Alternative titles; symbols
HGNC Approved Gene Symbol: SLC18A2
Cytogenetic location: 10q25.3 Genomic coordinates (GRCh38): 10:117,241,114-117,279,430 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.3 | Parkinsonism-dystonia, infantile, 2 | 618049 | Autosomal recessive | 3 |
The vesicular monoamine transporter acts to accumulate cytosolic monoamines into synaptic vesicles, using the proton gradient maintained across the synaptic vesicular membrane. Its proper function is essential to the correct activity of the monoaminergic systems that have been implicated in several human neuropsychiatric disorders. The transporter is a site of action of important drugs, including reserpine and tetrabenazine (summary by Peter et al., 1993).
See also SLC18A1 (193002).
Liu et al. (1992) and Erickson et al. (1992) investigated cDNAs encoding the synaptic vesicular monoamine transporter in rat brain. Using sequences from rat brain SVMT, Surratt et al. (1993) identified the human homolog. Human SVMT shares 92% amino acid identity with the rat sequence but displays one less consensus site for asparagine N-linked glycosylation and one more consensus site for phosphorylation by protein kinase C.
Tritsch et al. (2012) demonstrated that activation of dopamine neurons in striatal slices rapidly inhibits action potential firing in both direct- and indirect-pathway striatal projection neurons through vesicular release of the inhibitory transmitter GABA. GABA is released directly from dopaminergic axons but in a manner that is independent of the vesicular GABA transporter VGAT (SLC32A1; 616440). Instead, GABA release requires activity of the vesicular monoamine transporter VMAT2, which is the vesicular transporter for dopamine. Furthermore, VMAT2 expression in GABAergic neurons lacking VGAT is sufficient to sustain GABA release. Tritsch et al. (2012) concluded that their findings expand the repertoire of synaptic mechanisms used by dopamine neurons to influence basal ganglia circuits, show a new substrate whose transport is dependent on VMAT2, and demonstrate that GABA can function as a bona fide cotransmitter in monoaminergic neurons.
By Southern blot analysis of human/rodent hybrid cell lines and fluorescence in situ hybridization, Surratt et al. (1993) mapped the human SLC18A2 gene to chromosome 10q25. They also demonstrated a TaqI polymorphism that may prove useful in assessing the gene's involvement in neuropsychiatric disorders involving monoaminergic brain systems. Peter et al. (1993) likewise assigned the SLC18A2 gene to chromosome 10q25 using a panel of mouse/human hybrids and in situ hybridization.
Roghani et al. (1996) showed that the mouse Slc18a2 gene maps to mouse chromosome 19 by linkage analysis.
Infantile Parkinsonism-Dystonia 2
In affected members of a highly consanguineous Saudi Arabian family with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Rilstone et al. (2013) identified a homozygous missense mutation in the SLC18A2 gene (P387L; 193001.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in COS-7 cells showed that the mutation resulted in a severe, although not complete, loss of transport function for serotonin, consistent with a loss of function. The findings suggested that the disorder resulted from defective monoamine loading into synaptic vesicles, causing impaired synaptic neurotransmission and symptoms consistent with depletion of monoamines.
In 2 brothers, born to consanguineous parents, with PKDYS2, Jacobsen et al. (2016) identified a homozygous mutation in the SLC18A2 gene (P237H; 193001.0002). The mutation was identified by SNP homozygosity mapping and whole-exome sequencing. Functional studies in patient cells were not performed.
In a 7-year-old girl, born to consanguineous Iraqi parents, with PKDYS2, Rath et al. (2017) identified homozygosity for the P237H mutation in the SLC18A2 gene. The mutation was identified by whole-exome sequencing. DNA of a deceased, similarly affected sib showed homozygosity for the mutation. Functional studies in patient cells were not performed.
In a boy, born to consanguineous parents, with PKDYS2, Padmakumar et al. (2019) identified a homozygous mutation in the SLC18A2 gene (P316A; 193001.0003). VMAT2 protein expression was normal in platelets from the patient, but total serotonin levels were low in platelet extracts. Protein expression levels of the platelet dense granule membrane glycoproteins CD63 (155740) and LAMP2 (309060) were comparable between patient and controls, suggesting that the patient had a normal quantity of dense granules that were defective in total serotonin uptake due to a dysfunctional VMAT2 mutant.
Zhai et al. (2023) identified homozygosity for the P237H mutation in the SLC18A2 gene in a 6-month-old boy with PKDYS2. Whole-exome sequencing and SNP array analysis demonstrated that the patient's father was a mutation carrier, and homozygosity for the P237H mutation arose from paternal uniparental disomy of chromosome 10p15.3q26.3.
