Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside.
Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside.
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DOI：
10.1155/2011/179412
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发表时间：
2011
影响因子：
1.9
通讯作者：
Guy J
中科院分区：
文献类型：
--
作者：
Koilkonda RD;Guy J
Leber遗传性视神经病变（LHON）是一种由线粒体DNA（mtDNA）点突变引起的母系传播疾病。大多数情况是由于编码NADH-泛醌氧化还原酶亚基的基因突变，该亚基是电子传递链（ETC）的复合物I。这些突变位于线粒体基因组中的核苷酸位置3460、11778或14484处。这种疾病的特点是中风，双边和严重的视力丧失。虽然突变的mtDNA损害所有线粒体产生ATP，但只有视网膜神经节细胞的选择性丧失和视神经轴突的变性。因此，失明通常是永久性的。携带致病性mtDNA突变的男性中有一半和女性中有10%实际上发展了表型。这种不完全的性别歧视和性别偏见没有得到充分的理解。另外的线粒体和/或核遗传因子可以调节LHON的表型表达。在一项基于人群的研究中，单倍群J的mtDNA背景与低ATP产生和活性氧（ROS）产生增加的反向关系相关。LHON的有效治疗一直难以捉摸。在本文中，我们描述了相关的已发表的研究结果，并讨论了潜在的策略，以改善疾病的争议。
Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.
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