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Functional Analysis of Upstream Common Polymorphisms of the Dopamine Transporter Gene

机译：多巴胺转运蛋白基因上游常见多态性的功能分析

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The human dopamine transporter (DAT, SLC6A3) has been extensively investigated because of its potential involvement in neuropsychiatric disorders. The core elements responsible for its transcription have been identified. A regulatory role for certain genomic variants upstream to the core promoter is known. Recently, other single-nucleotide polymorphisms (SNPs) have been identified in this region and are thought to be associated with schizophrenia and bipolar I disorder. Hence, we have investigated the impact of common SNPs in a 2.8-kilobase region flanking the core promoter region (−2.7 to +63 base pair) in the neuroblastoma cell line SH-SY5Y. Haplotypes generated by site-directed mutagenesis revealed varying impact of individual SNPs on promoter activity using dual luciferase assays. In silico analyses also predicted allele-specific binding of transcription factors for some of these SNPs. Though electrophoretic mobility shift assays indicated several factors that appeared to bind to specific sites within this region, allele-specific binding was not detected for any SNP apart from rs3756450. We have thus identified novel putative regulatory domains flanking the core promoter of DAT that merit further investigation.
机译：人多巴胺转运蛋白（DAT，SLC6A3）已被广泛研究，因为它可能参与神经精神疾病。已经确定了负责其转录的核心元素。核心启动子上游的某些基因组变体的调节作用是已知的。最近，在该区域还发现了其他单核苷酸多态性（SNP），并被认为与精神分裂症和双相性I障碍有关。因此，我们研究了成神经细胞瘤细胞系SH-SY5Y中位于核心启动子区域（-2.7至+63个碱基对）的2.8碱基对区域中常见SNP的影响。通过定点诱变产生的单倍型显示了使用双重荧光素酶测定的单个SNP对启动子活性的不同影响。在计算机分析中还预测了其中一些SNP的转录因子的等位基因特异性结合。尽管电泳迁移率迁移分析表明有几个因素似乎与该区域内的特定位点结合，但除rs3756450外，未检测到任何SNP的等位基因特异性结合。因此，我们已经确定了在DAT核心启动子侧翼的新型推定调控域，值得进一步研究。

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  • 来源
    《Schizophrenia Bulletin》 |2010年第5期|p.977-982|共6页
  • 作者

    Vishwajit L. Nimgaonkar;

  • 作者单位

    Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine and Graduate School of Public Health, Room 441, 3811 O'Hara Street, Pittsburgh, PA 15213;

    tel: 412-246-6353, 1-877 363 5895,;

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