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

• 研究报告 • 上一篇    下一篇

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. 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-Chun1, 2, LIU Xiao-Ling2, ZHAO Fu-Xin2, ZHANG Juan-Juan2, ZHANG Yu1, 2, ZHOU Xiang-Tian2, QU Jia2, GUAN Min-Xin1, 3, 4   

  1. 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: 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tRNALeu(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 tRNALeu(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