Liu Yuqi, Li Ronghua, Li Zongbin, Wang Xin-Jian, Yang Li, Wang Shiwen, Guan Min-Xin
Institute of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing, China.
Hypertension. 2009 Jun;53(6):1083-90. doi: 10.1161/HYPERTENSIONAHA.109.128702. Epub 2009 Apr 27.
Mitochondrial DNA mutations have been associated with cardiovascular disease. We report here the clinical, genetic, and molecular characterization of 1 Han Chinese family with suggestively maternally transmitted hypertension. Matrilineal relatives in this family exhibited the variable degree of hypertension at the age at onset of 44 to 55 years old. Sequence analysis of entire mitochondrial DNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located immediately at the 3 prime end to the anticodon, corresponding with the conventional position 37 of tRNA(Met), and 35 other variants belonging to the Asian haplogroup B5a. The adenine (A37) at this position of tRNA(Met) is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition, the structural formation, and stabilization of functional tRNAs. In fact, a 40% reduction in the levels of tRNA(Met) was observed in cells carrying the 4435A>G mutation. As a result, a failure in mitochondrial tRNA metabolism, caused by the 4435A>G mutation, led to approximately 30% reduction in the rate of mitochondrial translation. However, the homoplasmic form, mild biochemical defect, and late onset of hypertension in subjects carrying the 4435A>G mutation suggest that the 4435A>G mutation itself is insufficient to produce a clinical phenotype. The other modifier factors, such as nuclear modifier genes, environmental, and personal factors may also contribute to the development of hypertension in the subjects carrying this mutation. Our findings imply that the 4435A>G mutation may act as an inherited risk factor for the development of hypertension in this Chinese pedigree.
线粒体DNA突变与心血管疾病有关。我们在此报告1个具有提示性母系遗传高血压的汉族家庭的临床、遗传和分子特征。该家族中的母系亲属在44至55岁发病时表现出不同程度的高血压。对这个家系的整个线粒体DNA进行序列分析，鉴定出已知的纯合4435A>G突变，该突变位于反密码子的3'末端紧邻处，对应于tRNA(Met)的传统位置37，以及属于亚洲单倍群B5a的其他35个变异。tRNA(Met)这个位置的腺嘌呤（A37）从细菌到人类线粒体都异常保守。这种修饰后的A37被证明有助于密码子识别的高保真度、功能性tRNA的结构形成和稳定。事实上，在携带4435A>G突变的细胞中观察到tRNA(Met)水平降低了40%。因此，由4435A>G突变导致的线粒体tRNA代谢失败，使线粒体翻译速率降低了约30%。然而，携带4435A>G突变的个体中纯合形式、轻度生化缺陷和高血压的晚发表明，4435A>G突变本身不足以产生临床表型。其他修饰因素，如核修饰基因、环境和个人因素，也可能导致携带这种突变的个体发生高血压。我们的研究结果表明，4435A>G突变可能是这个中国家系中高血压发生的一个遗传风险因素。
