Sequence variation in the 3′-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD)
Sequence variation in the 3′-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD)
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DOI：
10.1002/ajmg.b.30190
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发表时间：
2005-11-05
影响因子：
2.8
通讯作者：
Barr, CL
中科院分区：
文献类型：
--
作者：
Feng, Y;Wigg, KG;Barr, CL
多巴胺转运蛋白基因（DATP）已被报道与注意缺陷多动障碍（ADHD）有关[Cook et al. (1995): Am J Human gene 56(4):9993-998；Gill et al. (1997): Mol Psychiatry 2(4):311-313；Waldman et al. (1998): Am J Human Genet 63(6):1767-1776；Barr et al.(2001)：生物精神病学49(4):333-339；Curran et al. (2001): Mol Psychiatry 6(4):425-428；Chen et . (2003): Mol Psychiatry 8(4):393-396。具体而言，位于该基因3'非翻译区（UTR）的40 bp可变串联重复数（VNTR）多态性的10个重复等位基因已被发现与ADHD相关。体外研究证据表明，DAT1基因3'-UTR重复数的变异和序列变异可能影响多巴胺转运蛋白的水平[Fuke等人（2001）：Pharmacogenomics J 1(2):152-156；Miller and Madras (2002): Mol Psychiatry 7(1):44-55。在这项研究中，我们通过对178个ADHD家庭样本中VNTR区域周围的DNA变异进行基因分型，研究了DAT1 3'UTR的DNA变异是否导致了ADHD。这些包括Mspl多态性（rs27072），据报道影响DAT1表达水平的DraI DNA变化（T/C），以及除VNTR外的BstUI多态性（rs3863145）。我们还通过直接重测序筛选了VNTR区域，以确定重复单元内是否存在可能导致这种关联的序列变异。我们的研究结果表明，在我们的样本中，DAT1与ADHD有关，但与VNTR多态性的等位基因无关。在筛选的先证物中，我们没有发现10或9重复等位基因序列的任何变化，也没有观察到报道的DraI （T/C）变化。因此，我们的研究结果驳斥了报道的DraI变异或VNTR等位基因作为导致该疾病的功能变异的可能性。(c) 2005 Wiley-Liss, Inc。
The dopamine transporter gene (DATP has been reported to be associated with attention-deficit hyperactivity disorder (ADHD) in a number of studies [Cook et al. (1995): Am J Human Genet 56(4):9993-998; Gill et al. (1997): Mol Psychiatry 2(4):311-313; Waldman et al. (1998): Am J Human Genet 63(6):1767-1776; Barr et al. (2001): Biol Psychiatry 49(4):333-339; Curran et al. (2001): Mol Psychiatry 6(4):425-428; Chen et al. (2003): Mol Psychiatry 8(4):393-396]. Specifically, the 10-repeat allele of the 40-bp variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region (UTR) of the gene has been found to be associated with ADHD. There is evidence from in vitro studies indicating that variability in the repeat number, and sequence variation in the 3'-UTR of the DAT1 gene may influence the level of the dopamine transporter protein [Fuke et al. (2001): Pharmacogenomics J 1(2):152-156; Miller and Madras (2002): Mol Psychiatry 7(l):44-55]. In this study, we investigated whether DNA variation in the DAT1 3'UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. These included a Mspl polymorphism (rs27072), a DraI DNA change (T/C) reported to influence DAT1 expression levels, and a BstUI polymorphism (rs3863145) in addition to the VNTR. We also screened the VNTR region by direct resequencing to determine if there was sequence variation within the repeat units that could account for the association. Our results indicate that DAT1 is associated with ADHD in our sample but not with alleles of the VNTR polymorphism. We did not find any variation in the sequence for either the 10- or 9-repeat alleles in the probands screened nor did we observe the reported DraI (T/C) variation. Our results therefore refute the possibility of the reported DraI variation or alleles of the VNTR as the functional variants contributing to the disorder. (c) 2005 Wiley-Liss, Inc.