Alternative titles; symbols
HGNC Approved Gene Symbol: SLC18A3
Cytogenetic location: 10q11.23 Genomic coordinates (GRCh38): 10:49,610,310-49,612,720 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q11.23 | Myasthenic syndrome, congenital, 21, presynaptic | 617239 | Autosomal recessive | 3 |
The SLC18A3 gene encodes a transmembrane protein that transports acetylcholine (ACh) into presynaptic secretory vesicles for release at cholinergic nerve endings in the central and peripheral nervous systems (summary by O'Grady et al., 2016).
Erickson et al. (1994) cloned a vesicular acetylcholine transporter cDNA from a human neuroblastoma cDNA library. The amino acid conservation between rat and human VACHT is 94%. In situ hybridization studies demonstrated high levels of expression of rat VACHT mRNA in all major cholinergic cell groups examined. The distribution was virtually identical to that previously reported for choline acetyltransferase (CHAT; 118490) mRNA and protein and was consistent with the expression of both VACHT and CHAT exclusively in the cholinergic nervous system. Northern blot analysis of rat tissues detected a single, approximately 3-kb VACHT mRNA expressed in regions of the brain containing cholinergic neurons and in PC12 cells.
By in situ hybridization, Erickson et al. (1994) mapped the human VACHT gene to chromosome 10q11.2. They demonstrated that the VACHT gene is encoded by a sequence contained uninterrupted within the first intron of the CHAT gene (118490), the enzyme required for acetylcholine biosynthesis in the peripheral and central cholinergic nervous systems. Transcription of VACHT and CHAT mRNA from the same or contiguous promoters within the single regulatory locus provides a previously undescribed genetic mechanism for coordinate regulation of 2 proteins whose expression is required to establish a mammalian neuronal phenotype.
In 2 unrelated patients with presynaptic congenital myasthenic syndrome-21 (CMS21; 617239), O'Grady et al. (2016) identified biallelic mutations in the SLC18A3 gene: 1 patient was compound heterozygous for a missense mutation (G186A; 600336.0001) and a large deletion encompassing several genes, and the other patient had a homozygous missense mutation (D398H; 600336.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed.
Lara et al. (2010) noted that Vacht -/- mice are unable to release acetylcholine (ACh) in response to depolarization and die shortly after birth due to respiratory failure. Lara et al. (2010) studied a line of mutant mice termed 'Vacht knockdown homozygous' (Vacht KD(HOM)) that show reduced Vacht expression and altered ACh release. Young Vacht KD(HOM) mice had normal cardiac function, but by 3 months of age they exhibited reduced cardiac contractility and left ventricle fractional shortening. These changes were alleviated by pharmacologic restoration of ACh at synapses. Isolated Vacht KD(HOM) heart preparations had reduced systolic tension with elevated expression of markers of cardiomyocyte stress, and these changes were also alleviated by restoration of ACh. Vacht KD(HOM) and Vacht -/- mice exhibited altered autonomic control of heart rate, overexpression of the M2 muscarinic receptor (CHRM2; 118493), and decreased expression of beta-1 adrenergic receptors (ADRB1; 109630). Expression of the G-protein kinase Grk2 (ADRBK1; 109635) was also elevated in Vacht KD(HOM) hearts compared with wildtype.
In a boy, born of unrelated Filipino parents, with presynaptic congenital myasthenic syndrome-21 (CMS21; 617239), O'Grady et al. (2016) identified a heterozygous c.557G-C transversion (c.557G-C, NM_003055.2) in the SLC18A3 gene, resulting in a gly186-to-ala (G186A) substitution at a highly conserved residue in the fourth transmembrane domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Variant Server or the ExAC databases. The mutation was inherited from the unaffected mother. The other allele in the patient had a 4.83-Mb deletion encompassing 4 genes, including SLC18A3 and CHAT. DNA from the father was unavailable. Functional studies of the variants and studies of patient cells were not performed.
In a girl, born of consanguineous Turkish parents, with presynaptic congenital myasthenic syndrome-21 (CMS21; 617239), O'Grady et al. (2016) identified a homozygous c.1192G-C transversion (c.1192G-C, NM_003055.2) in the SLC18A3 gene, resulting in an asp398-to-his (D398H) substitution at a highly conserved residue in the tenth transmembrane domain. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder in the family and was not found in the Exome Variant Server or the ExAC databases. Functional studies of the variant and studies of patient cells were not performed.
Erickson, J. D., Varoqui, H., Schafer, M. K.-H., Modi, W., Diebler, M.-F., Weihe, E., Rand, J., Eiden, L. E., Bonner, T. I., Usdin, T. B. Functional identification of a vesicular acetylcholine transporter and its expression from a 'cholinergic' gene locus. J. Biol. Chem. 269: 21929-21932, 1994. [PubMed: 8071310]
Lara, A., Damasceno, D. D., Pires, R., Gros, R., Gomes, E. R., Gavioli, M., Lima, R. F., Guimaraes, D., Lima, P., Bueno, C. R., Jr., Vasconcelos, A., Roman-Campos, D., and 14 others. Dysautonomia due to reduced cholinergic neurotransmission causes cardiac remodeling and heart failure. Molec. Cell. Biol. 30: 1746-1756, 2010. [PubMed: 20123977] [Full Text: https://doi.org/10.1128/MCB.00996-09]
O'Grady, G. L., Verschuuren, C., Yuen, M., Webster, R., Menezes, M., Fock, J. M., Pride, N., Best, H. A., Benavides Damm, T., Turner, C., Lek, M., Engel, A. G., North, K. N., Clarke, N. F., MacArthur, D. G., Kamsteeg, E.-J., Cooper, S. T. Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome. Neurology 87: 1442-1448, 2016. [PubMed: 27590285] [Full Text: https://doi.org/10.1212/WNL.0000000000003179]