Kereszturi Eva, Király Orsolya, Csapó Zsolt, Tárnok Zsanett, Gádoros Júlia, Sasvári-Székely Mária, Nemoda Zsófia
Semmelweis Egyetem, Orvosi Vegytani, Molekuláris Biológiai és Pathobiokémiai Intézet, Budapest.
Neuropsychopharmacol Hung. 2007 Mar;9(1):11-8.
The human dopamine D4 receptor (DRD4) gene has been extensively studied as a candidate gene for attention deficit hyperactivity disorder (ADHD). Both the 5' regulatory region and the coding sequence contain a number of polymorphisms. The most widely investigated polymorphism of the DRD4 gene is the 48 bp VNTR (Variable Number of Tandem Repeats) in the third exon. The promoter variants have received particular attention in the past few years due to their possible role in the regulation of gene expression. In this study we describe an association analysis of the 120 bp duplication and three sequence variations (SNPs, Single Nucleotide Polymorphism; -616 C/G, -615 A/G, -521 C/T) in the 5' region of the DRD4 gene is presented among children with ADHD. In case-control approach, the 1-repeat form of the 120 bp duplication had a significantly higher frequency among ADHD children than controls, both in allele-(p=0.047), and genotype (p=0.019) distributions. There was no significant difference between the ADHD and control groups in the allele or genotype frequencies of the investigated SNPs. The transcriptional effect of the 120 bp duplication was analysed in luciferase reporter system. The different 120 bp duplication alleles (1-repeat, 2-repeat and the newly identified 4-repeat allele) was found to have an effect on transcriptional activity of the DRD4 gene in both neuroblastoma and retinoblastoma cell lines in a dose-dependent manner. The higher was the repeat number of the 120 bp sequence in the promoter, the stronger was the decrease of the gene transcription (1-repeat > 2-repeat > 4-repeat; p<0.01). These results of association and functional analyses suggest that the 1-repeat form of the 120 bp duplication might be a risk factor of ADHD.
人类多巴胺D4受体（DRD4）基因作为注意力缺陷多动障碍（ADHD）的候选基因已被广泛研究。其5'调控区和编码序列均包含许多多态性。DRD4基因研究最广泛的多态性是第三外显子中的48 bp可变串联重复序列（VNTR）。由于启动子变体可能在基因表达调控中发挥作用，在过去几年中受到了特别关注。在本研究中，我们对ADHD儿童中DRD4基因5'区域的120 bp重复及三个序列变异（单核苷酸多态性，SNP；-616 C/G、-615 A/G、-521 C/T）进行了关联分析。在病例对照研究中，120 bp重复的1重复形式在ADHD儿童中的等位基因频率（p=0.047）和基因型频率（p=0.019）分布均显著高于对照组。所研究SNP的等位基因或基因型频率在ADHD组和对照组之间无显著差异。在荧光素酶报告系统中分析了120 bp重复的转录效应。发现在神经母细胞瘤和视网膜母细胞瘤细胞系中，不同的120 bp重复等位基因（1重复、2重复和新发现的4重复等位基因）对DRD4基因的转录活性有剂量依赖性影响。启动子中120 bp序列的重复数越高，基因转录的降低越强（1重复>2重复>4重复；p<0.01）。这些关联和功能分析结果表明，120 bp重复的1重复形式可能是ADHD的一个危险因素。
