线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点

doi:10.3724/SP.J.1005.2011.00322

遗传 ›› 2011, Vol. 33 ›› Issue (4): 322-328.doi: 10.3724/SP.J.1005.2011.00322

线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点

冀延春^{1, 2}, 刘晓玲², 赵福新², 张娟娟², 章豫^{1, 2}, 周翔天², 瞿佳², 管敏鑫^1,3,4

1. 温州医学院Attardi 线粒体生物医学研究院和浙江省医学遗传学重点实验室, 温州 325035 2. 温州医学院眼视光学院, 温州 325027 3. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati OH 45229, USA 4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229, USA

收稿日期:2010-07-19 修回日期:2010-11-18 出版日期:2011-04-20 发布日期:2011-04-25
通讯作者: 管敏鑫 E-mail:gminxin88@gmail.com
基金资助:
国家杰出青年科学基金及海外、港澳青年学者合作研究基金(编号：30628013), 浙江省自然科学基金重大项目(编号：Z204492), 浙江省自然科学基金项目(编号：Y2090649), 温州市科技计划项目(编号：Y20090273)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：2010R413035)资助

The mitochondrial ND5 T12338C mutation may be associated with Leber’s hereditary optic neuropathy in two Chinese families

JI Yan-Chun^{1, 2}, LIU Xiao-Ling², ZHAO Fu-Xin², ZHANG Juan-Juan², ZHANG Yu^{1, 2}, ZHOU Xiang-Tian², QU Jia², GUAN Min-Xin^{1, 3, 4}

1. Giuseppe Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, China 2. School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, China 3. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati OH 45229, USA 4. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229, USA

Received:2010-07-19 Revised:2010-11-18 Online:2011-04-20 Published:2011-04-25
Contact: Guan Mian-xin E-mail:gminxin88@gmail.com

摘要/Abstract

摘要： Leber 遗传性视神经病变变(Leber’s hereditary optic neuropathy, LHON) 是一种与线粒体DNA (Mitochondrial DNA, mtDNA) 突变相关的母系遗传性眼科疾病。文章报道了两例具有典型LHON 临床、分子遗传特征的中国汉族家系。首先通过对家系先证者和其他成员进行眼科相关检查, 发现两个家系成员中视力都仅有先证者一人损害严重, 即外显率很低。经常规的方法对母系成员进行mtDNA 测序及相关软件分析, 结果发现携带ND4 G11696A和ND5 T12338C 同质性突变位点, 多态性变异位点均属于东亚单体型F2。线粒体DNA ND4 G11696A 是一个已知的与LHON 相关的突变位点, 而T12338C 位于线粒体氧化磷酸化复合体I 亚基ND5的第2个碱基, 该突变使起始密码子由蛋氨酸转变成苏氨酸, 并且紧连tRNA^Leu(CUN) 的3′末端。这可能影响tRNA ^Leu(CUN)空间结构和稳定性发生改变, 以及起始密码子改变导致线粒体ND5 蛋白合成功能受损和ATP 障碍, 最终导致需求能量高的视神经受损和视力损害。因此, 线粒体ND4 G11696A和ND5 T12338C 突变可能协同作用Leber遗传性视神经病变的发生, 是与LHON 相关的mtDNA 突变位点, 但外显率很低说明突变本身不足以造成LHON 的表型表达, 提示其他修饰因子(核修饰基因、环境等)可能对这两个家系发病起协同作用。

关键词: Leber 遗传性视神经病变变, 外显率, 线粒体DNA, 突变, 视力

Abstract: Leber’s hereditary optic neuropathy (LHON) associated with mitochondrial DNA mutation is a maternally inherited eye disease. We reported here the clinical, genetic and molecular characterization of two Han Chinese families with Leber’s hereditary optic neuropathy. Ophthalmologic examinations revealed that the variable severity and age-of-onset in visual impairment among probands and other matrilineal relatives of these families. Strikingly, there were extremely low penetrances of visual impairment in these families. Sequence analysis of complete mitochondrial genomes in these pedi-grees identified the homoplasmic ND4 G11696A and ND5 T12338C mutation and distinct sets of polymor-phism belonging to haplogroups F2. It is well known that mitochondrial DNA ND4 G11696A is associated with LHON. The ND5 T12338C mutation resulted in replacement of the first amino acid, translation-initiating methion-ine with a threonine, and shortening two amino acids of ND5. This mutation also locates in two nucleotides adjacent to the 3' end of the tRNA^Leu(CUN). Thus, this mutation may alter structural formation and stabilization of functional tRNA, thereby leading to a failure in protein synthesis and mitochondrial dysfunction involved in visual impairment. Therefore, the ND4 G11696A and ND5 T12338C mutation is likely associated with LHON in these two Chinese families. But these families exhibited extremely low penetrances of visual impairment. It suggests that other factors, such as nuclear modifier gene(s) or environmental factor(s), may play a role in the phenotypic expression of the LHON-associated ND4 G11696A and ND5 T12338C mutation.

