TORSIN GENE FAMILY AND DYSTONIA AND MODIFYING GENES

Torsin 基因家族与肌张力障碍和修饰基因

• 批准号: 6151622
• 负责人: Laurie J. Ozelius
• 金额: $ 21.24万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-30 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6151622
• 关键词: Jewish; autosomal dominant trait; dystonia; gene deletion mutation; gene expression; gene mutation; gene targeting; genetic carriers; genetic library; genetic models; genetic susceptibility; genetically modified animals; human genetic material tag; laboratory mouse; linkage mapping; model design /development; molecular cloning; neuromuscular disorder; nucleic acid sequence; single strand conformation polymorphism; site directed mutagenesis

Early onset torsion dystonia is movement disorder inherited in an autosomal dominant manner with reduced penetrance, that is characterized by twisting muscle contractures. Symptoms are believed to result from abnormality in the basal ganglia. The gene for this disorder, DYT1 has recently been cloned by our group and shown to contain a 3-bp deletion (GAG), removing a glutamic acid in a conserved region that is uniquely associated with affect status. In addition, this gene is related to three other highly homologous human genes (TORB, TRP1, TRP2). This proposal is aimed at characterizing the DYT1 gene and its relatives, determining genetic factors that may influence the penetrance of the disease, and generating an authentic murine model for the disorder. The genomic structure of the DYT1 and TORB genes will be fully characterized making possible efficient mutation screening, antibody production, and biochemical analyses in conjunction with the other cores and projects in this program. The TRP1 and TRP2 genes will be isolated from cDNA libraries, their expression patterns and chromosomal locations determined and scanned for involvement in other forms of dystonia using linkage analysis in non-9q34 linked families. If warranted, single- stranded conformation polymorphism analysis (SSCP) and direct sequencing of RNA/PCR products will be used to detect mutations in these genes. Affected genes which modify the expression of the GAG deletion resulting in the high level (60-70 percent) of reduced penetrance among carriers of the mutation. Various candidate genes will be screened first then, if necessary, we will proceed to a full genome scan. We also propose to generate targeted transgenic mice where the mouse DYT1 gene harboring the GAG deletion is introduced into the endogenous mouse locus by homologous recombination in ES cells. These animals will be analyzed for neuromorphological and behavioral phenotypes. The studies proposed here should help to elucidate how the deletion of a Glu residue causes early onset dystonia and the genetic factors that may modify its expression. This knowledge should lead to a better understanding of basal ganglia function and possible therapeutic interventions that could result in milder phenotypes.

早发性扭转肌张力障碍是一种遗传性运动障碍 外显率降低的常染色体显性方式，其特征是 通过扭转肌肉挛缩。 症状被认为是由 基底神经节异常。 这种疾病的基因 DYT1 有 最近被我们的团队克隆并显示包含 3-bp 删除 (GAG)，去除独特的保守区域中的谷氨酸 与情感状态相关。 此外，该基因还与 其他三个高度同源的人类基因（TORB、TRP1、TRP2）。 这 该提案旨在表征 DYT1 基因及其亲属， 确定可能影响外显率的遗传因素 疾病，并生成该疾病的真实小鼠模型。 这 DYT1 和 TORB 基因的基因组结构将得到全面表征 使有效的突变筛选、抗体生产和 与其他核心和项目结合进行生化分析 在这个节目中。 TRP1和TRP2基因将从cDNA中分离出来 文库、它们的表达模式和染色体位置 使用以下方法确定和扫描是否涉及其他形式的肌张力障碍 非 9q34 连锁家族的连锁分析。 如果有必要，单 链构象多态性分析（SSCP）和直接测序 RNA/PCR 产品将用于检测这些基因的突变。 受影响的基因会修改 GAG 缺失的表达 携带者外显率降低程度较高（60-70%） 的突变。然后先筛选各种候选基因， 如有必要，我们将进行全基因组扫描。 我们还建议 产生携带 DYT1 基因的靶向转基因小鼠 通过以下方式将 GAG 缺失引入到内源性小鼠基因座中 ES细胞中的同源重组。 这些动物将被分析 用于神经形态学和行为表型。 提出的研究 这里应该有助于阐明 Glu 残基的删除是如何导致的 早发性肌张力障碍和可能改变其的遗传因素 表达。 这些知识应该有助于更好地理解 基底神经节功能和可能的治疗干预措施 导致较温和的表型。

项目成果

Expression profiling in peripheral blood reveals signature for penetrance in DYT1 dystonia.

外周血中的表达谱揭示了 DYT1 肌张力障碍的外显率特征。

• DOI: 10.1016/j.nbd.2009.12.019
• 发表时间: 2010
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Walter,M;Bonin,M;Pullman,RSaunders;Valente,EM;Loi,M;Gambarin,M;Raymond,D;Tinazzi,M;Kamm,C;Glöckle,N;Poths,S;Gasser,T;Bressman,SB;Klein,C;Ozelius,LJ;Riess,O;Grundmann,K
• 通讯作者: Grundmann,K