三个携带线粒体DNAtRNA~(Gln)4363T>C突变的中国汉族原发性高血压家系临床及遗传特征分析
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摘要
目的:通过对3个携带tRNAGln 4363T>C突变的原发性高血压家系进行临床、遗传和分子特征分析评估,探讨线粒体tRNAGln 4363T>C突变在母系遗传原发性高血压发生发展中的作用。方法:PCR扩增848例原发性高血压患者和254例正常对照样本线粒体tRNA基因,对携带t RNAGln 4363T>C突变的3个家系进行家系及线粒体基因相关分析。结果:共发现3例患者携带tRNAGln 4363T>C突变,突变率为0.35%,患者家系中共有母系成员28位,其中12位患有不同程度的高血压,发病年龄从27到64岁,平均发病年龄为44岁,有1位非母系成员患病,母系成员中男性患者的后代均未表现出发病。3位先证者的线粒体基因全序列分析结果显示,除同质性tRNAGln 4363T>C突变外,还有64个多态性位点,分别属于东亚线粒体单体型Z3、Z3和B4d。tRNAGln 4363T位点在进化上高度保守,该位点对应tRNAGln二级结构反密码子环的A38位,tRNAGln4363T>C突变可能影响此位点与反密码子识别功能的高保真性和正常t RNA结构的形成及结构的稳定性。结论:3个携带tRNAGln 4363T>C突变的中国汉族原发性高血压家系母系遗传特征明显,线粒体tRNAGln 4363T>C突变可能是这3个原发性高血压家系发病的主要分子基础。3个携带线粒体tRNAGln 4363T>C突变的原发性高血压家系表现出的同质性突变、发病年龄及外显率不同等表型差异特征提示核修饰基因、环境因素和线粒体遗传背景等可能对tRNAGln 4363T>C突变家系原发性高血压的表型表达有一定的影响。
Objective: To analyze and evaluate the clinical, genetic and molecular characteristics of mt DNA in three Han Chinese pedigrees with essential hypertension and explore the role of tRNAGln 4363T>C mutation in the development of those maternally inherited essential hypertension. Method: Mitochondrial tRNA gene of 848 Chinese Han essential hypertension subjects and 254 control subjects were amplified with PCR. Members of 3 Chinese Han pedigrees with mitochondrial tRNAGln 4363T>C mutation underwent mitochondrial DNA genetic analysis and pedigree assessment. Result: Three essential hypertension subjects were found with tRNAGln4363T>C mutation, and with variable severity and age-of-onset in hypertension among the three pedigrees. The percentage of this mutation was 0.35%. Twelve of 28 matrilineal relatives in these families exhibited the variable degree of hypertension at the age at onset of 27 to 64 years old and at the average of 44 years old, while none of the offspring at affected father had hypertension. Sequence analysis of complete mitochondrial genomes in 3 pedigrees showed that, in addition to the homoplasmic 4363T>C mutation, there were also 64 other mutations, and the mt DNA polymorphisms belonged to haplogroups Z3, Z3 and B4 d, respectively. The tRNAGln 4363 T was localized at immediately 3'end to the anticodon, corresponding to highly conserved adenine at position 38 of tRNAGln, the 4363C>T mutation might affect the high fidelity of recognition and the formation and stability of normal tRNA structure. Conclusion: The occurrence of the tRNAGln 4363T>C mutation in three genetically unrelated pedigrees affected by hypertension and the absence in 254 Chinese controls strongly indicate that this mutation is associated with essential hypertension. The homoplasmic form, late onset and incomplete penetrance of hypertension observed in those Chinese pedigrees suggest that tRNAGln 4363T>C mutation may be insufficient to produce a clinical phenotype, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of essential hypertension related to tRNAGln 4363T>C mutation.
