Investigating the effects of CAG repeat structure and MSH3 variants on the molecular biology of Huntington's disease

亨廷顿氏病（HD）是一种遗传性退行性脑部疾病，患者会出现多种症状，包括不自主运动、情绪和行为变化以及痴呆。这种疾病进展缓慢，但无情地超过15-20年，并缩短寿命。我们没有任何治疗方法可以预防或减缓这种情况。病人往往需要长期复杂的护理，这给他们的照顾者和家庭以及一般医疗资源带来了相当大的压力。虽然HD是一种罕见的疾病（在英国大约每8000人中就有1人患病），但它是由基因中DNA重复片段扩增引起的30多种疾病之一。据估计，这些疾病加在一起影响到全世界300多万人（2000年1人），造成巨大的人力和经济代价。导致HD的基因突变在1993年被发现，但目前还不清楚这是如何导致大脑中特定的神经损伤和损失的。该突变由亨廷顿基因DNA中重复的“CAG”序列的扩增组成。未受影响的人有9到35个CAG重复; HD患者至少有36个，通常重复次数越多，疾病开始越早。受这种疾病影响最严重的脑神经细胞比同一患者的其他细胞含有更多的重复序列。所有人都有超过20，000个基因编码生命所需的不同蛋白质。虽然我们都有相同的基因（它们使我们成为人类），但在这些基因的确切序列中，我们每个人之间存在着成千上万的细微差异：这些差异共同使我们成为个体。我们利用这些天然差异来鉴定HD患者中罕见的基因变异，这些变异导致疾病症状的早期或晚期发作。有趣的是，这些变异存在于致病CAG重复序列的特定序列中（例如，被额外的CAA三联体中断的重复序列与更晚的疾病发作有关），以及各种DNA修复基因，如MSH 3和FAN 1。这些基因通常参与确保细胞DNA在损伤后得到修复，但它们现在与CAG重复序列的扩展/收缩有关，因此与HD有关。在这个MRC-NIH合作项目中，我们将测试这些新的蛋白质变体在DNA结合和修复反应中的作用，以确定与早发性或迟发性HD相关的蛋白质变体之间是否存在可测量的差异。如果我们能够显示出与我们的遗传数据相匹配的差异，这将使我们能够更详细地了解支持HD的分子反应-这将加速发现新的药物靶点。这个合作项目受益于将新的遗传见解与生化测试方面的成熟专业知识相结合，因此将对理解HD的驱动因素产生重大影响。

Huntington's disease (HD) is an inherited degenerative brain condition in which patients develop a mixture of symptoms including involuntary movements, changes in mood and behaviour, and dementia. The disease progresses slowly but relentlessly over 15-20 years, and is life-shortening. We have no treatments that can prevent or slow it. Patients often have complex care needs over a long period of time and these put a considerable strain on their carers and families, as well as on healthcare resources in general. Although HD is a rare condition (affecting about 1 in 8000 people in the UK), it is one of a family of over 30 diseases caused by expansion of repeating sections of DNA in genes. Together these conditions are estimated to affect over 3 million people worldwide (1 in 2000) at considerable human and economic cost. The genetic mutation causing HD was identified in 1993 but it is still unclear exactly how this leads to specific nerve damage and loss in the brain. The mutation consists of expansion of a repeating 'CAG' sequence in the DNA of the huntingtin gene. Unaffected people have between 9 and 35 CAG repeats; HD patients have at least 36, and generally the greater the number of repeats, the earlier the disease starts. The brain nerve cells that are most affected by the disease harbour more repeats than other cells in the same patient.All humans have over 20,000 genes that code for the different proteins required for life. Although we all have the same genes (they make us human) there are thousands of subtle differences between each of us in the exact sequences of these genes: together these differences make us individual. We have capitalised on these natural differences to identify rare gene variants in HD patients that lead to a surprisingly early or late onset of disease symptoms. Interestingly, these variants are found in the specific sequence of the disease-causing CAG repeat (for example, a repeat interrupted with extra CAA triplets is associated with much later disease onset) as well as in various DNA repair genes such as MSH3 and FAN1. These genes are usually involved in ensuring that cellular DNA is repaired after damage, but they are now implicated in expansion/contraction of CAG repeats and hence HD.In this MRC-NIH partnering project we will test these novel protein variants in DNA binding and repair reactions to see whether there are measurable differences between those associated with early or late onset HD. If we can show differences that match our genetic data this will enable us to understand the molecular reactions underpinning HD in much more detail- and this will accelerate the discovery of novel drug targets. This partnering project benefits from combining novel genetic insights with established expertise in biochemical tests and so stands to generate significant impact in understanding what drives HD.