Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
Hum Genet. 2010 Jul;128(1):39-49. doi: 10.1007/s00439-010-0821-8. Epub 2010 Apr 21.
Leber hereditary optic neuropathy (LHON) is the most common mitochondrially inherited disease causing blindness, preferentially in young adult males. Most of the patients carry the G11778A mitochondrial DNA (mtDNA) mutation. However, the marked incomplete penetrance and the gender bias indicate some additional genetic and/or environmental factors to disease expression. Herein, we first conducted a genome-wide linkage scan with 400 microsatellite markers in 9 large Thai LHON G11778A pedigrees. Using an affecteds-only nonparametric linkage analysis, 4 regions on chromosomes 3, 12, 13 and 18 showed Zlr scores greater than 2 (P < 0.025), which is consistently significant across several linkage statistics. The most suggestive marker D3S1565 (Zlr > 2 in 10 of 16 allele sharing models tested) was then expanded to include the region 3q26.2-3q28 covering SLC7A14 (3q26.2), MFN1 (3q26.32), MRPL47 (3q26.33), MCCC1 (3q27.1), PARL (3q27.1) and OPA1 (3q28-q29). All of these candidate genes were selected from the Maestro database and had known to be localized in mitochondria. Sixty tag SNPs were genotyped in 86 cases, 211 of their relatives and 32 unrelated Thai controls, by multiplex-PCR-based Invader assay. Analyses using a powerful association testing tool that adjusts for relatedness (the M(QLS) statistic) showed the most evidence of association between two SNPs, rs3749446 and rs1402000 (located in PARL presenilins-associated rhomboid-like) and LHON expression (both P = 8.8 x 10(-5)). The mitochondrial PARL protease has been recently known to play a role with a dynamin-related OPA1 protein in preventing apoptotic events by slowing down the release of cytochrome c out of mitochondrial cristae junctions. Moreover, PARL is required to activate the intramembranous proteolyses resulting in the degradation of an accumulated pro-apoptotic protein in the outer mitochondrial membrane. Under these circumstances, variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON.
Leber 遗传性视神经病变（LHON）是最常见的线粒体遗传疾病，导致失明，主要发生在年轻成年男性中。大多数患者携带 G11778A 线粒体 DNA（mtDNA）突变。然而，明显的不完全外显率和性别偏见表明，疾病表达还存在一些其他遗传和/或环境因素。在此，我们首次对 9 个大型泰国 LHON G11778A 家系进行了全基因组连锁扫描，使用 400 个微卫星标记。采用受累者非参数连锁分析，染色体 3、12、13 和 18 上的 4 个区域显示 Zlr 评分大于 2（P < 0.025），这在几个连锁统计中均具有一致性。最有提示意义的标记 D3S1565（在 16 个等位基因共享模型测试中的 10 个中 Zlr > 2）随后扩展到包含 3q26.2-3q28 区域，该区域包含 SLC7A14（3q26.2）、MFN1（3q26.32）、MRPL47（3q26.33）、MCCC1（3q27.1）、PARL（3q27.1）和 OPA1（3q28-q29）。这些候选基因均选自 Maestro 数据库，并且已知位于线粒体中。通过多重 PCR 基于 Invader 检测，对 86 例病例、211 名亲属和 32 名无关的泰国对照进行了 60 个标签 SNP 的基因分型。使用一种强大的关联测试工具（调整亲缘关系的 M(QLS)统计量）进行分析，结果显示两个 SNP（位于 PARL 早老素相关的类菱形）rs3749446 和 rs1402000 与 LHON 表达之间存在最明显的关联（均 P = 8.8 x 10(-5))。最近发现，线粒体 PARL 蛋白酶与一种与 dynamin 相关的 OPA1 蛋白一起，通过减缓细胞色素 c 从线粒体嵴连接部释放，在防止细胞凋亡事件中发挥作用。此外，PARL 被需要激活跨膜蛋白水解，导致外线粒体膜中积累的促凋亡蛋白降解。在这种情况下，PARL 的变体通过凋亡影响细胞死亡，凋亡一直被认为是 LHON 神经退行性变的关键因素。