Saida et al. (2023) reported homozygous mutations in the SLC18A2 in 42 patients from 27 families with PKDYS2. The mutations were identified by whole-exome or whole-genome sequencing and were confirmed by Sanger sequencing. The mutations, 17 of which were novel, included 4 nonsense mutations, 5 frameshift mutations, 1 splice site mutation, and 9 missense mutations. The most common mutations were P237H, which was present in 12 patients from 6 families, and P387L which was present in 6 patients from 3 families. The mutations were either ultrarare or absent in multiple population databases except for the P237H mutation, which was present at an allele frequency of 0.000024 in the gnomAD database and 0.000065 in the UK Biobank database.
Associations Pending Confirmation
Lin et al. (2005) sequenced the 17.4-kb SLC18A2 promoter region in 23 Caucasian individuals and identified 47 polymorphisms that conferred 13 haplotypes. In vitro analysis showed a 20% difference in promoter activity between 2 frequent haplotypes and identified some of the SNPs that influenced promoter activity. In 144 alcoholic patients and 189 controls, they found that haplotypes with -14234G (rs363371) and -2504C of the SLC18A2 promoter region represented a protective factor against alcoholism (p = 0.0038).
Fon et al. (1997) found that Vmat2 -/- mice survived through embryonic development but died within a few days of birth. Compared with wildtype and Vmat2 +/- littermates, Vmat2 -/- mice were smaller, fed poorly, did not gain weight, and moved less, although they moved vigorously in response to mild pain. Brains of Vmat2 -/- mice had extremely low total monoamines, such as dopamine, norepinephrine, and serotonin, suggesting that Vmat2 regulates monoamine storage and release. Primary midbrain cultures of Vmat2 -/- mice also exhibited a dramatic reduction in total dopamine levels, as there was essentially no exocytotic release of dopamine into culture media. Amphetamine induced the release of substantial dopamine into Vmat2 -/- midbrain culture media, and exposure of Vmat2 -/- midbrain cultures to amphetamine rather than depolarization drastically increased the total amount of dopamine. Vmat2 -/- mice injected with amphetamine moved more, fed better, increased slightly in weight, and survive substantially longer, indicating that amphetamine could circumvent the defect in vesicular release of monoamine transmitters. Brains of Vmat2 +/- mice also contained substantially lower monoamine levels than wildtype, and depolarization induced less dopamine release from Vmat2 +/- cultures than from wildtype cultures.
Independently, Wang et al. (1997) reported that newborn homozygous Vmat2-knockout mice were small, hypoactive, and were more prone to hypothermia compared with wildtype and heterozygous littermates. They exhibited severely stunted growth and died within a few days after birth. Monoamine levels in brains of newborn homozygous Vmat2-knockout mice were drastically reduced, whereas metabolite levels were not significantly altered, except for significantly increased serotonin. In brains of newborn homozygous Vmat2-knockout mice, activities of rate-limiting enzymes for monoamine synthesis were drastically increased, but no measurable dopamine overflow was detected. Adult heterozygous Vmat2-knockout mice showed impaired striatal dopamine storage and release, as depolarization- and amphetamine-evoked dopamine release were diminished. Further analysis demonstrated that altered presynaptic dopamine function in heterozygous Vmat2-knockout mice was associated with supersensitivity to the locomotor effects of direct and indirect dopamine agonists, including cocaine and amphetamine. Heterozygous mice did not develop further sensitization to repeated cocaine administration.
Mooslehner et al. (2001) identified and characterized a homozygous Vmat2 mutant mouse clone that had low-level expression of Vmat2 protein and survived into adulthood. These Vmat2-deficient mice showed no obvious physical abnormalities compared with wildtype controls, but they weighed less. Vmat2-deficient mice had decreased monoamines, especially dopamine, motor deficits, and a pattern of changes in peptides associated with the direct and indirect output pathways of striatum. However, these mutant mice did not exhibit overt dopamine cell loss in midbrain areas. Vmat2-deficient mice exhibited a lowered threshold for dopamine cell damage caused by neurotoxin, as significantly more dopamine cell loss occurred in substantia nigra and the ventral tegmental area following toxin administration compared with heterozygous and wildtype littermates.
Saida et al. (2023) deleted cat-1, the worm homolog of SLC18A2, in C. elegans. The mutant worms had abnormal curvature of the head and neck as well as slow movement compared to wildtype. The mutant worms also had a decreased pharyngeal pumping rate when foraging.
