Alternative titles; symbols
HGNC Approved Gene Symbol: SLC1A1
SNOMEDCT: 716747007;
Cytogenetic location: 9p24.2 Genomic coordinates (GRCh38): 9:4,490,468-4,587,469 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p24.2 | {?Schizophrenia susceptibility 18} | 615232 | 3 | |
| Dicarboxylic aminoaciduria | 222730 | Autosomal recessive | 3 |
The SLC1A1 gene encodes a high-affinity excitatory amino acid transporter expressed selectively by neurons in the central nervous system. Unlike other high-affinity glutamate transporters, SLC1A1 does not play a major role in clearing glutamate from the extracellular space. SLC1A1 is also the primary route for neuronal uptake of cysteine, the rate-limiting substrate in glutathione synthesis (summary by Kanai and Hediger, 1992, Aoyama et al., 2006, and Berman et al., 2011).
Kanai and Hediger (1992) cloned rabbit Slc1a1, which they called Eaac1. The deduced 524-amino acid protein has at least 10 potential transmembrane domains and a serine-rich motif found in receptors for acetylcholine and biogenic amines. Northern blot analysis detected variable Eaac1 expression in most rabbit tissues examined, with highest expression in intestine, kidney, and brain.
Berman et al. (2011) found expression of the SLC1A1 gene in dopaminergic neurons in the mouse and human midbrain.
Porton et al. (2013) reported the identification and characterization of 3 alternative SLC1A1/EAAC1 mRNAs: a transcript derived from an internal promoter, termed P2 to distinguish it from the transcript generated by the primary promoter (P1), and 2 alternatively spliced mRNAs: ex2skip, which is missing exon 2, and ex11skip, which is missing exon 11. All isoforms inhibit glutamate uptake from the full-length EAAC1 transporter. Ex2skip and ex11skip also display partial colocalization and interact with the full-length EAAC1 protein. The 3 isoforms are evolutionarily conserved between human and mouse, and are expressed in brain, kidney, and lymphocytes under nonpathologic conditions, suggesting that the isoforms are physiologic regulators of EAAC1. Porton et al. (2013) found that, under specific conditions, all SLC1A1 transcripts were differentially expressed in lymphocytes derived from subjects with obsessive-compulsive disorder (OCD; 164230) compared with controls.
By Southern analysis of a panel of human/rodent somatic cell hybrids and by fluorescence in situ hybridization (FISH), Smith et al. (1994) mapped the EAAC1 gene to chromosome 9p24.
Kanai and Hediger (1992) found that rabbit Eaac1 was a high-affinity glutamate transporter that also transported aspartate, but not other amino acids.
Smith et al. (1994) suggested that mutations in the EAAC1 gene may be responsible for dicarboxylic aminoaciduria (222730) or for a form of familial amyotrophic lateral sclerosis (ALS; 105400).
In the kidney, EAAC1 is expressed by renal tubule cells, in which it serves as a major route of glutamate and aspartate reuptake from the urine (Aoyama et al., 2006).
Lin et al. (2001) used a yeast 2-hybrid assay to identify a protein that interacts with EAAC1. This protein, termed GTRAP3-18 (605709), is expressed in numerous tissues, localizes to the cell membrane and cytoplasm, and specifically interacts with the carboxy-terminal intracellular domain of EAAC1. Increasing the expression of GTRAP3-18 in cells reduces EAAC1-mediated glutamate transport by lowering substrate affinity. The expression of GTRAP3-18 can be upregulated by retinoic acid, which results in a specific reduction of EAAC1-mediated glutamate transport. Lin et al. (2001) concluded that glutamate transport proteins can be regulated potently and that GTRAP can modulate the transport functions ascribed to EAAC1. GTRAP3-18 may be important in regulating the metabolic functions of EAAC1.
Schizophrenia 18, Susceptibility to
Myles-Worsley et al. (2013) investigated a 5-generation Palauan family (kindred 3501) segregating schizophrenia and schizoaffective disorder (SCZD18; 615232) in which Melhem et al. (2011) had identified a deletion at chromosome 9p24.2 containing the SLC1A1 glutamate transporter gene in several members of the family. Using quantitative PCR in an expanded sample of 21 family members, Myles-Worsley et al. (2013) confirmed the deletion of part of the SLC1A1 gene in all 7 family members with psychosis, 3 obligate carrier parents, and 1 unaffected sib, and found that 4 marry-in parents were noncarriers. Linkage analysis under an autosomal dominant model generated a lod score of 3.64, confirming cosegregation of the deletion with psychosis. Myles-Worsley et al. (2013) identified the breakpoint of the deletion and demonstrated that an 84,298-bp deletion occurs immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence, extends through exon 1 of the SLC1A1 mRNA, and removes the first 59 amino acids of the protein (133550.0001), including the first transmembrane sodium/dicarboxylate symporter domain, one of the domains responsible for glutamate transport. The deletion was not observed in any other Palauans studied, including Palauans with psychiatric disease outside of this family.