Objective: To analyze and evaluate the clinical, genetic and molecular characteristics of mt DNA in three Han Chinese pedigrees with essential hypertension and explore the role of tRNAGln 4363T>C mutation in the development of those maternally inherited essential hypertension. Method: Mitochondrial tRNA gene of 848 Chinese Han essential hypertension subjects and 254 control subjects were amplified with PCR. Members of 3 Chinese Han pedigrees with mitochondrial tRNAGln 4363T>C mutation underwent mitochondrial DNA genetic analysis and pedigree assessment. Result: Three essential hypertension subjects were found with tRNAGln4363T>C mutation, and with variable severity and age-of-onset in hypertension among the three pedigrees. The percentage of this mutation was 0.35%. Twelve of 28 matrilineal relatives in these families exhibited the variable degree of hypertension at the age at onset of 27 to 64 years old and at the average of 44 years old, while none of the offspring at affected father had hypertension. Sequence analysis of complete mitochondrial genomes in 3 pedigrees showed that, in addition to the homoplasmic 4363T>C mutation, there were also 64 other mutations, and the mt DNA polymorphisms belonged to haplogroups Z3, Z3 and B4 d, respectively. The tRNAGln 4363 T was localized at immediately 3'end to the anticodon, corresponding to highly conserved adenine at position 38 of tRNAGln, the 4363C>T mutation might affect the high fidelity of recognition and the formation and stability of normal tRNA structure. Conclusion: The occurrence of the tRNAGln 4363T>C mutation in three genetically unrelated pedigrees affected by hypertension and the absence in 254 Chinese controls strongly indicate that this mutation is associated with essential hypertension. The homoplasmic form, late onset and incomplete penetrance of hypertension observed in those Chinese pedigrees suggest that tRNAGln 4363T>C mutation may be insufficient to produce a clinical phenotype, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of essential hypertension related to tRNAGln 4363T>C mutation.
引文
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[19]Tanaka M,Cabrera VM,Gonzalez AM,et al.Mitochondrial genome variation in eastern Asia and the peopling of Japan[J].Genome Res,2004,14(10A):1832-1850.
[20]Andrews RM,Kubacka I,Chinnery PF,et al.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA[J].Nat Genet,1999,23(2):147.
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[22]Zhang M,Zhou X,Li C,et al.Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation[J].Mol Genet Metab,2010,101(2-3):192-199.
[23]Bibb MJ,Van Etten RA,Wright CT,et al.Sequence and gene organization of mouse mitochondrial DNA[J].Cell,1981,26(2 Pt 2):167-180.
[24]Gadaleta G,Pepe G,De Candia G,et al.The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome:cryptic signals revealed by comparative analysis between vertebrates[J].J Mol Evol,1989,28(6):497-516.
[25]Wong LJ,Liang MH,Kwon H,et al.Comprehensive scanning of the entire mitochondrial genome for mutations[J].Clin Chem,2002,48(11):1901-1912.
[26]Munscher C,Muller-Hocker J,Kadenbach B.Human aging is associated with various point mutations in t RNA genes of mitochondrial DNA[J].Biol Chem Hoppe Seyler,1993,374(12):1099-1104.
[27]Seibel P,Lauber J,Klopstock T,et al.Chronic progressive external ophthalmoplegia is associated with a novel mutation in the mitochondrial t RNA(Asn)gene[J].Biochem Biophys Res Commun,1994,204(2):482-489.
[28]Yoon KL,Aprille JR,Ernst SG.Mitochondrial t RNA(thr)mutation in fatal infantile respiratory enzyme deficiency[J].Biochem Biophys Res Commun,1991,176(3):1112-1115.
[29]Vasan RS,Beiser A,Seshadri S,et al.Residual lifetime risk for developing hypertension in middle-aged women and men:the framingham heart study[J].JAMA,2002,287(8):1003-1010.
[2]Lifton RP,Gharavi AG,Geller DS.Molecular mechanisms of human hypertension[J].Cell,2001,104(4):545-556.
[3]Wallace DC.Mitochondrial diseases in man and mouse[J].Science,1999,283(5407):1482-1488.
[4]Schon EA,Bonilla E,Di Mauro S.Mitochondrial DNA mutations and pathogenesis[J].J Bioenerg Biomembr,1997,29(2):131-149.
[5]Watson B Jr,Khan MA,Desmond RA,et al.Mitochondrial DNA mutations in black Americans with hypertension-associated end-stage renal disease[J].Am J Kidney Dis,2001,38(3):529-536.
[6]Lu Z,Chen H,Meng Y,et al.The t RNAMet 4435A>G mutation in the mitochondrial haplogroup G2a1 is responsible for maternally inherited hypertension in a Chinese pedigree[J].Eur J Hum Genet,2011,19(11):1181-1186.
[7]Liu Y,Li R,Li Z,et al.Mitochondrial transfer RNAMet4435A>G mutation is associated with maternally inherited hypertension in a Chinese pedigree[J].Hypertension,2009,53(6):1083-1090.
[8]Li R,Liu Y,Li Z,et al.Failures in mitochondrial t RNAMet and t RNAGln metabolism caused by the novel 4401A>G mutation are involved in essential hypertension in a Han Chinese Family[J].Hypertension,2009,54(2):329-337.