For a discussion of a Drosophila vesicular monoamine transporter model, see SLC18A1 (193002).
In affected members of a highly consanguineous Saudi Arabian family with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Rilstone et al. (2013) identified a homozygous c.1160C-T transition in exon 13 of the SLC18A2 gene, resulting in a pro387-to-leu (P387L) substitution at a highly conserved residue adjacent to a transmembrane segment. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the 1000 Genomes Project database. In vitro functional expression studies in COS-7 cells showed that the mutation resulted in a severe, although not complete, loss of transport function. The findings suggested that the disorder resulted from defective monoamine loading into synaptic vesicles, causing defective neurotransmission.
In 2 sibs, born to consanguineous parents, with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Jacobsen et al. (2016) identified homozygosity for a c.710C-A transversion (c.710C-A, NM_003054.4) in the SLC18A2 gene, resulting in a pro237-to-his (P237H) substitution. The mutation, which was identified by SNP homozygosity mapping and whole-exome sequencing, segregated with disease in the family. The mutation was present in the ExAC database at an allele frequency of 8.144 x 10(-6).
In a 7-year-old girl, born to consanguineous Iraqui parents, with PKDYS2, Rath et al. (2017) identified homozygosity for the P237H mutation in the SLC18A2 gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents and 7 unaffected sibs. DNA of a deceased, similarly affected sib showed homozygosity for the P237H mutation.
In a 6-month-old male with PKDYS2, Zhai et al. (2023) identified homozygosity for the P237H mutation in the SLC18A2 gene. The mutation was identified by trio whole-exome sequencing and SNP array analysis. The patient's father was a mutation carrier, and homozygosity for the P237H mutation arose from paternal uniparental disomy of chromosome 10p15.3q26.3.
In a 5-year-old boy, born to consanguineous parents, with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Padmakumar et al. (2019) identified homozygosity for a c.946C-G transversion in the SLC18A2 gene, resulting in a pro316-to-ala (P316A) substitution at a highly conserved residue. The mutation, which was identified by whole-genome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the gnomAD database.
In 3 Costa Rican sibs (family 21, patients 33-35), born to consanguineous parents, with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Saida et al. (2023) identified homozygosity for a 1-bp duplication (c.216dupA, NM_003054.6) in the SLC18A2 gene, resulting in a frameshift and premature termination (Asp73ArgfsTer11). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was present in the gnomAD database at an allele frequency of 1.18 x 10(-5) and was not present in the UK Biobank database.
In 3 patients (patients 36-38), including a sib pair, from 2 unrelated consanguineous families (families 22 and 23) with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Saida et al. (2023) identified homozygosity for a 5-bp deletion (c.240_244del, NM_003054.6) in the SLC18A2 gene, resulting in a tyr81-to-ter (Y81X) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the gnomAD and UK Biobank databases.
In a Norwegian patient (patient 30, family 18), born to consanguineous parents, with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Saida et al. (2023) identified homozygosity for a c.33G-A transition (c.33G-A, NM_003054.6) in the SLC18A2 gene, resulting in a trp11-to-ter (W11X) substitution. The mutation, which was identified by trio whole-exome sequencing and confirmed by Sanger sequencing, was not present in the gnomAD and UK Biobank databases.
