两个携带线粒体tRNAMet/tRNAGlnA4401G和tRNACysG5821A突变的中国汉族原发性高血压家系的临床及分子遗传学特征
收稿日期: 2013-09-16
修回日期: 2013-11-12
网络出版日期: 2014-01-25
基金资助
国家自然科学基金项目(编号：81070794, 30971600), 国家青年科学基金项目(编号：31100903), 浙江省自然科学基金项目(编号：Y2110399), 温州市瓯海区科技计划项目(编号：2011XM047), 温州市瓯海区科技局社会发展科学研究项目(编号：20120177)和浙江省大学生科技创新活动计划(新苗人才计划)项目(编号：2013R413045)资助
The mitochondrial tRNAMet/tRNAGlnA4401G and tRNACysG5821A mutations may be associated with hypertension in two Han Chinese families
Received date: 2013-09-16
Revised date: 2013-11-12
Online published: 2014-01-25
线粒体tRNA基因可能是原发性高血压发病相关的突变热点区域。文章报道了两个具有母系遗传特征的中国汉族原发性高血压家系的临床和分子遗传学特征。家系先证者和其他成员的临床数据表明, 家系中母系成员高血压发病的严重程度存在差异, 发病年龄也从36~79岁不等。对两个家系先证者使用24对有部分重叠的引物进行线粒体DNA全序列扩增分析, 结果发现这两个先证者均携带同质性的tRNAMet/tRNAGlnA4401G和tRNACysG5821A突变, 多态性变异位点都属于东亚单体型C。A4401G突变可能通过影响tRNAMet和tRNAGln前体的加工引起线粒体tRNA代谢水平的改变, 而tRNACysG5821A突变位于tRNACys氨基酸受体臂, 该突变使tRNACys氨基酸受体臂上原有的G6-C67配对消失, 可能影响tRNACys空间结构和功能的稳定性, 致使线粒体功能障碍。因此, tRNAMet/tRNAGlnA4401G和tRNACysG5821A突变可能是这两个原发性高血压家系的分子致病 基础。
许美芬, 何轶群, 耿军伟, 孟燕子, 于涵, 林枝, 施苏雪, 薛凌, 卢中秋, 管敏鑫 . 两个携带线粒体tRNAMet/tRNAGlnA4401G和tRNACysG5821A突变的中国汉族原发性高血压家系的临床及分子遗传学特征[J]. 遗传, 2014 , 36(2) : 127 -134 . DOI: 10.3724/SP.J.1005.2014.0127
Mitochondrial tRNA genes are the hot spots for mutations associated with essential hypertension. We report here the clinical and molecular genetic characterization of two Han Chinese pedigrees with materially inherited essential hypertension. Clinical evaluation revealed the variable severity and age-at-onset of hypertension among matrilineal relatives. In particular, the age-at-onset of hypertension in the maternal kindred ranged from 36 years to 79 years. The sequence analysis of entire mitochondrial genome in two probands showed that two probands carried the identical homoplasmic tRNAMet/tRNAGlnA4401G and tRNACysG5821A mutations and distinct sets of polymorphisms belonging to East Asian haplogroup C. The A4401G mutation may affect the processing of the precursors of tRNAMet and tRNAGln , thereby altering the tRNA metabolism. The tRNACys G5821A mutation is located in the acceptor stem of tRNACys. This mutation may abol-ish the predicted G6-C67 pairing and consequently affect the structure and stability of mitochondrial tRNACys, thereby leading to mitochondrial dysfunction. Therefore, these data suggested that the tRNAMet/tRNAGlnA4401G and tRNACys G5821A mutations are likely associated with essential hypertension in these two Chinese pedigrees.
