Department of Genetics, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China; School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China; Attardi Institute of Mitochondrial Biomedicine, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Mitochondrion. 2013 Nov;13(6):772-81. doi: 10.1016/j.mito.2013.05.002. Epub 2013 May 9.
Mitochondrial m.14484T>C (MT-ND6) mutation has been associated with Leber's hereditary optic neuropathy. Previous investigations revealed that the m.14484T>C mutation is a primary factor underlying the development of optic neuropathy but is not sufficient to produce a clinical phenotype. However, mitochondrial haplogroups have been proposed to modulate the phenotypic manifestation of the m.14484T>C mutation. Here, we performed the clinical, genetic evaluation and complete mitochondrial genome sequence analysis of 41 Han Chinese pedigrees carrying the m.14484T>C mutation. These families exhibited a wide range of penetrances and expressivities of optic neuropathy. The average ratio between affected male/female matrilineal relatives from 41 families was 2:1. The penetrance of optic neuropathy in these Chinese pedigrees ranged from 5.6% to 100%, with the average of 23.8%. Furthermore, the age-of-onset for optic neuropathy varied from 4 to 44 years, with the average of 19.3 years. Sequence analysis of their mitochondrial genomes identified distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups, indicating that the m.14484T>C mutation occurred through recurrent origins and founder events. We showed that mitochondrial haplogroups M9, M10 and N9 increased the penetrance of optic neuropathy in these Chinese families. In particular, these mitochondrial haplogroup specific variants: m.3394T>C (MT-ND1), m.14502T>C (MT-ND4) and m.14693A>G (MT-TE) enhanced the penetrance of visual loss in these Chinese families. These data provided the direct evidence that mitochondrial modifiers modulate the variable penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the m.14484T>C mutation.
线粒体 m.14484T>C（MT-ND6）突变与莱伯遗传性视神经病变有关。先前的研究表明，m.14484T>C 突变是导致视神经病变的主要因素，但不足以产生临床表型。然而，线粒体单倍群被认为可以调节 m.14484T>C 突变的表型表现。在这里，我们对携带 m.14484T>C 突变的 41 个汉族家系进行了临床、遗传评估和完整线粒体基因组序列分析。这些家系表现出视神经病变的广泛外显率和表现度。41 个家系中受累男性/女性母系亲属的平均比例为 2:1。这些中国家系中视神经病变的外显率从 5.6%到 100%不等，平均为 23.8%。此外，视神经病变的发病年龄从 4 岁到 44 岁不等，平均为 19.3 岁。线粒体基因组序列分析确定了属于十个东亚单倍群的不同组的多态性，表明 m.14484T>C 突变是通过反复起源和创始事件发生的。我们表明，线粒体单倍群 M9、M10 和 N9 增加了这些中国家系中视神经病变的外显率。特别是，这些线粒体单倍群特异性变体：m.3394T>C（MT-ND1）、m.14502T>C（MT-ND4）和 m.14693A>G（MT-TE）增强了这些中国家系中视力丧失的外显率。这些数据提供了直接证据，表明线粒体修饰因子调节携带 m.14484T>C 突变的中国家系中视神经病变的可变外显率和表现度。
