Siffert W, Rosskopf D, Siffert G, Busch S, Moritz A, Erbel R, Sharma A M, Ritz E, Wichmann H E, Jakobs K H, Horsthemke B
Institut für Pharmakologie, Universitätsklinikum Essen, Germany.
Nat Genet. 1998 Jan;18(1):45-8. doi: 10.1038/ng0198-45.
Hypertension is a common disorder of multifactorial origin that constitutes a major risk factor for cardiovascular events such as stroke and myocardial infarction. Previous studies demonstrated an enhanced signal transduction via pertussis toxin-sensitive G proteins in lymphoblasts and fibroblasts from selected patients with essential hypertension. We have detected a novel polymorphism (C825T) in exon 10 of the gene encoding the beta3 subunit of heterotrimeric G proteins (GNB3). The T allele is associated with the occurrence of a splice variant, GNB3-s (encoding G beta3-s), in which the nucleotides 498-620 of exon 9 are deleted. This in-frame deletion causes the loss of 41 amino acids and one WD repeat domain of the G beta subunit. By western-blot analysis, G beta3-s appears to be predominantly expressed in cells from individuals carrying the T allele. Significant enhancement of stimulated GTPgammaS binding to Sf9 insect cells expressing G beta3-s together with G alpha(i)2 and G gamma5 indicates that this splice variant is biologically active. Genotype analysis of 427 normotensive and 426 hypertensive subjects suggests a significant association of the T allele with essential hypertension.
高血压是一种多因素起源的常见病症，是中风和心肌梗死等心血管事件的主要危险因素。先前的研究表明，在部分原发性高血压患者的淋巴细胞和成纤维细胞中，通过百日咳毒素敏感的G蛋白的信号转导增强。我们在编码异三聚体G蛋白（GNB3）β3亚基的基因第10外显子中检测到一种新的多态性（C825T）。T等位基因与一种剪接变体GNB3-s（编码Gβ3-s）的出现相关，其中第9外显子的核苷酸498-620缺失。这种框内缺失导致Gβ亚基的41个氨基酸和一个WD重复结构域丢失。通过蛋白质印迹分析，Gβ3-s似乎主要在携带T等位基因的个体的细胞中表达。刺激的GTPγS与表达Gβ3-s以及Gα（i）2和Gγ5的Sf9昆虫细胞结合显著增强，表明这种剪接变体具有生物活性。对427名血压正常者和426名高血压患者的基因型分析表明，T等位基因与原发性高血压存在显著关联。
