Mitochondrial transfer RNAMet 4435A>G mutation is associated with maternally inherited hypertension in a Chinese pedigree.
Mitochondrial transfer RNAMet 4435A>G mutation is associated with maternally inherited hypertension in a Chinese pedigree.
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DOI：
10.1161/hypertensionaha.109.128702
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发表时间：
2009-06
期刊：
影响因子：
--
通讯作者：
Guan MX
中科院分区：
文献类型：
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作者：
Liu Y;Li R;Li Z;Wang XJ;Yang L;Wang S;Guan MX
线粒体DNA突变与心血管疾病有关。我们在此报告1个汉族家族的临床、遗传和分子特征，提示母传高血压。本家族母系亲属在44 ~ 55岁发病时表现出不同程度的高血压。对该家系的全线粒体DNA进行序列分析，发现了已知的同源4435A>G突变，该突变位于反密码子的3 '端，与tRNAMet的传统位置37相对应，另外35个突变属于亚洲单倍群B5a。tRNAMet这个位置的腺嘌呤（A37）从细菌到人类线粒体都是非常保守的。经过修饰的A37有助于高保真的密码子识别、结构形成和功能性trna的稳定。事实上，在携带4435A >g突变的细胞中观察到tRNAMet水平降低了40%。因此，4435A>G突变导致线粒体tRNA代谢失败，导致线粒体翻译率降低约30%。然而，携带4435A>G突变的受试者的同质形式、轻度生化缺陷和晚发性高血压表明，4435A>G突变本身不足以产生临床表型。其他修饰因子，如核修饰基因、环境和个人因素也可能导致携带该突变的受试者发生高血压。我们的研究结果表明，4435A >g突变可能是该中国家系高血压发生的遗传危险因素。
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 tRNAMet, and 35 other variants belonging to the Asian haplogroup B5a. The adenine (A37) at this position of tRNAMet 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 tRNAMet 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 ≈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.