对3个携带tRNALeu(CUN) 12308A>G突变的Leber遗传性视神经病变家系的检测分析

目的：探讨tRNALeu(CUN) 12308A＞G突变是否影响Leber遗传性视神经病变（LHON）的表型表达。方法：对295例无血缘关系的汉族LHON患者和316例正常对照者进行线粒体突变基因筛查，并对筛出的3个携带m.12308A＞G突变并具有典型LHON临床表现的家系进行线粒体全序分析、单体型分析以及拷贝数的测定。结果：3个家系均不携带主要原发突变位点，但在tRNALeu(CUN)上高度保守的44位发生了m.12308A＞G同质性突变，且3个先证者的单倍体型均属于东亚单倍体型H2，但发病年龄和视力损伤程度有所不同，并在正常对照者中未检出m.12308A＞G突变。在拷贝数测定中发现突变细胞的线粒体拷贝数明显减少。结论：m.12308A＞G突变可能是与LHON相关的突变位点，但突变本身并不足以造成LHON的表型表现，其他修饰因子（核基因修饰、线粒体单体型及环境因素）在LHON的发病进程中发挥了一定的作用。

Detection and analysis of 3 Leber’s hereditary optic neuropathy families carrying tRNALeu(CUN) 12308A>G mutation

Objective: To explore whether the inferred tRNALeu(CUN) 12308A>G mutation affects the phenotypic expression of Leber’s hereditary optic neuropathy (LHON). Methods: Screening of 295 unrelated Han LHON patients and 316 normal controls were performed for mitochondrial mutation genes, and three screened families carrying m.12308A>G mutation and having typical LHON clinical manifestations were analyzed for mitochondrial complete sequence analysis, haplotype analysis and mitochondrial copy number measurement. Results: None of the three pedigrees carried the major primary locus, but a m.12308A>G homogeneous mutation occurred at 44 positions, which was highly conserved on tRNALeu(CUN). The haplotypes of the three probands belonged to East Asian haplotype H2, but the age of onset and the degree of visual impairment were different and no 12308A>G mutation was detected in normal controls. It was found that the mitochondrial copy number of the mutant cells was significantly reduced in the copy number measuremen. Conclusion: The m.12308A>G mutation may be a mutation site associated with LHON. However, the low penetrance of the mutant family indicates that the mutation itself is not sufficient to cause the phenotypic expression of LHON, and that other modification factors (nuclear gene modification, mitochondrial haplotype and environmental factors) have played a role in the pathogenesis of LHON.