Dicarboxylic Aminoaciduria
Bailey et al. (2011) reported 3 patients from 2 unrelated families with dicarboxylic aminoaciduria (DCBXA; 222730) with homozygous mutations in the SLC1A1 gene (133550.0002 and 133550.0003). The probands had highly elevated glutamate and aspartate levels in urine due to failure of this transporter.
Peghini et al. (1997) found that Eaac1-null mice developed dicarboxylic aminoaciduria, with high urinary excretion of glutamate and aspartate. The findings suggested that EAAC1 specifically reabsorbs glutamate and aspartate in renal tubuli, and that other renal amino acid transporters could not compensate for its loss. No neurodegeneration was observed during a period of over 12 months, but homozygous mutants showed significantly reduced spontaneous locomotor activity. Peghini et al. (1997) concluded that dicarboxylic aminoaciduria associated with mental retardation in humans (222730) probably represents a more complex hereditary or multifactorial defect.
Aoyama et al. (2006) found that Slc1a1-null mice developed age-dependent behavioral changes, including cognitive and motivational impairment, and increased brain atrophy compared to wildtype mice. Hippocampal neurons of these mice had decreased glutathione content, increased oxidant levels, and increased susceptibility to oxidant injury. However, these neurons did not show increased vulnerability to glutamate, consistent with the idea that Slc1a1 has a negligible role in regulating extracellular glutamate concentrations. Treatment of Slc1a1-null mice with N-acetylcysteine, a membrane-permeable cysteine precursor, increased glutathione levels and decreased neuronal death after oxidant exposure. The findings suggested that Slc1a1 is the primary route for neuronal cysteine uptake and that Slc1a1 deficiency leads to impaired neuronal glutathione metabolism, oxidative stress, and age-dependent chronic neurodegeneration.
Berman et al. (2011) found that Slc1a1-null mice developed age-dependent progressive loss of dopaminergic neurons in the substantia nigra, with more than 40% of these neurons lost by age 12 months, and microglial activation in the substantia nigra. Mutant mice showed impaired motor performance compared to wildtype mice. These features were characteristic of Parkinson disease (PD; 168600) in humans. Dopaminergic neurons in the Slc1a1-null mice showed evidence of increased oxidative stress. Long-term treatment of mutant mice with N-acetylcysteine resulted in increased levels of glutathione, prevented dopaminergic neuronal loss, and resulted in improved motor performance. Berman et al. (2011) suggested that the Slc1a1-null mouse may be a useful model for the chronic neuronal oxidative stress that occurs in PD.
In a 5-generation Palauan family (kindred 3501) segregating schizophrenia and schizoaffective disorder (SCZD18; 615232), Myles-Worsley et al. (2013) identified an 84,298-bp deletion involving the SLC1A1 gene in 7 members with psychosis, 3 obligate carrier parents, and 1 unaffected sib; 4 marry-in parents were noncarriers. The deletion occurs immediately upstream of the SLC1A1 gene in a regulatory region that contains the full native promoter sequence (including histone-binding regions, transcription factor-binding regions, and a CpG island), extends through exon 1 of the SLC1A1 mRNA, and removes the first 59 amino acids of the protein, including the first transmembrane sodium/dicarboxylate symporter domain, one of the domains responsible for glutamate transport. The deletion was not observed in any other Palauans studied, including Palauans with psychiatric disease outside of this family.
In 2 brothers with dicarboxylic aminoaciduria (DCBXA; 222730), Bailey et al. (2011) identified a c.1333C-T transition in exon 12 of the SLC1A1 gene, resulting in an arg445-to-trp (R445W) substitution. Both affected sibs were homozygous, while unaffected family members were heterozygous. Arginine-445 is conserved through C. elegans in SLC1A1 orthologs and among the SLC1 transporter family. Functional studies in Xenopus oocytes showed that this mutation severely diminished glutamate transport. The mutation was not found in ethnically matched control populations.
