Failures in mitochondrial tRNAMet and tRNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese Family.
Failures in mitochondrial tRNAMet and tRNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese Family.
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DOI：
10.1161/hypertensionaha.109.129270
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发表时间：
2009-08
期刊：
影响因子：
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通讯作者：
Guan MX
中科院分区：
文献类型：
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作者：
Li R;Liu Y;Li Z;Yang L;Wang S;Guan MX
我们报告了1个汉族母系遗传高血压的临床、遗传和分子特征。在这个4代人的家族中，7个母系亲属中有3个在发病年龄(35-60岁)时表现出不同程度的高血压。对该家系线粒体DNA全序列进行分析，发现了位于tRNAMet和tRNAGln基因5‘端间隔区的新的同源突变4401a和gt；G，以及属于亚洲单倍群C的39个变异。在携带4401a和gt；G突变的2个淋巴母细胞系中观察到tRNAMet和tRNAGln的稳态水平比没有该突变的2个对照细胞系降低了约30%。线粒体代谢障碍显然是携带4401a>；G突变的淋巴母细胞系线粒体转换率降低和总呼吸能力降低的主要原因，包括苹果酸/谷氨酸促进的呼吸、琥珀酸/甘油-3-磷酸促进的呼吸或N，N，N‘，N′-tetramethyl-p-phenylenediamine/ascorbate-promoted呼吸。在这个家系中，高血压的同质性形式、轻微的生化缺陷、起病晚、外显性不完全表明，4401A>；G突变本身不足以产生临床表型。因此，其他修饰因素，如核修饰基因以及环境和个人因素，也可能有助于这些携带该突变的受试者发生高血压。这些数据表明，线粒体功能障碍，由4401a和gt；G突变引起，参与了这个中国家系高血压的发展。
We report here on the clinical, genetic, and molecular characterization of 1 Han Chinese family with maternally transmitted hypertension. Three of 7 matrilineal relatives in this 4-generation family exhibited the variable degree of essential hypertension at the age at onset, ranging from 35 to 60 years old. Sequence analysis of the complete mitochondrial DNA in this pedigree identified the novel homoplasmic 4401A>G mutation localizing at the spacer immediately to the 5′ end of tRNAMet and tRNAGln genes and 39 other variants belonging to the Asian haplogroup C. The 4401A>G mutation was absent in 242 Han Chinese controls. Approximately 30% reductions in the steady-state levels of tRNAMet and tRNAGln were observed in 2 lymphoblastoid cell lines carrying the 4401A>G mutation compared with 2 control cell lines lacking this mutation. Failures in mitochondrial metabolism are apparently a primary contributor to the reduced rate of mitochondrial translation and reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate–promoted respiration, or N,N,N′,N′-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration in lymphoblastoid cell lines carrying the 4401A>G mutation. The homoplasmic form, mild biochemical defect, late onset, and incomplete penetrance of hypertension in this family suggest that the 4401A>G mutation itself is insufficient to produce a clinical phenotype. Thus, the other modifier factors, eg, nuclear modifier genes and environmental and personal factors, may also contribute to the development of hypertension in these subjects carrying this mutation. These data suggest that mitochondrial dysfunctions, caused by the 4401A>G mutation, are involved in the development of hypertension in this Chinese pedigree.