Abstract
The vesicular monoamine transporter 2 (VMAT2, SLC18A2) takes up cytosolic monoamines into intracellular secretory vesicles, preventing their neurotoxicity in the cytosol and discharging them into extracellular space by exocytosis. It has been shown that one-copy deletion of the VMAT2 gene increases locomotion activity significantly in response to drug treatments and dopamine neuron death rate in response to neurotoxin treatments in knockout mice. Little is known about promoter polymorphisms and their influence on SLC18A2 promoter activity. We have re-sequenced a 17.4 kb DNA in the SLC18A2 promoter region for Caucasians and revealed 47 polymorphisms that confer 13 haplotypes. One of the haplotypes reaches a frequency as high as 65%, likely due to positive selection. In vitro analysis showed a 20% difference in promoter activity between two frequent haplotypes and identified some of the polymorphisms that influence promoter activity. Four haplotype-defining single nucleotide polymorphisms (hdSNPs) can define the frequent haplotypes and by genotyping these hdSNPs, we find that haplotypes with -14234G and -2504C of SLC18A2 promoter region represent a protective factor against alcoholism (P = 0.0038 by Fisher's exact tests). Therefore, SLC18A2 promoter haplotypes defined here create a foundation for transcriptional characterization of individuality and for association study on monoamine-related human diseases.
Highlights
The vesicular monoamine transporter 2 (VMAT2) is an important molecule for the function of monoaminergic neurons that are key participants in locomotion, reward and mnemonic brain systems
Four haplotype-defining single nucleotide polymorphisms can define the frequent haplotypes and by genotyping these hdSNPs, we find that haplotypes with 214234G and 22504C of SLC18A2 promoter region represent a protective factor against alcoholism (P 5 0.0038 by Fisher’s exact tests)
For 13 of the individuals, we obtained complete genotype data, providing 95% power to detect polymorphisms of 11% frequency and 74% power to detect polymorphisms of 5% frequency. These sequences appeared to be overlapped by another gene(s), because six different expressed sequence tags (ESTs) of unknown function have homology to this genomic region (Fig. 1)
Summary
The vesicular monoamine transporter 2 (VMAT2) is an important molecule for the function of monoaminergic neurons that are key participants in locomotion, reward and mnemonic brain systems. Levels of VMAT2 expression help determine the efficacy of spatio-temporal buffering of intracellular monoamines and minimize the degree of neurotoxicity. Expression of VMAT2 displays a distinct tissue pattern. VMAT2-reactive immunostaining is only seen in central, peripheral and enteric neurons [1]. VMAT2 is expressed only in certain regions such as nigra compacta, hypothalamus, ventral tegmental area (VTA), subventricular zone cells and olfactory bulb (2 –4). VMAT2 is expressed in monoaminergic and histaminergic neurons. Within VTA, VMAT2 expression level is different from subdivision to subdivision [5]. The regulatory mechanisms underlying these tissue-specific expression patterns are unknown
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