Molecular and cellular characterisation of an important new human DNA repair disorder

有一组罕见的遗传疾病是由通常保护我们的基因免受损害的基因突变引起的。构成我们遗传信息DNA的化学物质很容易受到各种来源的损害，包括环境暴露或细胞代谢。遗传这些DNA损伤敏感性障碍的个体有不同的症状组合，这是由突变基因的异常行为造成的。这些症状包括早衰、生长缺陷、神经退行性变、对阳光或x射线敏感以及皮肤色素沉着异常。我们最近在俄亥俄州阿米什社区发现了一种新的综合征，它不同于已知的DNA损伤敏感性疾病，如XP（着色性干皮病）、CS（科凯恩综合征）或AT（共济失调毛细血管扩张症）。受影响的个体有一种独特的症状组合，这使我们假设一种以前未报道的突变一定是导致这种综合征的原因。利用最先进的基因定位技术和基因组测序，我们已经确定了导致这种疾病的基因和突变。我们现在需要了解这种特殊的基因变化是如何引起受影响个体的症状的。这一点很重要，原因有三。首先，如果我们更好地了解受影响个体的细胞所面临的问题，我们应该能够更有效地管理他们的状况。其次，了解这种基因改变时细胞的行为将为我们提供有关未突变基因正常功能的重要信息。这是至关重要的，因为我们所有的细胞都在不断地面临DNA损伤，如果不能正确地处理这种损伤，就会导致突变，从而导致癌症、衰老和神经变性。因此，了解细胞通常用来检测、修复或耐受DNA损伤的过程，对于理解癌症和神经退行性疾病通常是如何预防的，以及它们发生的原因有很大的价值。最后，在临床环境中，我们使用化学物质和治疗方法来诱导DNA损伤，作为许多不同类型癌症的化疗和放疗。更好地了解我们的细胞是如何耐受DNA损伤的，以及如何使特定细胞更容易受到这些治疗的影响，可以帮助研究旨在改进治疗方法和开发恶性疾病的新疗法。通过一个长期的社区合作项目，我们有独特的途径获得来自受影响个人和未受影响家庭成员的皮肤活检和血液样本的细胞材料。我们的建议是在实验室测试这些细胞，以找出它们的行为与正常细胞有何不同，例如当受到DNA损伤剂的处理时。我们将使用最先进的分子生物学，显微镜和生化方法来揭示为什么突变的基因会导致这些改变的细胞行为。在整个项目过程中，我们将与当地临床医生保持密切沟通，以确保我们的发现用于优化受影响个体的治疗，我们还将确保其他研究人员了解我们的结果（通过出版物、网络和会议报告），以便我们的研究可以转化为对人类健康产生最大益处。

There are a group of rare inherited genetic disorders that are caused by the mutation of genes that normally act to protect our genes from damage. The chemical that comprises our genetic information, DNA, is susceptible to damage from a wide variety of sources, including environmental exposure or cellular metabolism. Individuals that inherit these DNA damage sensitivity disorders have distinctive combinations of symptoms, resulting from the abnormal behaviour of the mutated genes. These symptoms can include premature ageing, growth defects, neurodegeneration, sunlight or X-ray sensitivity and abnormal skin pigmentation. We recently identified a new syndrome in the Ohio Amish community that is distinct from, but appears related to, known DNA damage sensitivity conditions such as the disorders known as XP (xeroderma pigmentosum), CS (Cockayne's syndrome) or AT (ataxia telangiectasia). The affected individuals have a unique combination of symptoms that led us to hypothesize that a previously unreported mutation must be causing the syndrome. Using state of the art genetic mapping techniques and genome sequencing we have identified the gene and the mutation responsible for causing this disorder.We now need to understand what this particular genetic change does in order to cause the symptoms of the affected individuals. This is important for three reasons. Firstly, if we understand better the problems faced by the cells of affected individuals we should be able to manage their condition more effectively. Secondly, understanding how cells behave when this gene is altered will give us important information about how the unmutated gene normally functions. This is crucial because all our cells are constantly facing DNA damage, and failure to deal with this damage properly can lead to mutations that can result in cancer, ageing and neurodegeneration. A knowledge of the processes that cells normally use to detect, repair or tolerate DNA damage can therefore be hugely valuable in understanding how cancer and neurodegeneration are normally prevented, and what has to go wrong in order for them to occur. Finally, in the clinical setting we use chemicals and treatments that induce DNA damage as chemo- and radio-therapies for many different type of cancer. A better understanding of how our cells tolerate DNA damage, and how specific cells can be made more susceptible to these treatments, can help research aimed at improving therapies and developing novel treatments for malignant disease. Through a longstanding community collaborative program we have unique access to cellular material derived from skin biopsies and blood samples from the affected individuals and unaffected family members. Our proposal is to test these cells in the laboratory to find out how their behaviour differs from normal cells, for example when treated with DNA damaging agents. We will use state-of the-art molecular biology, microscopy and biochemical approaches to uncover why the mutated gene causes these altered cell behaviours. We will throughout the project keep in close communication with the local clinicians to ensure that our findings are used to optimise the treatment of the affected individuals, and we will also make sure that other researchers are informed about our results (via publication, networking and presentation at conferences), so that our research can be translated to generate maximum benefit for human health.