Pleiotropic disorders of mitochondrial translation

线粒体翻译的多效性障碍

• 批准号: MR/W019027/1
• 负责人: William Newman
• 金额: $ 59.53万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW019027%2F1
• 关键词: Pleiotropic; disorders; mitochondrial; translation

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.

许多罕见的条件是由正常人类健康必不可少的生物过程所需的基因变化引起的。听力损失和不育是遗传变化可能引起的两个重要的常见健康问题。研究罕见条件的原因对受影响的个体及其家人很重要，但通常可以帮助我们理解为什么人们会受到更常见的条件的影响。因此，我们的研究将集中在一种非常罕见的疾病上，称为Perrault综合征，这会导致男性和女性的严重听力损失，女性生育能力以及大约一半受影响的个体的神经问题。虽然佩罗综合症很少见，但它的诊断不足，尤其是在青春期之前的男人或女孩中。 Perrault综合征也可能是一种更严重的疾病，这在幼儿时期可能是致命的。在过去的十年中，我们和其他人发现，七个基因的变化可能会导致病情。导致perrault综合征的基因是线粒体功能所必需的，线粒体的功能是一种产生能量的结构，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会引起这种情况的新基因。我们将进行一项研究计划，以我们最近在这种情况下导致这种变化导致这种变化。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有关这种情况如何产生的全新信息。在我们尚未找到原因的患者中，我们将使用一种新技术来查看一个称为整个基因组测序的细胞中的所有DNA，以为这些家族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合作者联系的专家团队，以支持这些研究。我们已经收集了受Perrault综合征影响的家庭的遗传样本和信息，这些家庭对我们已经知道导致病情的基因没有变化。我们将深入研究我们发现的新基因，并了解它们如何破坏线粒体的起作用。这些信息将帮助我们了解设计有效治疗方法的下一步。这项工作的应用和好处将很大。我们获得的信息将通过提供更精确和快速的诊断来帮助受到这种毁灭性疾病影响的患者及其家人，这将减少从首次看到患者获得一定诊断并获得适当临床护理并减少不必要研究的需求的时间。我们的研究发现将立即用于在整个NHS中为听力损失和不育的人提供的标准基因检测。

项目成果

Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54.

• DOI: 10.1038/s41431-023-01437-2
• 发表时间: 2023-10
• 期刊: European journal of human genetics : EJHG

A Novel Homozygous Founder Variant of RTN4IP1 in Two Consanguineous Saudi Families.

• DOI: 10.3390/cells11193154
• 发表时间: 2022-10-07
• 期刊: Cells
• 影响因子: 6

Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability.

• DOI: 10.15252/emmm.202216775
• 发表时间: 2023-05-08
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Erdinc, Direnis;Rodriguez-Luis, Alejandro;Fassad, Mahmoud R.;Mackenzie, Sarah;Watson, Christopher M.;Valenzuela, Sebastian;Xie, Xie;Menger, Katja E.;Sergeant, Kate;Craig, Kate;Hopton, Sila;Falkous, Gavin;Poulton, Joanna;Garcia-Moreno, Hector;Giunti, Paola;Aschoff, Carlos A. de Moura;Saute, Jonas A. Morales;Kirby, Amelia J.;Toro, Camilo;Wolfe, Lynne;Novacic, Danica;Greenbaum, Lior;Eliyahu, Aviva;Barel, Ortal;Anikster, Yair;McFarland, Robert;Gorman, Grainne S.;Schaefer, Andrew M.;Gustafsson, Claes M.;Taylor, Robert W.;Falkenberg, Maria;Nicholls, Thomas J.
• 通讯作者: Nicholls, Thomas J.

Nonstop mRNAs generate a ground state of mitochondrial gene expression noise.

• DOI: 10.1126/sciadv.abq5234
• 发表时间: 2022-11-16
• 期刊: Science advances
• 影响因子: 13.6

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.

• DOI: 10.15252/embj.2022112767
• 发表时间: 2023-07-03
• 期刊: The EMBO journal