Erickson, J. D., Eiden, L. E., Hoffman, B. J. Expression cloning of a reserpine-sensitive vesicular monoamine transporter. Proc. Nat. Acad. Sci. 89: 10993-10997, 1992. [PubMed: 1438304] [Full Text: https://doi.org/10.1073/pnas.89.22.10993]
Fon, E. A., Pothos, E. N., Sun, B.-C., Killeen, N., Sulzer, D., Edwards, R. H. Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19: 1271-1283, 1997. [PubMed: 9427250] [Full Text: https://doi.org/10.1016/s0896-6273(00)80418-3]
Jacobsen, J. C., Wilson, C., Cunningham, V., Glamuzina, E., Prosser, D. O., Love, D. R., Burgess, T., Taylor, J., Swan, B., Hill, R., Robertson, S. P., Snell, R. G., Lehnert, K. Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder. J. Inherit. Metab. Dis. 39: 305-308, 2016. [PubMed: 26497564] [Full Text: https://doi.org/10.1007/s10545-015-9897-6]
Lin, Z., Walther, D., Yu, X.-Y., Li, S., Drgon, T., Uhl, G. R. SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism. Hum. Molec. Genet. 14: 1393-1404, 2005. [PubMed: 15829504] [Full Text: https://doi.org/10.1093/hmg/ddi148]
Liu, Y., Peter, D., Roghani, A., Schuldiner, S., Prive, G. G., Eisenberg, D., Brecha, N., Edwards, R. H. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter. Cell 70: 539-551, 1992. [PubMed: 1505023] [Full Text: https://doi.org/10.1016/0092-8674(92)90425-c]
Mooslehner, K. A., Chan, P. M., Xu, W., Liu, L., Smadja, C., Humby, T., Allen, N. D., Wilkinson, L. S., Emson, P. C. Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: potential mouse model for parkinsonism. Molec. Cell. Biol. 21: 5321-5331, 2001. [PubMed: 11463816] [Full Text: https://doi.org/10.1128/MCB.21.16.5321-5331.2001]
Padmakumar, M., Jaeken, J., Ramaekers, V., Lagae, L., Greene, D., Thys, C., Van Geet, C., BioResource, N., Stirrups, K., Downes, K., Turro, E., Freson, K. A novel missense variant in SLC18A2 causes recessive brain monoamine vesicular transport disease and absent serotonin in platelets. JIMD Rep. 47: 9-16, 2019. [PubMed: 31240161] [Full Text: https://doi.org/10.1002/jmd2.12030]
Peter, D., Finn, J. P., Klisak, I., Liu, Y., Kojis, T., Heinzmann, C., Roghani, A., Sparkes, R. S., Edwards, R. H. Chromosomal localization of the human vesicular amine transporter genes. Genomics 18: 720-723, 1993. [PubMed: 7905859] [Full Text: https://doi.org/10.1016/s0888-7543(05)80383-0]
Rath, M., Korenke, G. C., Najm, J., Hoffmann, G. F., Hagendorff, A., Strom, T. M., Felbor, U. Exome sequencing results in identification and treatment of brain dopamine-serotonin vesicular transport disease. J. Neurol. Sci. 379: 296-297, 2017. [PubMed: 28716265] [Full Text: https://doi.org/10.1016/j.jns.2017.06.034]
Rilstone, J. J., Alkhater, R. A., Minassian, B. A. Brain dopamine-serotonin vesicular transport disease and its treatment. New Eng. J. Med. 368: 543-550, 2013. [PubMed: 23363473] [Full Text: https://doi.org/10.1056/NEJMoa1207281]
Roghani, A., Welch, C., Xia, Y.-R., Liu, Y., Peter, D., Finn, J. P., Edwards, R. H., Lusis, A. J. Assignment of the mouse vesicular monoamine transporter genes, Slc18a1 and Slc18a2, to chromosomes 8 and 19 by linkage analysis. Mammalian Genome 7: 393-394, 1996. [PubMed: 8661734] [Full Text: https://doi.org/10.1007/s003359900114]
Saida, K., Maroofian, R., Sengoku, T., Mitani, T., Pagnamenta, A. T., Marafi, D., Zaki, M. S., O'Brien, T. J., Karimiani, E. G., Kaiyrzhanov, R., Takizawa, M., Ohori, S., and 75 others. Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: a study in 42 affected individuals. Genet. Med. 25: 90-102, 2023. [PubMed: 36318270] [Full Text: https://doi.org/10.1016/j.gim.2022.09.010]
Surratt, C. K., Persico, A. M., Yang, X.-D., Edgar, S. R., Bird, G. S., Hawkins, A. L., Griffin, C. A., Li, X., Jabs, E. W., Uhl, G. R. A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs. FEBS Lett. 318: 325-330, 1993. [PubMed: 8095030] [Full Text: https://doi.org/10.1016/0014-5793(93)80539-7]
Tritsch, N. X., Ding, J. B., Sabatini, B. L. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490: 262-266, 2012. [PubMed: 23034651] [Full Text: https://doi.org/10.1038/nature11466]
Wang, Y.-M., Gainetdinov, R. R., Fumagalli, F., Xu, F., Jones, S. R., Bock, C. B., Miller, G. W., Wightman, R. M., Caron, M. G. Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19: 1285-1296, 1997. [PubMed: 9427251] [Full Text: https://doi.org/10.1016/s0896-6273(00)80419-5]
Zhai, H., Zheng, Y., He, Y., Zhang, Y., Guo, Z., Cui, W., Sun, L. A case report of infantile parkinsonism-dystonia-2 caused by homozygous mutation in the SLC18A2 gene. Int. J. Neurosci. 133: 574-577, 2023. [PubMed: 34078222] [Full Text: https://doi.org/10.1080/00207454.2021.1938036]