Genetic analysis in families with neurological disease

神经系统疾病家族的遗传分析

基本信息

批准号：
7732376
负责人：
Andrew B Singleton
金额：
$ 66.16万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

The identification of gene mutations causing disease lends new insight into the pathogenesis and etiology of the disorder under examination. The past year has been incredibly successful for the Laboratory of Neurogenetics in terms of disease gene identification. Our identification of mutation at ITPR1 as the cause of SCA15 was expanded upon by us and others, defining other families with ataxia and mutation at this locus, and the relevance of this work was further bolstered by the observation by others that SCA16, formerly thought to be distinct from SCA15 is actually allelic, something we predicted in our original cloning paper. Also in ataxia, we identified with our collaborators, the genetic mutation underlying SCA11, which turned out to be mutation of the gene TTBK2, implicated in the phosphorylation of microtubule protein tau, a protein central to several forms of neurodegenerative disease. Most recently our work describing the mutation underlying SCA20 has been accepted for publication; this work shows clearly that in the only family described to date, the disease is associated with a large genomic duplication. In the field of parkinsonism and dystonia we made two findings, in the first we identified a novel locus for dystonia parkinsonism and describe a disease segregating mutation in the gene PRKRA; in the second we show that mutation in PLA2G6, previously associated with a distinct neurodegeneration with brain iron accumulation, can cause a form of dystonia parkinsonism.

引起疾病的基因突变的鉴定为所检查疾病的发病机制和病因学提供了新的见解。过去的一年，神经遗传学实验室在疾病基因识别方面取得了令人难以置信的成功。我们和其他人扩展了我们对 ITPR1 突变作为 SCA15 病因的鉴定，定义了其他患有共济失调和该基因座突变的家族，并且其他人的观察进一步支持了这项工作的相关性，即 SCA16（以前被认为是与 SCA15 不同的是，它实际上是等位基因，这是我们在最初的克隆论文中预测的。同样在共济失调中，我们与合作者一起发现了 SCA11 的基因突变，结果证明它是 TTBK2 基因的突变，与微管蛋白 tau 的磷酸化有关，微管蛋白 tau 是几种神经退行性疾病的核心蛋白。最近，我们描述 SCA20 潜在突变的工作已被接受发表；这项工作清楚地表明，在迄今为止描述的唯一一个家族中，该疾病与大量基因组重复有关。在帕金森症和肌张力障碍领域，我们取得了两项发现，第一个发现是肌张力障碍帕金森症的新基因座，并描述了 PRKRA 基因中的一种疾病分离突变；在第二个研究中，我们发现 PLA2G6 的突变（之前与脑铁积累引起的明显神经变性有关）可导致某种形式的肌张力障碍帕金森病。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multiple system atrophy: the application of genetics in understanding etiology.

DOI：
10.1007/s10286-014-0267-5
发表时间：
2015-02
期刊：
CLINICAL AUTONOMIC RESEARCH
影响因子：
5.8
作者：
Federoff, Monica;Schottlaender, Lucia V.;Houlden, Henry;Singleton, Andrew
通讯作者：
Singleton, Andrew

Mutation analysis of patients with neurodegenerative disorders using NeuroX array.

DOI：
10.1016/j.neurobiolaging.2014.07.038
发表时间：
2015-01
期刊：
Neurobiology of aging
影响因子：
4.2
作者：
Ghani M;Lang AE;Zinman L;Nacmias B;Sorbi S;Bessi V;Tedde A;Tartaglia MC;Surace EI;Sato C;Moreno D;Xi Z;Hung R;Nalls MA;Singleton A;St George-Hyslop P;Rogaeva E
通讯作者：
Rogaeva E

Clinical heterogeneity and genotype-phenotype correlations in hereditary spastic paraplegia because of Spatacsin mutations (SPG11).