Gene discovery in primary dystonia using whole exome sequencing

使用全外显子组测序发现原发性肌张力障碍的基因

• 批准号: 8423313
• 负责人: Laurie J. Ozelius
• 金额: $ 24.54万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423313
• 关键词: Adult; Affect; Age of Onset; Biological; Biological Markers; Cephalic; Cervical; Childhood; Clinical; Code; Collection; Complex; Contracture; DNA; DNA Resequencing; Development; Disease; Dystonia; Dystonia Musculorum Deformans; Exons; Family; Family member; Foundations; Functional disorder; Generations; Genes; Genetic; Genetic Variation; Genetic screening method; Grant; Heterogeneity; Human Genome; Individual; Lead; Libraries; Limb structure; Molecular; Movement Disorders; Muscle; Mutation; Nerve Degeneration; Pathway interactions; Patients; Penetrance; Phenotype; Population Heterogeneity; Primary Dystonias; Research; Site; TOR1A gene; Techniques; Technology; Testing; Variant; base; cohort; disease-causing mutation; early onset; exome; exome sequencing; gene discovery; genetic risk factor; genome sequencing; innovation; insight; novel; novel therapeutic intervention; positional cloning; screening; segregation; success; therapeutic target; tool

DESCRIPTION (provided by applicant): ABSTRACT Primary torsion dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign and there is no evidence of neuronal degeneration or an acquired cause. There are eight PTD loci assigned (DYT1, 2, 4, 6, 7, 13, 17 and 21), but only two of the genes (TOR1A-DYT1 and THAP1-DYT6) have been isolated. Apparent locus heterogeneity, reduced penetrance and significant phenotypic overlap between different forms of PTD limit the success of positional cloning approaches for dystonia gene discovery. New second generation sequencing technologies combined with whole exome capture libraries have revolutionized our ability to identify disease-causing mutations. Exome sequencing is based on capturing all exons of an individual's genome and sequencing them to an average 30X depth of coverage. We propose to apply exome sequencing to discover causative mutations in four multi- generation dystonia families. We will identify coding changes shared by a group of affected individuals in each family. These changes will be further tested for co-segregation with the disease in the remaining family members. The identified genes will be confirmed by screening for additional mutations in a collection of phenotypically similar small PTD families. Finally, in order to define the phenotypic spectrum associated with mutations, each gene will be examined in a large cohort of singleton PTD cases. The proposed research will lead to the identification of novel PTD genes and pathogenic mutations thus providing a key to understanding the molecular pathophysiology of the disease and the foundation for devising new therapeutic interventions.

描述（由申请人提供）： 摘要 原发性扭转性肌张力障碍 (PTD) 是一组以扭转性肌肉挛缩为特征的运动障碍，其中肌张力障碍是唯一的临床症状，并且没有神经元变性或后天原因的证据。有八个指定的 PTD 位点（DYT1、2、4、6、7、13、17 和 21），但仅分离出其中两个基因（TOR1A-DYT1 和 THAP1-DYT6）。不同形式的 PTD 之间明显的基因座异质性、外显率降低和显着的表型重叠限制了肌张力障碍基因发现的定位克隆方法的成功。新的第二代测序技术与全外显子组捕获文库相结合，彻底改变了我们识别致病突变的能力。外显子组测序的基础是捕获个体基因组的所有外显子，并对它们进行平均 30 倍覆盖深度的测序。我们建议应用外显子组测序来发现四个多代肌张力障碍家族的致病突变。我们将确定每个家庭中受影响的一组人共享的编码更改。这些变化将在其余家庭成员中进一步测试与疾病的共隔离。将通过在一系列表型相似的小型 PTD 家族中筛选其他突变来确认已识别的基因。最后，为了定义与突变相关的表型谱，将在一大群单一 PTD 病例中检查每个基因。拟议的研究将导致新的 PTD 基因和致病突变的鉴定，从而为理解该疾病的分子病理生理学提供关键，并为设计新的治疗干预措施奠定基础。

项目成果

Genetics in dystonia: an update.

• DOI: 10.1007/s11910-013-0410-z
• 发表时间: 2013-12
• 期刊: CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS
• 影响因子: 5.6
• 作者: Fuchs, Tania;Ozelius, Laurie J.
• 通讯作者: Ozelius, Laurie J.