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.

在过去的一年中，我们发表了几项研究，以确定LRRK2突变和变异的程度和性质。这项工作主要是在帕金森病患者中进行的。与大多数协议不同，我们采用了完整的筛选方法，对LRRK2的所有51个编码外显子进行了测序。在该分析中使用的同类之一，可从NIH资助的神经源性存储库中获得，我们还对PARK2和PARK6 Loci进行了完整的序列和基因剂量分析。这些数据显示了高水平的公园突变，并且还表明，当纯合频率以杂合的变化而存在纯合的频率（2％）时具有致病性的突变；这反对一种流行的观点，即这种杂合突变是典型的帕金森氏病的典型零星形式的风险基因座。 我们一直在帕金森氏病同伴，GCH1，PRKRA（由美国鉴定）和Dystonia Cohorts和TTBK2，ITPR1和SCA20（我们所有的Ataxia Cohorts中的park6，Park7，GCH1和SNCA）评估。这项工作导致了几个新型突变的识别。 此外，我们还在另一种突触核力病（多个系统萎缩）中启动了一项研究计划，以检查这种疾病的受试者的脑组织，除了寻找突触包括在这种疾病中的风险修饰剂的潜在影响外，还要研究突触核蛋白基因座的体细胞突变。 我们在ALS上的工作集中在检查SOD1，IFT74和TDP43中突变病例的检查，并导致了这种突变患病率的估计以及与新型疾病相关变体的鉴定。

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

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

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

Genetic players in multiple system atrophy: unfolding the nature of the beast.

• DOI: 10.1016/j.neurobiolaging.2011.04.001
• 发表时间: 2011-10
• 期刊: Neurobiology of aging
• 影响因子: 4.2
• 作者: Stemberger S;Scholz SW;Singleton AB;Wenning GK
• 通讯作者: Wenning GK