Assessment of Candidate Loci in Neurological diseases

神经系统疾病候选基因座的评估

• 批准号: 7732375
• 负责人: Andrew B Singleton
• 金额: $ 50.82万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7732375
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Ataxia; Code; Data; Disease; Dystonia; Exons; Family; Frequencies; Funding; Gene Dosage; Genes; ITPR1 gene; Individual; LRRK2 gene; Lead; Molecular; Multiple System Atrophy; Mutation; Nature; PARK2 gene; PARK6 gene; PARK7 gene; Parkinson Disease; Patients; Prevalence; Primary Lateral Sclerosis; Process; Protocols documentation; Publishing; Research; Risk; Screening procedure; Somatic Mutation; TOR1A gene; United States National Institutes of Health; Variant; Work; alpha synuclein; brain tissue; cohort; insight; nervous system disorder; neurogenetics; novel; programs; repository; research study; synuclein

During the past year we have published several studies identifying the extent and nature of LRRK2 mutation and variation. This work has been performed primarily in Parkinsons disease patients. Unlike most protocols we have taken a full screening approach, sequencing all 51 coding exons of LRRK2. In one of the cohorts used for this analysis, available from the NIH funded neurogenetics repository, we have also performed full sequence and gene dosage analysis of PARK2 and PARK6 loci. These data show a high level of PARK mutations and also demonstrate that mutations which are pathogenic when homozygous are present at a relatively high frequency (2%) as heterozygous changes in controls; this opposes a popular view that such heterozygous mutations act as risk loci for typical sporadic forms of Parkinson's disease. We have continued assessment of PARK2, PARK6, PARK7, GCH1 and SNCA in Parkinson's disease cohorts, GCH1, PRKRA (identified by us) and TOR1A in dystonia cohorts and TTBK2, ITPR1 and SCA20 (all identified by us) in ataxia cohorts. This work has lead to the identification of several novel mutations. We have, in addition, initiated a program of research in another synucleinopathy, multiple system atrophy, to examine brain tissue from subjects for this disease for somatic mutation at the synuclein locus, in addition to looking for the potential effects of synuclein SNPs as risk modifiers in this disease. Our work on ALS has focussed on the examination of cases for mutations in SOD1, IFT74 and TDP43 and has resulted in the estimation of prevalence of such mutations and the identification of novel disease associated variants.

在过去的一年里，我们发表了几项研究，确定了 LRRK2 突变和变异的程度和性质。这项工作主要在帕金森病患者中进行。与大多数方案不同，我们采取了全面筛选方法，对 LRRK2 的所有 51 个编码外显子进行测序。在用于此分析的队列之一（可从 NIH 资助的神经遗传学存储库中获取）中，我们还对 PARK2 和 PARK6 位点进行了完整序列和基因剂量分析。这些数据显示了高水平的 PARK 突变，并且还证明纯合时致病的突变与对照中的杂合变化相比以相对较高的频率 (2%) 存在；这与一种流行的观点相反，即这种杂合突变是典型散发性帕金森病的风险位点。 我们继续评估帕金森病队列中的 PARK2、PARK6、PARK7、GCH1 和 SNCA，肌张力障碍队列中的 GCH1、PRKRA（由我们鉴定）和 TOR1A，以及共济失调队列中的 TTBK2、ITPR1 和 SCA20（均由我们鉴定）。这项工作导致了几种新突变的鉴定。 此外，我们还启动了另一种突触核蛋白病（多系统萎缩）的研究计划，以检查患有这种疾病的受试者的脑组织中突触核蛋白位点的体细胞突变，此外还寻找突触核蛋白 SNP 作为风险调节剂的潜在影响。在这种疾病中。 我们在 ALS 方面的工作重点是检查 SOD1、IFT74 和 TDP43 突变病例，从而估计此类突变的患病率并鉴定新的疾病相关变异。

项目成果

Familiality in simple and complex disease.

熟悉简单和复杂疾病。

• DOI: 10.1007/s10286-003-0091-9
• 发表时间: 2003
• 期刊: Clinical autonomic research : official journal of the Clinical Autonomic Research Society
• 作者: Singleton,Andrew

Parkin-related disease clinically diagnosed as a pallido-pyramidal syndrome.

Parkin相关疾病临床诊断为苍白锥体综合征。

• DOI: 10.1002/mds.22181
• 发表时间: 2009
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Wickremaratchi,MindhuM;Majounie,Elisa;Morris,HuwR;Williams,NigelM;Lewis,Helen;Gill,StevenS;Khan,Sadaquate;Heywood,Peter;Hardy,John;Wiles,CharlesM;Singleton,AndrewB;Quinn,NiallP
• 通讯作者: Quinn,NiallP

Rapid genetic diagnosis in single-gene movement disorders.

单基因运动障碍的快速基因诊断。

• DOI: 10.1002/mds.24896
• 发表时间: 2012
• 期刊: Movement disorders : official journal of the Movement Disorder Society
• 作者: Singleton,AndrewB

Analysis of Nigerians with apparently sporadic Parkinson disease for mutations in LRRK2, PRKN and ATXN3.

• DOI: 10.1371/journal.pone.0003421
• 发表时间: 2008
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Okubadejo, Njideka;Britton, Angela;Crews, Cynthia;Akinyemi, Rufus;Hardy, John;Singleton, Andrew;Bras, Jose
• 通讯作者: Bras, Jose

A case of dementia with PRNP D178Ncis-129M and no insomnia.

• DOI: 10.1097/wad.0b013e3181ae3a76
• 发表时间: 2009-10
• 期刊: Alzheimer disease and associated disorders
• 影响因子: 2.1
• 作者: Guerreiro RJ;Vaskov T;Crews C;Singleton A;Hardy J
• 通讯作者: Hardy J