ERANET 1 NEURON 3: Identification of copy number variants in familial and pathologically proven PD

人类基因组计划最初的主要影响之一是我们对基因组多样性知之甚少。在过去的2-3年里，很明显，人类基因组的很大一部分在拷贝数量上存在巨大的差异。有一些引人注目的例子表明拷贝数导致人类疾病。神经系统疾病的最佳特征是PMP22周围的重排引起CMT1a和遗传性压力性麻痹。在帕金森病中，在目前鉴定的基因中，大多数都发现了重排，包括a-synuclein(1)、parkin(2)和PINK1(3)。事实上，a-突触核蛋白复制或三倍复制是最常见的突变机制。拷贝数变异（CNVs）可以从两方面考虑。首先，罕见的情况下（如上所述），基因组区域的重复或缺失可能导致高渗透的“孟德尔”形式的疾病。第二，“共同”重排在对疾病的易感性中有潜在的作用。在PD的情况下，上面列出的重排都是在经典的位置克隆策略确定它们为PD基因后发现的，并且在这些基因的遗传特征中证明了重排。遗传技术的最新进展使得对CNVs的快速、稳健的全基因组搜索成为可能。我们计划对我们的一系列患者进行CNVs筛查。本质上，我们将在我们的隐性家族中寻找CNV，特别强调纯合重排。这项工作补充了子项目2的目标。我们也知道，单杂合重排可引起常染色体显性疾病（如a-syn）。因此，在子项目1的同时，我们将询问AD - PD家族。最后，“常见”CNVs在帕金森病中的作用尚未得到评估，我们将对400例散发性病理证实的帕金森病进行全基因组搜索。

One of the major initial impacts of the human genome project was how little we understood about genomic diversity. Over the past 2-3 years it has become clear that there is tremendous variation in the numbers of copies of a large proportion of the human genome. There are some striking examples of copy numbers leading to human disease. The best characterised in neurological disease is the rearrangements around PMP22 giving rise to CMT1a and hereditary liability to pressure palsies. In Parkinson’s disease, of the currently identified genes,rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-synuclein duplication or triplication is the commonest mutational mechanism. Copy number variation (CNVs) can be considered in 2 broad ways. First there are rare occurrences (as above) where the duplication or deletion of genomic region may lead to a highly penetrant ‘mendelian’ form of disease. In the second, there is the potential role of ‘common’ rearrangements in susceptibility to disease. In the case of PD the rearrangementslisted above were all found after classical positional cloning strategies had identified them as PD genes and it was during the genetic characterisation of these genes that the rearrangements were demonstrated. Recent advances in genetic technologies allows for a rapid, robust genome wide search for CNVs. We plan to screen our series of patients for CNVs. In essence we will look in our recessive families for CNV, with particular emphasis on homozygous rearrangements. This work complements the objectives of subproject 2. We are also aware that single heterozygous rearrangements can cause autosomal dominant disease (eg a-syn). Therefore, in parallel with subproject 1 we will interrogate our AD PD families. Finally the role of ‘common’ CNVs has not been assessed in PD and we will adopt a genome wide search in 400 cases of sporadic pathologically proven PD.