Pleiotropic disorders of mitochondrial translation

许多罕见的疾病是由人类正常健康所必需的生物过程所需的基因变化引起的。听力损失和不孕症是两个重要的常见健康问题，可能由遗传变化引起。研究罕见疾病的原因对受影响的个人及其家庭很重要，但通常有助于我们理解为什么人们会受到更常见的疾病的影响。因此，我们的研究将集中在一种非常罕见的疾病，称为Perrault综合征，它会导致男性和女性严重的听力损失，女性生育问题，以及大约一半受影响个体的神经衰弱问题。虽然Perrault综合征很罕见，但诊断不足，特别是在青春期前的男性或女孩中。佩罗特综合征也可能是一种严重得多的疾病，在儿童早期可能是致命的。在过去的10年里，我们和其他人发现，七个基因的变化可能导致这种情况。导致佩罗综合征的基因是线粒体功能所必需的，线粒体是细胞内产生能量的结构，对人类健康非常重要。我们最近的研究发现了六个以前不知道的导致这种疾病的新基因。我们将开展一项研究计划，建立在我们最近发现的基础上，为什么这六个新基因的变化导致这种疾病。重要的是，这些基因中的三个从未被证明在线粒体中起作用，因此我们的研究将提供关于这种情况如何发生的全新信息。在我们尚未找到病因的患者中，我们将使用一种新技术来观察细胞中的所有DNA，称为全基因组测序，为这些家庭提供解释并了解这种情况的生物学。我们已经组建了一个与世界各地的合作者联系的专家团队来支持这些研究。我们已经从受佩罗综合征影响的家庭收集了基因样本和信息，这些家庭没有我们已知的导致这种情况的基因变化。我们将深入研究我们发现的新基因，看看它们是如何破坏线粒体的工作的。这些信息将帮助我们了解设计有效治疗方法的下一步步骤。这项工作的应用和好处将是显着的。我们获得的信息将通过提供更准确和快速的诊断来帮助受这种毁灭性疾病影响的患者及其家属，这将减少从首次看到患者到获得某种诊断和获得适当临床护理所需的时间，并减少不必要的调查。我们的研究结果将立即被纳入整个NHS为听力损失和不孕症患者提供的标准基因测试中。

Many rare conditions are caused by changes in genes required for biological processes essential for normal human health. Hearing loss and infertility are two important common health problems that can be caused by genetic changes. Studying the causes of rare conditions is important for the affected individuals and their families, but often helps us to understand why people are affected by more common conditions. Therefore, our research will focus on a very rare condition called Perrault Syndrome, which causes severe hearing loss in both males and females, problems with fertility in females, and debilitating nerve problems in about half of affected individuals. While Perrault syndrome is rare, it is under-diagnosed, especially in men or in girls before puberty. Perrault syndrome can also be a far more severe condition, which can be fatal in early childhood. Over the past 10 years we, and others, have found that changes in seven genes can cause the condition. The genes that cause Perrault syndrome are required for the function of the mitochondria, a structure within a cell that produces energy and is very important for human health.Our recent research has discovered six new genes not previously known to cause this condition.We will carry out a programme of research, building on our recent discoveries of why the changes in these six new genes result in this condition. Importantly, three of these genes have never been shown to act in mitochondria, so our studies will provide completely new information as to how this condition can come about. In patients where we have not yet found the cause we will use a new technique to look at all of the DNA in a cell called whole genome sequencing to provide these families with an explanation and understand the biology of this condition. We have assembled an expert team linked with collaborators around the world to support these studies.We have already collected genetic samples and information from families affected by Perrault Syndrome who do not have changes in the genes that we already know cause the condition. We will study in depth the new genes that we have discovered and see how they disrupt the workings of the mitochondria. This information will help us to understand the next steps in designing effective treatment approaches.The applications and benefits of this work will be significant. The information we obtain will help patients and their families affected by this devastating condition by providing a more precise and rapid diagnosis, which will reduce the time it takes from when a patient is first seen to obtain a certain diagnosis and to get appropriate clinical care and reduce the need for unnecessary investigations. Our research findings will be immediately adopted into standard genetic tests provided throughout the NHS for individuals with hearing loss and infertility.