Alternative titles; symbols
HGNC Approved Gene Symbol: SLC6A1
SNOMEDCT: 230421008; ICD10CM: G40.4;
Cytogenetic location: 3p25.3 Genomic coordinates (GRCh38) : 3:10,992,748-11,039,247 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.3 | Myoclonic-atonic epilepsy | 616421 | Autosomal dominant | 3 |
The SLC6A1 gene encodes a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft (Hirunsatit et al., 2009).
Nelson et al. (1990) cloned and sequenced a cDNA clone encoding the transporter for the neurotransmitter gamma-aminobutyric acid in human brain. The cDNA contained an open reading frame encoding a hydrophobic protein of 599 amino acids with a calculated molecular weight of 67,022 daltons. Hydropathy analysis showed 12 potential transmembrane segments. The human protein is highly homologous to that from rat brain. Northern hybridization demonstrated a ubiquitous distribution of the transporter in various parts of the brain. This gene, which they called GABATHG, was also cloned and sequenced by Lam et al. (1993).
Lam et al. (1993) determined that the SLC6A1 gene contains 15 exons and is approximately 25 kb.
Hirunsatit et al. (2009) stated that the SLC6A1 gene contains 16 exons. There are 2 main transcripts generated by alternative splicing: 1 includes exons 1 through 16, and the other includes exons 2 through 16.
Zomot et al. (2007) showed that introduction of a negatively charged amino acid at or near 1 of the 2 putative sodium binding sites of the GABA transporter GAT1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride independent. In contrast to wildtype GAT1, a marked stimulation of the rate of net flux, but not of exchange, was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11; 607952) and the human dopamine transporter DAT (SLC6A3; 126455) also result in chloride-independent transport, whereas the reciprocal mutations in LeuT and Tyt1 render substrate binding and/or uptake by these bacterial neurotransmitter:sodium symporters chloride independent. Zomot et al. (2007) concluded that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the cotransported sodium ions.
Huang et al. (1995) used fluorescence in situ hybridization to map the SLC6A1 gene to chromosome 3p25-p24.
Hirunsatit et al. (2007) identified a 21-bp insertion polymorphism in the predicted promoter region of the SLC6A1 gene upstream of exon 1 that creates a second tandem copy of the sequence. The insertion represents a variable number of tandem repeat (VNTR) polymorphism. The insertion allele was detected only in individuals of African descent, with a frequency of 39%. By in vitro functional expression studies, Hirunsatit et al. (2009) showed that the SLC6A1 insertion promoter (2 copies of the sequence) had significantly greater promoter activity than the noninsertion (1 copy of the sequence) promoter, which in turn had greater activity than a promoterless control. The 2-copy insertion polymorphism created an enhancer element. Studies of postmortem hippocampus from 69 African American individuals showed that the SLC6A1 promoter genotype predicted SLC6A1 RNA expression and that overall SLC6A1 expression decreased with age. The allele frequency for the insertion was 14.5% in the African American postmortem sample and 18.1% in a sample of 69 Tanzanian individuals. Hirunsatit et al. (2009) postulated that this genetic variation may affect clinical response to drugs that bind the SLC6A1 receptor in populations of African descent.
Myoclonic-Atonic Epilepsy
In 7 patients, including a mother and daughter, with myoclonic-atonic epilepsy (MAE; 616421), Carvill et al. (2015) identified 6 different heterozygous mutations in the SLC6A1 gene (see, e.g., 137165.0001-137165.0005). One additional patient had a heterozygous deletion of chromosome 3p25 that included part of the SLC6A1 gene. Four of the mutations and the deletion occurred de novo; 1 affected child inherited the mutation from an affected mother, and another affected child inherited the mutation from an unaffected mother who was somatic mosaic for the mutation. Functional studies of the variants were not performed, but Carvill et al. (2015) postulated that the mutations resulted in a loss of function and disrupted the transport of GABA from the extracellular space into the presynaptic terminal. The mutations were found by direct sequencing of the SLC6A1 gene in 2 cohorts: the first 4 mutations were found in 4 of 569 individuals with epileptic encephalopathies, and the remaining 2 mutations were found in 2 of 75 individuals with myotonic-atonic epilepsy. Overall, SLC6A1 mutations occurred in 6 (4%) of 160 probands with MAE, suggesting that mutations in this gene result in a specific epilepsy syndrome.
Cope et al. (2009) found that Slc6a1-knockout mice developed spike-wave discharges characteristic of absence seizures (see, e.g., ECA1, 600131). The activation of peri- or extrasynaptic GABA receptors by ambient GABA causes a persistently active, or tonic, inhibitory current. Extrasynaptic GABA-A receptors in thalamocortical neurons contain the delta subunit (GABRD; 137163). In an established rat model of absence epilepsy with spontaneous spike-wave discharges called GAERS (genetic absence epilepsy rats from Strasbourg), Cope et al. (2009) found increased tonic current amplitude at thalamocortical GABA-A receptors beginning at postnatal day 17 compared to controls. Similarly increased tonic GABA-A receptor activation was observed in other mouse strains of absence epilepsy, including stargazer and lethargic mice, but not in tottering mice. Increased tonic inhibition was due to compromised GABA uptake by the GABA transporter GAT1 in the thalamus. Blockade or knockout of GAT1 in normal animals induced absence-like seizures. Mice without thalamic GABA-A receptors were resistant to pharmacologically induced seizures. Overall, these results showed that enhanced extrasynaptic GABA-A receptor activation in the thalamus may underlie absence seizures.
