Davies Vanessa J, Powell Kate A, White Kathryn E, Yip Wanfen, Hogan Vanessa, Hollins Andrew J, Davies Jennifer R, Piechota Malgorzata, Brownstein David G, Moat Stuart J, Nichols Philip P, Wride Michael A, Boulton Michael E, Votruba Marcela
School of Optometry and Vision Sciences, Cardiff University, Maindy Road, Cathays, Cardiff CF24 4LU, UK.
Brain. 2008 Feb;131(Pt 2):368-80. doi: 10.1093/brain/awm333.
Opa3 mRNA is expressed in all tissues examined to date, but currently the function of the OPA3 protein is unknown. Intriguingly, various mutations in the OPA3 gene lead to two similar diseases in humans: autosomal dominant inherited optic atrophy and cataract (ADOAC) and a metabolic condition; type 3-methylglutaconic aciduria (MGA). Early onset bilateral optic atrophy is a common characteristic of both disorders; retinal ganglion cells are lost and visual acuity is impaired from an early age. In order to investigate the function of the OPA3 protein, we have generated a novel ENU-induced mutant mouse carrying a missense mutation in the OPA3 gene. The heterozygous mutation in exon 2, causes an amino acid change p.L122P (c.365T>C), which is predicted to alter tertiary protein structure. In the heterozygous state, the mice appear uncompromised however; in the homozygous state mice display some of the features of MGA. Visual function is severely reduced, consistent with significant loss of retinal ganglion cells and degeneration of axons in the optic nerve. In the homozygous optic nerve, there was evidence of increased mitochondrial activity, as demonstrated by the increased presence of mitochondrial marker Cytochrome C Oxidase (COX) histochemistry. Mice homozygous for the opa3(L122P) mutation also display a severe multi-systemic disease characterized by reduced lifespan (majority dying before 4 months), decreased weight, dilated cardiomyopathy, extrapyramidal dysfunction and gross neuro-muscular defects. All of these defects are synonymous with the phenotypic characteristics of Type III MGA found in humans. This model will be of major importance for future studies of the specific function of the OPA3 gene.
到目前为止，在所有检测的组织中均有Opa3信使核糖核酸（mRNA）表达，但目前Opa3蛋白的功能尚不清楚。有趣的是，Opa3基因的各种突变会导致人类出现两种相似的疾病：常染色体显性遗传性视神经萎缩和白内障（ADOAC）以及一种代谢性疾病，即3-甲基戊二酸尿症（MGA）。早发性双侧视神经萎缩是这两种疾病的共同特征；视网膜神经节细胞丢失，视力从小就受损。为了研究Opa3蛋白的功能，我们培育出了一种新型的ENU诱导突变小鼠，其Opa3基因携带一个错义突变。外显子2中的杂合突变导致氨基酸变化p.L122P（c.365T>C），预计会改变蛋白质的三级结构。然而，在杂合状态下，小鼠看起来并无异常；在纯合状态下，小鼠表现出一些MGA的特征。视觉功能严重下降，这与视网膜神经节细胞的大量丢失以及视神经轴突的退化相一致。在纯合视神经中，线粒体活性增加，线粒体标记细胞色素C氧化酶（COX）组织化学显示其存在增加，证明了这一点。opa3（L122P）突变的纯合小鼠还表现出一种严重的多系统疾病，其特征为寿命缩短（大多数在4个月前死亡）、体重减轻、扩张型心肌病、锥体外系功能障碍和严重的神经肌肉缺陷。所有这些缺陷都与人类III型MGA的表型特征相同。该模型对于未来研究Opa3基因的具体功能将具有重要意义。
