Identifying novel genes causing cytochrome c oxidase (COX) deficiency

我们的身体通过叫做线粒体的微小细胞发电厂将食物转化为能量。每年大约有50名澳大利亚儿童遗传线粒体能量产生障碍。最严重的疾病会导致婴儿死亡，而其他疾病则会在以后的生活中导致退行性疾病，特别是影响大脑和肌肉。在大多数情况下，我们缺乏有效的治疗方法。线粒体疾病的遗传原因非常多样，已知的疾病基因有70多种。有些位于我们只从母亲那里遗传的独特的线粒体DNA上。更多的基因等待发现。本研究的重点是线粒体疾病细胞色素c氧化酶（COX）缺乏症，我们已经诊断了80名澳大利亚患者。COX需要13个独立的成分组合在一起才能正常工作，但大多数患者中不存在编码这些成分的基因突变。我们认为，最常见的问题将出现在参与组装组件的基因上，而不是组件本身。我们将使用多种方法来确定疾病基因在基因组中的位置。我们策略的一个关键是确定同一基因可能发生突变的患者。我们已经确定了两个这样的群体，并将进行研究，包括将两个细胞系融合在一起，以确认它们患有相同的疾病。然后，我们将使用DNA （SNP）芯片进行遗传作图以寻找基因组中的相似性区域。我们将测试这些区域的基因表达得如何，我们是否可以通过引入该染色体的健康副本来纠正培养皮肤细胞中的问题，并寻找基因突变。识别这些基因将使我们能够改进未来的诊断和预防，并可能使我们开发新的治疗方法。轻微的线粒体问题也会导致一系列更常见的疾病，如糖尿病和阿尔茨海默病，因此任何新的治疗方法都可能有广泛的应用

Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This study focuses on the mitochondrial disorder cytochrome c oxidase (COX) deficiency, for which we have diagnosed 80 Australian patients. COX requires 13 separate components to be assembled together in order to work properly, but mutations in the genes encoding these components are not present in most patients. We believe that the most common problems will be in genes involved in assembling the components rather than in the components themselves. We will use a number of methods to pinpoint where in the genome the disease genes are located. A key to our strategy is identifying patients likely to have mutations in the same gene. We have identified two such groups, and will do studies that involving fusing two cell lines together to confirm they have the same disorder. We will then perform genetic mapping to look for regions of similarity in the genome using DNA (SNP) chips. We will test how well the genes in such regions are expressed, whether we can correct the problem in cultured skin cells by introducing a healthy copy of that chromosome, and look for gene mutations. Identifying these genes will allow us to improve future diagnosis and prevention and may allow us to develop new methods of treatment. Milder mitochondrial problems also contribute to a range of more common diseases such as diabetes and Alzheimer disease, so any new treatments could potentially have wide application