Key words: Leber’s hereditary optic neuropathy, visual impairment, mitochondrial DNA, penetrance, mutation

冀延春，刘晓玲，赵福新，张娟娟，章豫，周翔天，瞿佳，管敏鑫. 线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点[J]. 遗传, 2011, 33(4): 322-328.

JI Yan-Chun, LIU Xiao-Ling, ZHAO Fu-Xin, ZHANG Juan-Juan, ZHANG Yu, ZHOU Xiang-Tian, QU Jia, GUAN Min-Xin. The mitochondrial ND5 T12338C mutation may be associated with Leber’s hereditary optic neuropathy in two Chinese families[J]. HEREDITAS, 2011, 33(4): 322-328.

参考文献

[1] Qu J, Guan MX. Molecular pathogenetic mechanism of Leber's hereditary optic neuropathy. Chin J Optometry Ophthalmol, 2006, 8(6): 341-348.
[2] Man PYW, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet, 2002, 39(3): 162-169.
[3] Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science, 1988, 242(4884): 1427-1430.
[4] MITOMAP: A Human Mitochondrial Genome Database. http://www.mitomap.org, 2009.
[5] Man PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet, 2003, 72(2): 333-339.
[6] Mashima Y, Yamada K, Wakakura M, Kigasawa K, Ku-doh J, Shimizu N, Oguchi Y. Spectrum of pathogenic mitochondrial DNA mutations and clinical features in Japa-nese families with Leber's hereditary optic neuropathy. Curr Eye Res, 1998, 17(4): 403-408.
[7] Mackey DA, Oostra RJ, Rosenberg T, Nikoskelainen E, Bronte-Stewart J, Poulton J, Harding AE, Govan G, Bolhuis PA, Norby S. Primary pathogenic mtDNA mutations in multigeneration pedigrees with Leber hereditary optic neuropathy. Am J Hum Genet, 1996, 59(2): 481-485.
[8] Brown MD, Torroni A, Reckord CL, Wallace DC. Phylogenetic analysis of Leber's hereditary optic neuropathy mitochondrial DNA's indicates multiple independent occurrences of the common mutations. Hum Mutat, 1995, 6(4): 311-325.
[9] Liang M, Guan MQ, Zhao FX, Zhou XT, Yuan MX, Tong Y, Yang L, Wei QP, Sun YH, Lu F, Qu J, Guan MX. Leber’s hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation. Biochem Biophys Res Commun, 2009, 383(3): 286-292.
[10] Qu J, Li RH, Zhou XT, Tong Y, Lu F, Qian YP, Hu YW, Mo JQ, West CE, Guan MX. The novel A4435G mutation in the mitochondrial tRNA^Met may modulate the phenotypic expression of the LHON-associated ND4 G11778A mutation. Invest Ophthalmol Vis Sci, 2006, 47(2): 475-483.
[11] Zhou XT, Wei QP, Yang L, Tong Y, Zhao FX, Lu CJ, Qian YP, Sun YG, Lu F, Qu J, Guan MX. Leber’s heredi-tary optic neuropathy is associated with the mitochondrial ND4 G11696A mutation in five Chinese families. Biochem Biophys Res Commun, 2006, 340(1): 69-75.
[12] Zhao FX, Guan MQ, Zhou XT, Yuan MX, Liang M, Liu Q, Liu Y, Zhang YM, Yang L, Tong Y, Wei QP, Sun YH, Qu J, Guan MX. Leber's hereditary optic neuropathy is associated with mitochondrial ND6 T14502C mutation. Biochem Biophys Res Commun, 2009, 389(3): 466-472.
[13] Li RH, Qu J, Zhou XT, Tong Y, Hu YW, Qian YP, Lu F, Mo JQ, West CE, Guan MX. The mitochondrial tRNA^Thr A15951G mutation may influence the phenotypic expression of the LHON-associated ND4 G11778A mutation in a Chinese family. Gene, 2006, 376(1): 79-86.