In a French Canadian girl diagnosed with dicarboxylic aminoaciduria (DCBXA; 222730) via newborn screening, Bailey et al. (2011) identified a 3-bp deletion in exon 10 of the SLC1A1 gene (c.1184_1186delTCA), resulting in deletion of isoleucine at position 395 of the protein (I395del). Isoleucine-395 is a conserved hydrophobic residue at identical positions in SLC1A1 orthologs and is located in a conserved hairpin loop structure that acts as an extracellular gate governing access of the substrate to the binding site. Functional studies showed that glutamate transport was abrogated in Xenopus oocytes expressing the I395del mutant. The mutation was not found in ethnically matched controls.
Aoyama, K., Suh, S. W., Hamby, A. M., Liu, J., Chan, W. Y., Chen, Y., Swanson, R. A. Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nature Neurosci. 9: 119-126, 2006. [PubMed: 16311588] [Full Text: https://doi.org/10.1038/nn1609]
Bailey, C. G., Ryan, R. M., Thoeng, A. D., Ng, C., King, K., Vanslambrouck, J. M., Auray-Blais, C., Vandenberg, R. J., Broer, S., Rasko, J. E. J. Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J. Clin. Invest. 121: 446-453, 2011. [PubMed: 21123949] [Full Text: https://doi.org/10.1172/JCI44474]
Berman, A. E., Chan, W. Y., Brennan, A. M., Reyes, R. C., Adler, B. L., Suh, S. W., Kauppinen, T. M., Edling, Y., Swanson, R. A. N-acetylcysteine prevents loss of dopaminergic neurons in the EAAC1-/- mouse. Ann. Neurol. 69: 509-520, 2011. [PubMed: 21446024] [Full Text: https://doi.org/10.1002/ana.22162]
Kanai, Y., Hediger, M. A. Primary structure and functional characterization of a high-affinity glutamate transporter. Nature 360: 467-471, 1992. [PubMed: 1280334] [Full Text: https://doi.org/10.1038/360467a0]
Lin, C. G., Orlov, I., Ruggiero, A. M., Dykes-Hoberg, M., Lee, A., Jackson, M., Rothstein, J. D. Modulation of the neuronal glutamate transporter EAAC1 by the interacting protein GTRAP3-18. Nature 410: 84-88, 2001. [PubMed: 11242046] [Full Text: https://doi.org/10.1038/35065084]
Melhem, N., Middleton, F., McFadden, K., Klei, L., Faraone, S. V., Vinogradov, S., Tiobech, J., Yano, V., Kuartei, S., Roeder, K., Byerley, W., Devlin, B., Myles-Worsley, M. Copy number variants for schizophrenia and related psychotic disorders in Oceanic Palau: risk and transmission in extended pedigrees. Biol. Psychiatry 70: 1115-1121, 2011. [PubMed: 21982423] [Full Text: https://doi.org/10.1016/j.biopsych.2011.08.009]
Myles-Worsley, M., Tiobech, J., Browning, S. R., Korn, J., Goodman, S., Gentile, K., Melhem, N., Byerley, W., Faraone, S. V., Middleton, F. A. Deletion at the SLC1A1 glutamate transporter gene co-segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family. Am. J. Med. Genet. 162B: 87-95, 2013. [PubMed: 23341099] [Full Text: https://doi.org/10.1002/ajmg.b.32125]
Peghini, P., Janzen, J., Stoffel, W. Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J. 16: 3822-3832, 1997. [PubMed: 9233792] [Full Text: https://doi.org/10.1093/emboj/16.13.3822]
Porton, B., Greenberg, B. D., Askland, K., Serra, L. M., Gesmonde, J., Rudnick, G., Rasmussen, S. A., Kao, H.-T. Isoforms of the neuronal glutamate transporter gene, SLC1A1/EAAC1, negatively modulate glutamate uptake: relevance to obsessive-compulsive disorder. Transl. Psychiat. 3: e259, 2013. Note: Electronic Article. [PubMed: 23695234] [Full Text: https://doi.org/10.1038/tp.2013.35]
Smith, C. P., Weremowicz, S., Kanai, Y., Stelzner, M., Morton, C. C., Hediger, M. A. Assignment of the gene coding for the human high-affinity glutamate transporter EAAC1 to 9p24: potential role in dicarboxylic aminoaciduria and neurodegenerative disorders. Genomics 20: 335-336, 1994. [PubMed: 8020993] [Full Text: https://doi.org/10.1006/geno.1994.1183]