[9]Qiu QM,Li RH,Jiang PP,et al.Mitochondrial t RNA mutations are associated with maternally inherited hypertension in two Han Chinese pedigrees[J].Human Mutation,2012,33(8):1285-1293.
[10]Jia Z,Wang X,Qin Y,et al.Coronary heart disease is associated with a mutation in mitochondrial t RNA[J].Hum Mol Genet,2013,22(20):4064-4073.
[11]薛凌,陈红,孟燕子.高血压相关的线粒体DNA突变[J].遗传,2011,33(9):911-918.
[12]Gong S,Peng Y,Jiang P,et al.A deafness-associated t RNAHis mutation alters the mitochondrial function,ROS production and membrane potential[J].Nucleic Acids Res,2014,42(12):8039-8048.
[13]Postnov Iu V,Orlov SN,Budnikov E,et al.[Mitochondrial energy conversion disturbance with decrease in ATP production as a source of systemic arterial hypertension][J].Kardiologiia,2008,48(8):49-59.
[14]Dromparis P,Michelakis ED.Mitochondria in vascular health and disease[J].Annu Rev Physiol,2013,75:95-126.
[15]Sutendra G,Dromparis P,Kinnaird A,et al.Mitochondrial activation by inhibition of PDKII suppresses HIF1a signaling and angiogenesis in cancer[J].Oncogene,2013,32(13):1638-1650.
[16]Moser M.World Health Organization-International Society of hypertension guidelines for the management of hypertension-do these differ from the U.S.recommendations?Which guidelines should the practicing physician follow?[J].J Clin Hypertens(Greenwich),1999,1(1):48-54.
[17]Canzanello VJ,Sheps SG.The sixth report of the Joint National Committee on prevention,detection,evaluation,and treatment of high blood pressure:What’s New?What’s Different?[J].Cardiol Rev,1998,6(5):272-277.
[18]Rieder MJ,Taylor SL,Tobe VO,et al.Automating the identification of DNA variations using quality-based fluorescence re-sequencing:analysis of the human mitochondrial genome[J].Nucleic Acids Res,1998,26(4):967-973.
[19]Tanaka M,Cabrera VM,Gonzalez AM,et al.Mitochondrial genome variation in eastern Asia and the peopling of Japan[J].Genome Res,2004,14(10A):1832-1850.
[20]Andrews RM,Kubacka I,Chinnery PF,et al.Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA[J].Nat Genet,1999,23(2):147.
[21]Brandon MC,Lott MT,Nguyen KC,et al.MITOMAP:a human mitochondrial genome database——2004 update[J].Nucleic Acids Res,2005,33(Database issue):D611-613.
[22]Zhang M,Zhou X,Li C,et al.Mitochondrial haplogroup M9a specific variant ND1 T3394C may have a modifying role in the phenotypic expression of the LHON-associated ND4 G11778A mutation[J].Mol Genet Metab,2010,101(2-3):192-199.
[23]Bibb MJ,Van Etten RA,Wright CT,et al.Sequence and gene organization of mouse mitochondrial DNA[J].Cell,1981,26(2 Pt 2):167-180.
[24]Gadaleta G,Pepe G,De Candia G,et al.The complete nucleotide sequence of the Rattus norvegicus mitochondrial genome:cryptic signals revealed by comparative analysis between vertebrates[J].J Mol Evol,1989,28(6):497-516.
[25]Wong LJ,Liang MH,Kwon H,et al.Comprehensive scanning of the entire mitochondrial genome for mutations[J].Clin Chem,2002,48(11):1901-1912.
[26]Munscher C,Muller-Hocker J,Kadenbach B.Human aging is associated with various point mutations in t RNA genes of mitochondrial DNA[J].Biol Chem Hoppe Seyler,1993,374(12):1099-1104.
[27]Seibel P,Lauber J,Klopstock T,et al.Chronic progressive external ophthalmoplegia is associated with a novel mutation in the mitochondrial t RNA(Asn)gene[J].Biochem Biophys Res Commun,1994,204(2):482-489.
[28]Yoon KL,Aprille JR,Ernst SG.Mitochondrial t RNA(thr)mutation in fatal infantile respiratory enzyme deficiency[J].Biochem Biophys Res Commun,1991,176(3):1112-1115.
[29]Vasan RS,Beiser A,Seshadri S,et al.Residual lifetime risk for developing hypertension in middle-aged women and men:the framingham heart study[J].JAMA,2002,287(8):1003-1010.