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HGNC Approved Gene Symbol: SLC6A9
Cytogenetic location: 1p34.1 Genomic coordinates (GRCh38) : 1:43,996,483-44,031,462 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p34.1 | Glycine encephalopathy with normal serum glycine | 617301 | Autosomal recessive | 3 |
The SLC6A9 gene encodes the GLYT1 glycine transporter, which is located predominantly on astrocytes and is essential for the clearance of glycine from the extracellular space and termination of glycinergic neurotransmission (summary by Kurolap et al., 2016).
Glycine transport is mediated by 2 sodium-dependent carriers, GLYT1 and GLYT2 (604159), that have distinct tissue distributions. Borowsky et al. (1993) isolated 2 glycine transporter variants with distinct localizations in the central nervous system (CNS) and peripheral tissues, encoded by a common gene. While the 3-prime sequences of these 2 cDNAs were identical, the 5-prime noncoding regions and the N termini were completely different. GLYT1b was found only in the white matter of the CNS, while GLYT1a was found in the gray matter of the CNS as well as in macrophages and mast cells in peripheral tissues. The findings of Borowsky et al. (1993) suggested that tissue-specific alternative splicing or alternative promoter usage from a single gene resulted in 2 mRNA products encoding similar but distinct glycine transporters. The anatomic distribution of GLYT1a mRNA supported the emerging status of glycine as a supraspinal neurotransmitter and suggested that glycine may function as a chemical messenger outside the CNS.
In mouse brain, Kurolap et al. (2016) found high expression of the Glyt1 gene in the caudal region of the central nervous system known to be rich in glycinergic neurons. Glyt1 was not observed in peripheral tissues, such as liver, muscle, and skin.
West et al. (2004) found that mouse Hmgn3 (604502) upregulated expression of Glyt1 following transfection into a mouse hepatoma cell line. Hmgn3 and Glyt1 were coexpressed in mouse retina, and chromatin immunoprecipitation assays showed that Hmgn3 bound to a region of the Glyt1 gene encompassing the Glyt1a transcriptional start site.
By yeast 2-hybrid analysis, Hanley et al. (2000) identified a C-terminal variant of bovine Glyt1 that interacted specifically with the rho-1 subunit of the GABA-C receptor (137161). They also found that variations in the C-terminal domain of Glyt1 dramatically affected its kinetic properties.
Kim et al. (1994) mapped the gene encoding GLYT1, SLC6A9, to 1p32-p31.3 using isotopic in situ hybridization. They also mapped the mouse gene to chromosome 4 in a region near the 'clasper' locus. Using fluorescence in situ hybridization, Jones et al. (1995) mapped the gene more precisely to 1p33.
In a 15-month-old girl, born of consanguineous Saudi parents, with glycine encephalopathy with normal serum glycine (617301), Alfadhel et al. (2016) identified a homozygous missense mutation in the SLC6A9 gene (S407G; 601019.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In affected children from 2 unrelated consanguineous Muslim-Arab families with glycine encephalopathy with normal serum glycine, Kurolap et al. (2016) identified 2 different homozygous truncating mutations in the SLC6A9 gene (601019.0002 and 601019.0003). The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing; the mutation in the second family was found by direct sequencing of the SLC6A9 gene. Functional studies of the variant and studies of patient cells were not performed. However, mice treated with a Glyt1 inhibitor developed increased CSF glycine levels, hypoactivity, and hypertonic seizures, whereas total blood glycine was not elevated. These features were similar to those observed in the patients, suggesting that loss of SLC6A9 causing impaired glycine neurotransmission was responsible for the neurologic disorder.
SLCC6A9 maintains subsaturating concentrations of glycine at synaptic N-methyl-D-aspartate receptors (NMDAR; see 138249), which require the binding of both glycine and glutamate for activation. Tsai et al. (2004) disrupted the Glyt1 gene in mice. Homozygous mice died within 12 hours of birth. Heterozygous mice expressed 50% of the wildtype levels of Glyt1, and heterozygote forebrain homogenates showed a 50% reduction in Na(+)-dependent glycine transport. Reduced Glyt1 expression enhanced hippocampal NMDAR function and memory retention and protected against an amphetamine disruption of sensory gating.
Gomeza et al. (2003) created Glyt1-deficient mice. Homozygous null mice were born at expected mendelian ratios; however, they showed severe motor and respiration deficits and died during the first postnatal day. Histologic examination of several tissues and systematic analysis of the CNS revealed no obvious defect. Since Glyt1-null mice did not breathe properly, Gomeza et al. (2003) analyzed transverse slices from the caudal medulla for neuronal activity. In contrast to the regular rhythmic bursting observed in medulla slices from wildtype animals, Glyt1-null medulla slices showed prolonged periods of inactivity and variable interburst intervals. Respiratory activity was partly normalized by the glycine receptor agonist, strychnine. Conversely, glycine or a GLYT1 inhibitor suppressed respiratory activity in wildtype medulla slices. Gomeza et al. (2003) concluded that GLYT1 is essential for regulating glycine concentrations at inhibitory glycine receptors.
Although Borowsky et al. (1993) referred to the 2 variants that they isolated as GLYT1 and GLYT2, in a subsequent paper (Borowsky and Hoffman, 1998) these variants were referred to as GLYT1b and GLYT1a, respectively.
In a 15-month-old girl, born of consanguineous Saudi parents, with glycine encephalopathy with normal serum glycine (617301), Alfadhel et al. (2016) identified a homozygous c.1219A-G transition (c.1219A-G, NM_201649.3) in exon 9 of the SLC6A9 gene, resulting in a ser407-to-gly (S407G) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 2,000 Saudi control exomes. Functional studies of the variant and studies of patients cells were not performed.
In a 2-year-old girl, born of consanguineous Muslim-Arab parents, with glycine encephalopathy with normal serum glycine (617301), Kurolap et al. (2016) identified a homozygous 5-bp deletion (c.928_932delAAGTC, NM_201649.3) in exon 6 of the SLC6A9 gene, resulting in a frameshift and premature termination (Lys310PhefsTer31). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 300 in-house control chromosomes. The same homozygous mutation was found in the affected fetus of a subsequent pregnancy in this family. Functional studies of the variant and studies of patient cells were not performed.
In 3 sibs, born of consanguineous Muslim-Arab parents, with glycine encephalopathy with normal serum glycine (617301), Kurolap et al. (2016) identified a homozygous c.1717C-T transition (c.1717C-T, NM_201649.3) in the SLC6A9 gene, resulting in a gln573-to-ter (Q573X) substitution. The mutation, which was found by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 300 in-house control chromosomes. Functional studies of the variant and studies of patient cells were not performed.
Alfadhel, M., Nashabat, M., Al Qahtani, H., Alfares, A., Al Mutairi, F., Al Shaalan, H., Douglas, G. V., Wierenga, K., Juusola, J., Alrifai, M. T., Arold, S. T., Alkuraya, F., Ali, Q. A. Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Hum. Genet. 135: 1263-1268, 2016. [PubMed: 27481395] [Full Text: https://doi.org/10.1007/s00439-016-1719-x]
Borowsky, B., Hoffman, B. J. Analysis of a gene encoding two glycine transporter variants reveals alternative promoter usage and a novel gene structure. J. Biol. Chem. 273: 29077-29085, 1998. [PubMed: 9786914] [Full Text: https://doi.org/10.1074/jbc.273.44.29077]
Borowsky, B., Mezey, E., Hoffman, B. J. Two glycine transporter variants with distinct localization in the CNS and peripheral tissues are encoded by a common gene. Neuron 10: 851-863, 1993. [PubMed: 8494645] [Full Text: https://doi.org/10.1016/0896-6273(93)90201-2]
Gomeza, J., Hulsmann, S., Ohno, K., Eulenberg, V., Szoke, K., Richter, D., Betz, H. Inactivation of the glycine transporter 1 gene discloses vital role of glial glycine uptake in glycinergic inhibition. Neuron 40: 785-796, 2003. Note: Erratum: Neuron 41: 675 only, 2004. [PubMed: 14622582] [Full Text: https://doi.org/10.1016/s0896-6273(03)00672-x]
Hanley, J. G., Jones, E. M. C., Moss, S. J. GABA receptor rho-1 subunit interacts with a novel splice variant of the glycine transporter, GLYT-1. J. Biol. Chem. 275: 840-846, 2000. [PubMed: 10625616] [Full Text: https://doi.org/10.1074/jbc.275.2.840]
Jones, E. M. C., Fernald, A., Bell, G. I., Le Beau, M. M. Assignment of SLC6A9 to human chromosome band 1p33 by in situ hybridization. Cytogenet. Cell Genet. 71: 211, 1995. [PubMed: 7587377] [Full Text: https://doi.org/10.1159/000134110]
Kim, K.-M., Kingsmore, S. F., Han, H., Yang-Feng, T. L., Godinot, N., Seldin, M. F., Caron, M. G., Giros, B. Cloning of the human glycine transporter type 1: molecular and pharmacological characterization of novel isoform variants and chromosomal localization of the gene in the human and mouse genomes. Molec. Pharm. 45: 608-617, 1994. [PubMed: 8183239]
Kurolap, A., Armbruster, A., Hershkovitz, T., Hauf, K., Mory, A., Paperna, T., Hannappel, E., Tal, G., Nijem Y., Sella, E., Mahajnah, M., Ilivitzki, A., Hershkovitz, D., Ekhilevitch, N., Mandel, H., Eulenburg, V., Baris, H. N. Loss of glycine transporter 1 causes a subtype of glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid glycine. Am. J. Hum. Genet. 99: 1172-1180, 2016. [PubMed: 27773429] [Full Text: https://doi.org/10.1016/j.ajhg.2016.09.004]
Tsai, G., Ralph-Williams, R. J., Martina, M., Bergeron, R., Berger-Sweeney, J., Dunham, K. S., Jiang, Z., Caine, S. B., Coyle, J. T. Gene knockout of glycine transporter 1: characterization of the behavioral phenotype. Proc. Nat. Acad. Sci. 101: 8485-8490, 2004. [PubMed: 15159536] [Full Text: https://doi.org/10.1073/pnas.0402662101]
West, K. L., Castellini, M. A., Duncan, M. K., Bustin, M. Chromosomal proteins HMGN3a and HMGN3b regulate the expression of glycine transporter 1. Molec. Cell. Biol. 24: 3747-3756, 2004. [PubMed: 15082770] [Full Text: https://doi.org/10.1128/MCB.24.9.3747-3756.2004]