In an 8-year-old girl with myoclonic-atonic epilepsy (MAE; 616421), Carvill et al. (2015) identified a de novo heterozygous c.131G-A transition (c.131G-A, NM_003042.3) in the SLC6A1 gene, resulting in an arg44-to-gln (R44Q) substitution at a highly conserved residue in the cytoplasmic domain. The mutation, which was found by direct sequencing of SLC6A1, was not present in the Exome Aggregation Consortium database. Functional studies of the variant were not performed.
In a 16-year-old girl with myoclonic-atonic epilepsy (MAE; 616421), Carvill et al. (2015) identified a de novo heterozygous c.889G-A transition (c.889G-A, NM_003042.3) in the SLC6A1 gene, resulting in a gly297-to-arg (G297R) substitution at a highly conserved residue in transmembrane domain 6, which clusters around the GABA-binding pocket. The mutation, which was found by direct sequencing of SLC6A1, was not present in the Exome Aggregation Consortium database. Functional studies of the variant were not performed.
In a 10-year-old girl with myoclonic-atonic epilepsy (MAE; 616421), Carvill et al. (2015) identified a heterozygous c.1000G-C transversion (c.1000G-C, NM_003042.3) in the SLC6A1 gene, resulting in an ala334-to-pro (A334P) substitution at a highly conserved residue in transmembrane domain 7, which clusters around the GABA-binding pocket. The mutation was inherited from the unaffected mother, who was somatic mosaic (18% mutation load in white cells). The mutation, which was found by direct sequencing of SLC6A1, was not present in the Exome Aggregation Consortium database. Functional studies of the variant were not performed.
In a 10-year-old boy with myoclonic-atonic epilepsy (MAE; 616421), Carvill et al. (2015) identified a de novo heterozygous 2-bp deletion (c.1369_1370delGG, NM_003042.3) in the SLC6A1 gene, resulting in a frameshift and premature termination (Gly457HisfsTer10). The mutation, which was found by direct sequencing of SLC6A1 gene, was not present in the Exome Aggregation Consortium database. Functional studies of the variant were not performed.
In a mother and daughter with myoclonic-atonic epilepsy (MAE; 616421), Carvill et al. (2015) identified a heterozygous c.863C-T transition (c.863C-T, NM_003042.3) in the SLC6A1 gene, resulting in an ala288-to-val (A288V) substitution at a highly conserved residue adjacent to transmembrane domain 6. The mutation was found by direct sequencing of SLC6A1. Functional studies of the variant were not performed.
Carvill, G. L., McMahon, J. M., Schneider, A., Zemel, M., Myers, C. T., Saykally, J., Nguyen, J., Robbiano, A., Zara, F., Specchio, N., Mecarelli, O., Smith, R. L., and 13 others. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am. J. Hum. Genet. 96: 808-815, 2015. [PubMed: 25865495] [Full Text: https://doi.org/10.1016/j.ajhg.2015.02.016]
Cope, D. W., Di Giovanni, G., Fyson, S. J., Orban, G., Errington, A. C., Lorincz, M. L., Gould, T. M., Carter, D. A., Crunelli, V. Enhanced tonic GABA-A inhibition in typical absence epilepsy. Nature Med. 15: 1392-1398, 2009. [PubMed: 19966779] [Full Text: https://doi.org/10.1038/nm.2058]
Hirunsatit, R., George, E. D., Lipska, B. K., Elwafi, H. M., Sander, L., Yrigollen, C. M., Gelernter, J., Grigoenko, E. L., Lappalainen, J., Mane, S., Nairn, A. C., Kleinman, J. E., Simen, A. A. Twenty-one-base-pair insertion polymorphism creates an enhancer element and potentiates SLC6A1 GABA transporter promoter activity. Pharmacogenet. Genomics 19: 53-65, 2009. [PubMed: 19077666] [Full Text: https://doi.org/10.1097/FPC.0b013e328318b21a]
Hirunsatit, R., Ilomaki, R., Malison, R., Rasanen, P., Ilomaki, E., Kranzler, H. R., Kosten, T., Sughondhabirom, A., Thavichachart, N., Tangwongchai, S., Listman, J., Mutirangura, A., Gelernter, J., Lappalainen, J. Sequence variation and linkage disequilibrium in the GABA transporter-1 gene (SLC6A1) in five populations: implications for pharmacogenetic research. BMC Genet. 8: 71, 2007. Note: Electronic Article. [PubMed: 17941974] [Full Text: https://doi.org/10.1186/1471-2156-8-71]
Huang, F., Shi, L. J., Heng, H. H. Q., Fei, J., Guo, L.-H. Assignment of the human GABA transporter gene (GABATHG) locus to chromosome 3p24-p25. Genomics 29: 302-304, 1995. [PubMed: 8530094] [Full Text: https://doi.org/10.1006/geno.1995.1253]
Lam, D. M.-K., Fei, J., Zhang, X.-Y., Tam, A. C. W., Zhu, L.-H., Huang, F., King, S. C., Guo, L.-H. Molecular cloning and structure of the human (GABATHG) GABA transporter gene. Molec. Brain Res. 19: 227-232, 1993. [PubMed: 8412566] [Full Text: https://doi.org/10.1016/0169-328x(93)90032-k]
Nelson, H., Mandiyan, S., Nelson, N. Cloning of the human brain GABA transporter. FEBS Lett. 269: 181-184, 1990. [PubMed: 2387399] [Full Text: https://doi.org/10.1016/0014-5793(90)81149-i]
Zomot, E., Bendahan, A., Quick, M., Zhao, Y., Javitch, J. A., Kanner, B. I. Mechanism of chloride interaction with neurotransmitter:sodium symporters. Nature 449: 726-730, 2007. [PubMed: 17704762] [Full Text: https://doi.org/10.1038/nature06133]