Li Ronghua, Qu Jia, Zhou Xiangtian, Tong Yi, Hu Yongwu, Qian Yaping, Lu Fan, Mo Jun Qin, West Constance E, Guan Min-Xin
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Gene. 2006 Jul 5;376(1):79-86. doi: 10.1016/j.gene.2006.02.014. Epub 2006 Apr 19.
We report here the characterization of a three-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON). This Chinese family exhibited high penetrance and expressivity of visual impairment. The average age-of-onset was 19 years in this family. All male and 33% female matrilineal relatives in this Chinese family developed visual loss with a wide range of severity, ranging from blindness to normal vision. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the ND4 G11778A mutation and 40 other variants, belonging to the Asian haplogroup D4. The G11778A mutation is present at homoplasmy in matrilineal relatives of this Chinese family. Of other variants, the homoplasmic A15951G mutation is of special interest as it is located adjacent to 3' end, at conventional position 71 of tRNA(Thr). The adenine (A71) at this position of tRNA(Thr), highly conserved from bacteria to human mitochondria, has been implicated to be important for tRNA identity and pre-tRNA processing. In fact, the significant reduction of the steady-state levels in tRNA(Thr) was observed in cells carrying both the A15951G and G11778A mutations but not cells carrying only G11778A mutation. Thus, the A15951G mutation most probably leads to a failure in mitochondrial tRNA metabolism, worsening the mitochondrial dysfunction associated with the primary G11778A mutation. These imply that the tRNA(Thr) A15951G mutation may have a potential modifier role in increasing the penetrance and expressivity of the primary LHON-associated G11778A mutation in this Chinese family.
我们在此报告一个患有Leber遗传性视神经病变（LHON）的三代汉族家庭的特征。这个中国家庭中视力损害具有高外显率和表现度。该家庭的平均发病年龄为19岁。这个中国家庭中所有男性和33%的女性母系亲属出现了视力丧失，严重程度范围广泛，从失明到正常视力。对这个家系的完整线粒体DNA进行序列分析，发现存在ND4 G11778A突变以及其他40个变异，属于亚洲单倍群D4。G11778A突变在这个中国家庭的母系亲属中呈纯质性存在。在其他变异中，纯质性的A15951G突变特别令人关注，因为它位于3'端附近，在tRNA(Thr)的常规位置71处。tRNA(Thr)这个位置的腺嘌呤（A71），从细菌到人类线粒体高度保守，被认为对tRNA的特性和前体tRNA加工很重要。事实上，在同时携带A15951G和G11778A突变的细胞中观察到tRNA(Thr)的稳态水平显著降低，但仅携带G11778A突变的细胞中未观察到。因此，A15951G突变很可能导致线粒体tRNA代谢失败，使与原发性G11778A突变相关的线粒体功能障碍恶化。这些表明tRNA(Thr) A15951G突变可能在增加这个中国家庭中与LHON相关的原发性G11778A突变的外显率和表现度方面具有潜在的修饰作用。
