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）： 抽象的原发性扭力肌张力障碍（PTD）是一组运动障碍，其特征是扭曲肌肉缩水，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果原因的证据。分配了八个PTD基因座（DYT1、2、4、6、7、13、17和21），但仅分离了两个基因（TOR1A-DYT1和THAP1-DYT6）。明显的基因座异质性，降低的渗透率和不同形式的PTD之间的显着表型重叠限制了位置克隆方法对肌张力障碍基因发现的成功。新的第二代测序技术与整个外显子捕获库相结合，彻底改变了我们识别引起疾病突变的能力。外显子测序基于捕获个人基因组的所有外显子，并将其测序至平均30倍覆盖范围。我们建议应用外显子组测序，以发现四个多代肌张力障碍家族中的因果突变。我们将确定每个家庭中一组受影响的人共享的编码更改。这些变化将进一步测试与其余家庭成员的疾病共隔离。通过在表型相似的小PTD家族中筛选额外的突变，将确认已确定的基因。最后，为了定义与突变相关的表型谱，将在大量的单胎PTD病例中检查每个基因。拟议的研究将导致对新型PTD基因和致病突变的鉴定，从而为理解疾病的分子病理生理和设计新的治疗性干预措施提供了关键。

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.