Key words： essential hypertension; mitochondrial DNA; mutation; haplotype
[1] Chalmers J, MacMahon S, Mancia G, Whitworth J, Beilin L, Hansson L, Neal B, Rodgers A, Ni Mhurchu C, Clark T. 1999 World Health Organization-International Society of Hypertension Guidelines for the management of hyperten-sion. Guidelines sub-committee of the World Health Or-ganization. Clin Exp Hypertens, 1999, 21(5?6): 1009?1060. <\p>
[2] Gu D, Reynolds K, Wu X, Chen J, Duan X, Muntner P, Huang G, Reynolds RF, Su S, Whelton PK, He J. Prevalence, awareness, treatment, and control of hyperten¬sion in China. Hypertension, 2002, 40(6): 920–927. <\p>
[3] 李宗斌, 刘昱圻, 李彦华, 陈瑞, 王琳, 朱庆磊, 李泱, 王士雯. 中国汉族原发性高血压患者线粒体tRNAMet基因突变. 遗传, 2011, 33(6): 601–606. <\p>
[4] Fuentes RM, Notkola IL, Shemeikka S, Tuomilehto J, Nissinen A. Familial aggregation of blood pressure: a population-based family study in eastern Finland. J Hum Hypertens, 2000, 14(7): 441–445. <\p>
[5] Wang S, Li R, Fettermann A, Li Z, Qian Y, Liu Y, Wang X, Zhou A, Mo JQ, Yang L, Jiang P, Taschner A, Rossmanith W, Guan MX. Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mi-tochondrial tRNAIle gene in a large Han Chinese family. Circ Res, 2011, 108(7): 862–870. <\p>
[6] Wilson FH, Hariri A, Farhi A, Zhao HY, Petersen KF, Toka HR, Nelson-Williams C, Raja KM, Kashgarian M, Shul- man GI, Scheinman SJ, Lifton RP. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science, 2004, 306(5699): 1190–1194. <\p>
[7] Merante F, Myint T, Tein I, Benson L, Robinson BH. An additional mitochondrial tRNA(Ile) point mutation (A-to-G at nucleotide 4295) causing hypertrophic cardiomyopathy. Hum Mutat, 1996, 8(3): 216–222. <\p>
[8] Li RH, Liu YQ, Li ZB, Yang L, Wang SW, Guan MX. Failures in mitochondrial tRNAMet and tRNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese Family. Hypertension, 2009, 54(2): 329–337. <\p>
[9] Liu YQ, Li RH, Li ZB, Wang XJ, Yang L, Wang SW, Guan MX. Mitochondrial transfer RNAMet4435A>G mutation is associated with maternally inherited hypertension in a Chinese pedigree. Hypertension, 2009, 53(6): 1083–1090. <\p>
[10] Li R, Greinwald JH Jr, Yang L, Choo DI, Wenstrup RJ, Guan MX. Molecular analysis of the mitochondrial 12S rRNA and tRNASer(UCN)genes in paediatric subjects with non-syndromic hearing loss. J Med Genet, 2004, 41(8): 615–620. <\p>
[11] Rieder MJ, Taylor SL, Tobe VO, Nickerson DA. Automating the identification of DNA variations using quality based fluorescence re-sequencing: analysis of the human mitochondrial genome. Nucleic Acids Res, 1998, 26(4): 967–973. <\p>
[12] Andrews RM, Kubacka I, Chinnery PF, Lightowlers RN, Turnbull DM, Howell N. Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA. Nat Genet, 1999, 23(2): 147. <\p>
[13] Ruiz-Pesini E, Wallace DC. Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA. Hum Mutat, 2006, 27(11): 1072–1081. <\p>
[14] Lu JX, Li ZY, Zhu Y, Yang AF, Li RH, Zheng J, Cai Q, Peng GH, Zheng WW, Tang XW, Chen BB, Chen JF, Liao ZS, Yang L, Li YY, You JY, Ding Y, Yu H, Wang JD, SunDM, Zhao JY, Xue L, Wang JY, Guan MX. Mitochondrial 12S rRNA variants in 1642 Han Chinese pediatric subjects with aminoglycoside-induced and nonsyndromic hearing loss. Mitochondrion, 2010, 10(4): 380–390. <\p>
[15] Kong QP, Bandelt HJ, Sun C, Yao YG, Salas A, Achilli A, Wang CY, Zhong L, Zhu CL, Wu SF, Torroni A, Zhang YP. Updating the East Asian mtDNA phylogeny: a prerequisite for the identification of pathogenic mutations. Hum Mol Genet, 2006, 15(13): 2076–2086. <\p>
[16] 薛凌, 陈红, 孟燕子, 王燕, 卢中秋, 吕建新, 管敏鑫. 高血压相关的线粒体DNA突变. 遗传, 2011, 33(9): 911–918. <
/
| 〈 |
|
〉 |
www.chinagene.cn
备案号：京ICP备09063187号-4
总访问:,今日访问:,当前在线:
