School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Ophthalmology. 2011 May;118(5):978-85. doi: 10.1016/j.ophtha.2010.09.003. Epub 2010 Dec 4.
To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families.
Six Han Chinese families who seem to have maternally transmitted LHON were studied by clinical, genetic, and molecular evaluations.
One hundred twenty-seven subjects from 6 Chinese families with a wide range of age-at-onset and severity of visual impairment.
All subjects underwent clinical examination, genetic evaluation, and molecular analysis of mitochondrial DNA (mtDNA).
The ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. The mtDNA analysis included the polymerase chain reaction (PCR) amplification of entire mtDNA and subsequent sequence determination.
Six families exhibited low penetrance of visual impairment, with an average of 10.8%. In particular, 9 (6 males/3 females) of 86 matrilineal relatives in these families exhibited variable severity and age at onset in visual dysfunction. The average age at onset of visual loss was 20 years. Molecular analysis of mtDNA in these families identified the homoplasmic ND5T12338C mutation and distinct set of variants belonging to the Asian haplogroup F2. The T12338C mutation is only present in the maternal lineage of those pedigrees and not in 178 Chinese controls. This mutation resulted in the replacement of the first amino acid, a translation-initiating methionine with a threonine, shortening 2 amino acids of ND5 polypeptide. The T12338C mutation is also located in 2 nucleotides adjacent to the 3' end of the tRNA(Leu(CUN)). Thus, this mutation may alter ND5 mRNA metabolism and the processing of RNA precursors. As a result, this mutation impairs respiratory function, leading to visual impairment.
Several lines of evidence suggest that the mitochondrial ND5T12338C mutation is associated with LHON. The tissue specificity of this mutation is likely due to the involvement of nuclear modifier genes. The identification of nuclear modifiers is important for the elucidation of the pathogenic mechanism of LHON and an open avenue for therapeutic interventions. The T12338C mutation should be added to the list of inherited risk factors for future molecular diagnosis. Our findings are helpful for counseling families with LHON.
探讨 Leber 遗传性视神经病变（LHON）在中国家系中的分子发病机制。
通过临床、遗传和分子评估，对 6 个似乎具有母系传递 LHON 的汉族家系进行了研究。
6 个中国家系的 127 名受试者，其发病年龄和视力损害严重程度差异较大。
所有受试者均接受眼科检查、遗传评估和线粒体 DNA（mtDNA）的分子分析。
眼科检查包括视力、视野检查、视觉诱发电位和眼底照相。mtDNA 分析包括整个 mtDNA 的聚合酶链反应（PCR）扩增和随后的序列测定。
6 个家系表现出低外显率的视力损害，平均为 10.8%。特别是，这些家系的 86 位母系亲属中有 9 人（6 男/3 女）表现出不同程度和发病年龄的视觉功能障碍。视觉丧失的平均发病年龄为 20 岁。对这些家系的 mtDNA 分子分析发现了同型的 ND5T12338C 突变和一组属于亚洲单倍群 F2 的独特变体。T12338C 突变仅存在于家系的母系谱系中，而不存在于 178 名中国对照者中。该突变导致起始甲硫氨酸被苏氨酸取代，ND5 多肽缩短了 2 个氨基酸。T12338C 突变也位于 tRNA（Leu（CUN））的 3'端附近的 2 个核苷酸上。因此，该突变可能改变 ND5 mRNA 代谢和 RNA 前体的加工。结果，该突变损害了呼吸功能，导致视力损害。
有几条证据表明，线粒体 ND5T12338C 突变与 LHON 相关。该突变的组织特异性可能归因于核修饰基因的参与。核修饰基因的鉴定对于阐明 LHON 的发病机制和开辟治疗干预途径非常重要。T12338C 突变应添加到未来分子诊断的遗传危险因素列表中。我们的研究结果有助于对 LHON 患者进行家庭咨询。
