Mitochondrial abnormalities in patients with primary open-angle glaucoma
Mitochondrial abnormalities in patients with primary open-angle glaucoma
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DOI：
10.1167/iovs.05-1639
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Bosley, Thomas M.
中科院分区：
文献类型：
--
作者：
Abu-Amero, Khaled K.;Morales, Jose;Bosley, Thomas M.
目的.原发性开角型青光眼（POAG）是第二大常见的致盲原因。它与myocilin（MYOC）和optineurin（OPTN）基因的突变有关，尽管在< 5%的患者中发现了突变。POAG的病理机制尚不清楚，但可能包括视网膜神经节细胞凋亡，导致视神经乳头轴突的进行性损伤。对27例确诊的原发性开角型青光眼患者进行MYOC和OPTN基因测序，线粒体DNA编码区全序列测定，线粒体DNA相对含量测定，线粒体呼吸功能测定。在POAG患者和对照组中，MYOC和OPTN仅发现了三种良性多态性。相反，仅在POAG患者（而非对照组）中发现了27种不同的新的非同义mtDNA变化，其中22种（在14例患者中发现）具有潜在的致病性。与Leber遗传性视神经病变不同，POAG患者的大多数mtDNA序列改变是改变嘌呤/嘧啶方向并暗示氧化应激的颠换序列改变。与年龄匹配的对照组相比，17例POAG患者的mtDNA含量相对增加，这也意味着可能对氧化应激有反应。与对照组相比，青光眼患者的平均线粒体呼吸活性降低了21%（P < 0.001）。这些结果揭示了POAG患者的一系列线粒体异常，涉及氧化应激，并暗示线粒体功能障碍可能是POAG的危险因素。这一概念可能会开启新的实验和治疗机会。
PURPOSE. Primary open-angle glaucoma (POAG) is the second most common cause of blindness. It has been linked to mutations in the myocilin (MYOC) and optineurin (OPTN) genes, although mutations have been found in < 5% of patients. The pathologic mechanism(s) of POAG remain unknown but may include retinal ganglion cell apoptosis, Which causes progressive damage to axons at the optic nerve head.METHODS. In 27 patients with definite POAG, the MYOC and OPTN genes were sequenced, the entire mitochondrial (mt)DNA coding region was sequenced, relative mtDNA content was investigated, and mitochondrial respiratory function was assessed.RESULTS. Only three benign polymorphisms were identified in MYOC and OPTN in patients with POAG and in control subjects. Conversely, 27 different novel nonsynonymous mtDNA changes were found, only in patients with POAG (not control subjects), 22 of which (found in 14 patients) were potentially pathogenic. Unlike Leber hereditary optic neuropathy, most mtDNA sequence alterations in patients with POAG were transversions-sequence changes that alter the purine/pyrimidine orientation and imply oxidative stress. mtDNA content was relatively increased in 17 patients with POAG compared with age-matched control subjects, also implying a possible response to oxidative stress. Mean mitochondrial respiratory activity was decreased by 21 % in patients with glaucoma compared with control subjects (P < 0.001).CONCLUSIONS. These results reveal a spectrum of mitochondrial abnormalities in patients with POAG, implicating oxidative stress and implying that mitochondria dysfunction may be a risk factor for POAG. This concept may open tip new experimental and therapeutic opportunities.