BBAMBD：Leber遗传性视神经病变突变可引发高血压

高血压病是严重危害人类健康的常见疾病，全世界的患病人数已接近10亿，每年有接近760万的患者死于该病。我国每年用于治疗高血压的医疗费高达360多亿元。因此，高血压病是全球亟待解决的重大公共卫生问题和社会问题。母系遗传性高血压病（maternally inherited essential hypertension，MIEH）是在临床工作中观察到的高血压病的一种遗传模式，线粒体DNA (mtDNA)突变在其发病过程中可能起到重要的作用，但具体发病机制尚未完全明确。

近期，博士后郭皓和庄馨瑛博士等在姚永刚研究员的指导下，对来自云南的一个母系遗传性高血压病家系进行了深入研究。他们在先证者及其母系成员中发现了Leber遗传性视神经病变（LHON）的原发性突变m.14484T>C，但该家系成员未表现出任何LHON临床症状如急性或亚急性视力下降或丧失，高血压是该家系中唯一外显的临床表型，提示m.14484T>C突变在该家系中表现出疾病的异质性。进一步对mtDNA基因组进行测定，未能发现其他潜在的致病突变。含有m.14484T>C突变的母系成员大动脉硬化程度均比不含有该突变的非母系成员严重。临床资料分析显示，年龄、性别、吸烟、动态血压水平、高血糖、高血脂等加速动脉硬化的因子在母系成员和非母系成员中无显著性差异，因此遗传因素是导致母系成员动脉硬化的重要原因。对含有m.14484T>C突变的母系成员永生化淋巴细胞株进行的细胞功能测定显示，线粒体呼吸率和线粒体膜电势均较正常人永生化淋巴细胞株显著性下降，胞内氧化自由基水平增高，并且含m.14484T>C突变的细胞株线粒体质量出现代偿性增高。他们的研究结果表明，视神经病变突变原发突变m.14484T>C在一定情况下可以导致高血压病的发生，对LHON患者有必要开展常规血压测量、动脉硬化检查等心血管评价。他们的结果也显示了mtDNA突变致病的复杂性。该研究为今后临床进行母系遗传性高血压病的遗传咨询、阐明其发病机制提供了新的参考和依据，近期在线发表于国际知名期刊Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease。

该研究工作得到国家自然科学基金委、云南省和中国科学院的资助。

doi:10.1016/j.bbadis.2012.06.010
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Presence of mutation m.14484T>C in a Chinese family with maternally inherited essential hypertension but no expression of LHON

Hao Guoa, b, 1, Xin-Ying Zhuanga, 1, A-Mei Zhanga, Wen Zhanga, c, Yong Yuand, Li Guod, Dan-Dan Yua, Juan Liud, Da-Kuan Yangd, Yong-Gang Yaoa, ,

Essential hypertension (EH, MIM 145500) is the most common cardiovascular disease and affects one-quarter of the world's adult population. Families with EH in a mode of maternal transmission have been occasionally observed in clinical settings and suggested an involvement of mitochondrial DNA (mtDNA) mutation. We aimed to characterize the role of mtDNA mutation in EH. We reported a large Han Chinese family with a maternally inherited EH and an extraordinarily high percentage of sudden death mainly in affected females. Analysis of the entire mtDNA genome of the proband identified a homoplasmic primary mutation m.14484T>C for Leber's hereditary optic neuropathy (LHON), along with several variants indicating haplogroup F1 status. Intriguingly, no maternal member in this family had LHON though they all harbored m.14484T>C. The arterial stiffness of the members carrying mutation m.14484T>C was significantly increased than that of non-maternal members without this mutation. No environmental factor (including age, sex, smoking, diabetes, hyperlipidemia) was correlated with the decreased aortic elastic properties observed in affected members. Mitochondrial respiration rate and membrane potential (ΔΨm) were significantly reduced in lymphoblastoid cell lines established from affected members carrying m.14484T>C when compared to control cell lines (P < 0.05). There was an elevation of reactive oxygen species and a compensatory increase of mitochondrial mass in mutant cell lines. Our results suggest that m.14484T>C causes EH under certain circumstance. This study provides a paradigm for diverse phenotypes of the primary LHON mutation and suggests for the necessity of routine cardiac evaluation in patients with the primary LHON mutation.