[14] 刘燕, 庄淑流, 童绎, 瞿佳, 周翔天, 赵福新, 张娟娟, 张永梅, 章豫, 管敏鑫. 线粒体ND1基因T3866C 突变可能是Leber’s 遗传性视神经病和四肢畸形跛行相关的突变. 遗传, 2010, 32(2): 141-147.
[15] 张永梅, 冀延春, 刘晓玲, 周翔天, 赵福新, 孙艳红, 韦企平, 张娟娟, 刘燕, 瞿佳, 管敏鑫. 线粒体tRNA^Glu A14693G 可能是与Leber 遗传性视神经病变相关的基因突变. 遗传, 2010, 32(4): 353-359.
[16] 赵福新, 周翔天, 瞿佳, 韦企平, 童绎, 杨丽, 吕建新, 管敏鑫. 中国Leber 遗传性视神经病变G11696A突变的两个家系分析. 中华医学遗传学杂志, 2007, 24(5): 556-559.
[17] Rieder MJ, Taylor SL, Tobe VO, Nickerson DA. Automating the identification of DNA variations using quality-based fluorescence resequencing: analysis of the human mitochondrial genome. Nucleic Acids Res, 1998, 26(4): 967-973.
[18] 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.
[19] 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.
[20] Chen BB, Sun DM, Yang L, Zhang C, Yang A, Zhu Y, Zhao J, Chen Y, Guan M, Wang X, Li R, Tang X, Wang J, Tao Z, Lu J, Guan MX. Mitochondrial ND5 T12338C, tRNACys T5802C, and tRNA^ThrG15927A variants may have a modifying role in the phenotypic manifestation of deafness-associated 12S rRNA 1555A>G mutation in three Han Chinese pedigrees. Am J Med Genet, 2008, 146(10): 1248-1258.
[21] Li XM, Fischel-Ghodsian N, Schwartz F, Yan QF, Fried-man RA, Guan MX. Biochemical characterization of the mitochondrial tRNA^Ser(UCN) T7511C mutation associated with nonsyndromic deafness. Nucleic Acids Res, 2004, 32(3): 867-877
[22] Qu J, Zhou XT, Zhang JJ, Zhao FX, Sun YH, Tong Y, Wei QP, Cai WS, Yang L, West CE, Guan MX. Extremely low penetrance of Leber’s hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation. Ophthalmology, 2009, 116(3): 558-564.
[23] Tong Y, Sun YH, Zhou X, Zhao F, Mao Y, Wei QP, Yang L, Qu J, Guan MX. Very low penetrance of Leber's hereditary optic neuropathy in five Han Chinese families carrying the ND1 G3460A mutation. Mol Genet Metab, 2010, 99(4): 417-424.
[24] Qu J, Zhou XT, Zhao FX, Liu XL, Zhang ML, Sun YH, Li-ang M, Yuan MX, Liu Q, Tong Y, Wei QP, Yang L, Guan MX. Low penetrance of Leber's hereditary optic neuropathy in ten Han Chinese families carrying the ND6 T11484C mutation. Biochim Biophys Acta, 2010, 1800(3): 305-312
[25] Qu J, Li RH, Zhou XT, Tong Y, Yang L, Chen J, Zhao FX, Lu CJ, Qian YP, Lu F, Guan MX. Cosegregation of the ND4 G11696A mutation with the LHON-associated ND4 G11778A mutation in a four generation Chinese family. Mitochondrion, 2007, 7(1-2): 140-146.
[26] Zhou XT, Zhang HX, Zhao FX, Ji YC, Tong Y, Zhang JJ, Zhang Y, Yang L, Qian YP, Lu F, Qu J, Guan MX. Very high penetrance and occurrence of Leber’s hereditary op-tic neuropathy in a large Han Chinese pedigree carrying the ND4 G11778A mutation. Mol Genet Me-tab, 2010, 100 (4): 379-384.

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线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点

The mitochondrial ND5 T12338C mutation may be associated with Leber’s hereditary optic neuropathy in two Chinese families

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