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

ERANET 1 NEURON 3：家族性和病理证实的 PD 中拷贝数变异的识别

• 批准号: MC_PC_09003
• 负责人: Nicholas Wood
• 金额: $ 39.41万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_PC_09003
• 关键词: ERANET; NEURON; Identification; copy; number

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.

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的了解是多么少。在过去的2-3年里，很明显，人类基因组的大部分拷贝数存在巨大的差异。有一些令人震惊的例子表明，基因拷贝数导致人类疾病。在神经系统疾病中，最具特征的是PMP 22周围的重排，引起CMT 1a和遗传性压力性麻痹。在帕金森病中，在目前鉴定的基因中，大多数基因都发现了重排，包括a-突触核蛋白（1），parkin（2）和PINK 1（3）。事实上，对于α-突触核蛋白来说，重复或三倍是最常见的突变机制。拷贝数变异（CNVs）可以以两种广泛的方式考虑。首先，有罕见的发生（如上所述），其中基因组区域的复制或缺失可能导致高度渗透的“孟德尔”形式的疾病。在第二种情况下，存在“常见”重排在疾病易感性中的潜在作用。在帕金森病的情况下，上述重排都是在经典的位置克隆策略将其鉴定为帕金森病基因后发现的，并且在这些基因的遗传表征过程中证实了重排。遗传技术的最新进展允许对CNV进行快速、稳健的全基因组搜索。我们计划对我们的一系列患者进行CNV筛查。本质上，我们将在我们的隐性家系中寻找CNV，特别强调纯合重排。这项工作补充了次级项目2的目标。我们还意识到单个杂合重排可能导致常染色体显性遗传病（例如a-syn）。因此，在子项目1的同时，我们将询问我们的AD PD家族。最后，尚未评估“常见”CNVs在PD中的作用，我们将在400例经病理证实的散发性PD病例中采用全基因组搜索。

项目成果

NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases.

• DOI: 10.1016/j.neurobiolaging.2017.05.009
• 发表时间: 2017-09
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Blauwendraat C;Faghri F;Pihlstrom L;Geiger JT;Elbaz A;Lesage S;Corvol JC;May P;Nicolas A;Abramzon Y;Murphy NA;Gibbs JR;Ryten M;Ferrari R;Bras J;Guerreiro R;Williams J;Sims R;Lubbe S;Hernandez DG;Mok KY;Robak L;Campbell RH;Rogaeva E;Traynor BJ;Chia R;Chung SJ;International Parkinson's Disease Genomics Consortium (IPDGC), COURAGE-PD Consortium;Hardy JA;Brice A;Wood NW;Houlden H;Shulman JM;Morris HR;Gasser T;Krüger R;Heutink P;Sharma M;Simón-Sánchez J;Nalls MA;Singleton AB;Scholz SW
• 通讯作者: Scholz SW

Genome-wide association studies: the key to unlocking neurodegeneration?

• DOI: 10.1038/nn.2584
• 发表时间: 2010-07-01
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Gandhi, Sonia;Wood, Nicholas W.
• 通讯作者: Wood, Nicholas W.

Mutations in HPCA cause autosomal-recessive primary isolated dystonia.

• DOI: 10.1016/j.ajhg.2015.02.007
• 发表时间: 2015-04-02
• 期刊: American journal of human genetics
• 影响因子: 9.8
• 作者: Charlesworth G;Angelova PR;Bartolomé-Robledo F;Ryten M;Trabzuni D;Stamelou M;Abramov AY;Bhatia KP;Wood NW
• 通讯作者: Wood NW

Mutations in ANO3 Cause Dominant Craniocervical Dystonia: Ion Channel Implicated in Pathogenesis

• DOI: 10.1016/j.ajhg.2012.10.024
• 发表时间: 2012-12-07
• 期刊: AMERICAN JOURNAL OF HUMAN GENETICS
• 影响因子: 9.8
• 作者: Charlesworth, Gavin;Plagnol, Vincent;Wood, Nicholas W.
• 通讯作者: Wood, Nicholas W.