos, T. P., Howard, B. D., Baloh, R. W. Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures. Neurology 65: 529-534, 2005. [PubMed: 16116111] [Full Text: https://doi.org/10.1212/01.wnl.0000172638.58172.5a]
Keppen, L. D., Gollin, S. M., Edwards, D., Sawyer, J., Wilson, W., Overhauser, J. Clinical phenotype and molecular analysis of a three-generation family with an interstitial deletion of the short arm of chromosome 5. Am. J. Med. Genet. 44: 356-360, 1992. [PubMed: 1488985] [Full Text: https://doi.org/10.1002/ajmg.1320440317]
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Matsugami, T. R., Tanemura, K., Mieda, M., Nakatomi, R., Yamada, K., Kondo, T., Ogawa, M., Obata, K., Watanabe, M., Hashikawa, T., Tanaka, K. Indispensability of the glutamate transporters GLAST and GLT1 to brain development. Proc. Nat. Acad. Sci. 103: 12161-12166, 2006. [PubMed: 16880397] [Full Text: https://doi.org/10.1073/pnas.0509144103]
Pyle, A., Smertenko, T., Bargiela, D., Griffin, H., Duff, J., Appleton, M., Douroudis, K., Pfeffer, G., Santibanez-Koref, M., Eglon, G., Yu-Wai-Man, P., Ramesh, V., Horvath, R., Chinnery, P. F. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain 138: 276-283, 2015. [PubMed: 25497598] [Full Text: https://doi.org/10.1093/brain/awu348]
Shashidharan, P., Huntley, G. W., Meyer, T., Morrison, J. H., Plaitakis, A. Neuron-specific human glutamate transporter: molecular cloning, characterization and expression in human brain. Brain Res. 662: 245-250, 1994. [PubMed: 7859077] [Full Text: https://doi.org/10.1016/0006-8993(94)90819-2]
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Takai, S., Yamada, K., Kawakami, H., Tanaka, K., Nakamura, S. Localization of the gene (SLC1A3) encoding human glutamate transporter (GluT-1) to 5p13 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 69: 209-210, 1995. [PubMed: 7698014] [Full Text: https://doi.org/10.1159/000133965]
Watase, K., Hashimoto, K., Kano, M., Yamada, K., Watanabe, M., Inoue, Y., Okuyama, S., Sakagawa, T., Ogawa, S., Kawashima, N., Hori, S., Takimoto, M., Wada, K., Tanaka, K. Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Europ. J. Neurosci. 10: 976-988, 1998. [PubMed: 9753165] [Full Text: https://doi.org/10.1046/j.1460-9568.1998.00108.x]
Winter, N., Kovermann, P., Fahlke, C. A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. Brain 135: 3416-3425, 2012. [PubMed: 23107647] [Full Text: https://doi.org/10.1093/brain/aws255]