Rosskopf D, Busch S, Manthey I, Siffert W
Institut für Pharmakologie Universitätsklinikum Essen, Essen, Germany.
Hypertension. 2000 Jul;36(1):33-41. doi: 10.1161/01.hyp.36.1.33.
Recent studies have shown that a polymorphism (C825T) in the gene encoding the G protein beta 3 subunit (GNB3) is associated with hypertension and obesity. We characterized the entire GNB3 gene, which spans 7.5 kb and is composed of 11 exons and 10 introns. Its promoter lacks a TATA box but harbors GC-rich regions. The functional activity of the GNB3 promoter was verified with reporter gene assays that also demonstrated its inducibility by phorbol esters. A novel polymorphism in the promoter region A(-350)G occurred with frequencies (G allele) of 76%, 97%, and 61% in Africans, Chinese, and Germans, respectively. Reporter gene constructs with either the A or the G allele did not differ with regard to inducement of the reporter protein. A silent nucleotide exchange in the coding region (A657T) occurred with T allele frequencies ranging from 0.5% to 2.4%. Another polymorphism (G814A) results in the replacement of glycine by serine at position 272. In Germans, the A allele occurred at a frequency of 10%. Finally, a C1429T polymorphism in the 3' untranslated region of GNB3 was identified that occurred at T allele frequencies of 38%, 17%, and 30% in Africans, Chinese, and Germans, respectively. Haplotype prediction indicated in Germans an almost complete association of GNB3 825T with 1429T, and vice versa. An analysis of these polymorphic loci in nonhuman primates revealed that the ancestral GNB3 gene harbored the (-350)G, 825C, and 1429C alleles. This is the first complete characterization of the human GNB3 gene and its promoter region, which will enable refined epidemiological and biochemical investigations of GNB3 in hypertension and obesity.
近期研究表明，编码G蛋白β3亚基（GNB3）的基因中的一种多态性（C825T）与高血压和肥胖症相关。我们对整个GNB3基因进行了特征分析，该基因跨度为7.5 kb，由11个外显子和10个内含子组成。其启动子缺乏TATA框，但含有富含GC的区域。通过报告基因检测验证了GNB3启动子的功能活性，该检测还证明了其可被佛波酯诱导。启动子区域A（-350）G出现了一种新型多态性，在非洲人、中国人和德国人中的频率（G等位基因）分别为76%、97%和61%。携带A或G等位基因的报告基因构建体在报告蛋白诱导方面没有差异。编码区域发生了一个沉默核苷酸交换（A657T），T等位基因频率在0.5%至2.4%之间。另一种多态性（G814A）导致第272位的甘氨酸被丝氨酸取代。在德国人中，A等位基因的出现频率为10%。最后，在GNB3的3'非翻译区鉴定出一种C1429T多态性，在非洲人、中国人和德国人中的T等位基因频率分别为38%、17%和30%。单倍型预测表明，在德国人中，GNB3 825T与1429T几乎完全关联，反之亦然。对非人类灵长类动物中这些多态性位点的分析表明，祖先GNB3基因携带（-350）G、825C和1429C等位基因。这是对人类GNB3基因及其启动子区域的首次完整特征分析，这将有助于对GNB3在高血压和肥胖症中的流行病学和生化研究进行细化。
