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Exome re-sequencing candidate loci for familial essential tremor

家族性特发性震颤候选位点的外显子组重测序

基本信息

批准号：
8263025
负责人：
BARRY E KOSOFSKY
金额：
$ 21.13万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-05-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8263025
关键词：
2p24 6p23 Address Affect Aging Alleles American Ataxia Base Pairing Binding Proteins Bioinformatics Candidate Disease Gene Chromosomes Classification Complex Computer software DNA DNA Resequencing DNA Sequence Databases Development Diagnostic Dideoxy Chain Termination DNA Sequencing Disease Dominant Genetic Conditions Dystonia Enhancers Essential Tremor European Exons Family Feline Leukemia Virus Future Gene Mutation Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genetic screening method Genome Haplotypes Hematopoietic High Prevalence Human In Vitro Individual Inheritance Patterns Inherited Intercistronic Region Knowledge Korea Koreans Lead Length Libraries Light Link Lod Score Manuscripts Methodology Missense Mutation Molecular Movement Disorders Mutation Neurobiology Nucleic Acid Regulatory Sequences Nucleotides Outcome Parkinson Disease Penetrance Phase Phenocopy Phenotype Polymorphism Analysis Population Population Database Predisposition Prevalence Process Proteins RNA Splicing Reporting Research Research Personnel Retinitis Pigmentosa Sample Size Screening procedure Singapore Single-Stranded Conformational Polymorphism Site Solid Subgroup Techniques Technology Therapeutic Intervention Transcript Tremor United States Variant base clinical practice density design diagnostic accuracy dopamine D3 receptor dorsal column effective therapy exome genetic association genetic linkage genetic variant genome-wide linkage improved in vivo Model instrumentation mutant nervous system disorder novel novel strategies outcome forecast public health relevance receptor research study transmission process

项目摘要

DESCRIPTION (provided by applicant): Essential tremor (ET) is one of the most common neurological disorders in humans with a prevalence reaching almost four percent. ET is inherited as a dominant trait with incomplete penetrance in most familial cases but complex multi-genic transmission is possible. Three genetic susceptibility loci for familial ET exist on chromosomes 3p13.1 (ETM1), 2p24 (ETM2), and 6p23 (ETM3), but the causal genes have not been identified in the families linked to these loci. Polymorphic ETM1 loci in 16 Icelandic families and a variant in the dopamine receptor D3 gene in 23 French families are associated with an ET phenotype. ETM2 loci are linked to a disease allele in four American families. Further studies suggest a tight allelic association between ETM2 and the ET phenotype in populations from the United States, Singapore, and Korea. Two North American families are linked to ETM3 loci with the largest family showing a mixed phenotype that includes dystonia in addition to ET. An unclear pattern of inheritance due to the presence of phenocopies, incomplete penetrance, and the high prevalence of ET, hinder the search for causal genes. Advances in solid- phase microarrays, and instrumentation have partially alleviated these barriers by permitting large scale DNA sequencing. Advances in genome bioinformatics and the availability of validated normative population databases (e.g. 1000 Genomes SNP database, dbSNP, and HapMap) provide the capability to filter genetic variants from putative mutations. By using this technology, we recently identified missense mutations in a novel gene, feline leukemia virus subgroup C receptor 1 gene, as the cause of the Mendelian disorder, posterior column ataxia and retinitis pigmentosa, in three unrelated families by high density sequencing of the 4.2 megabase (Mb) candidate region. This discovery confirms our expertise in all of the specific technologies required to carry out the proposed genetic studies and provides proof of principle for Specific Aim 1 to identify the genes that cause ET in two large, informative families linked to the ETM2 and ETM3 loci using high- throughput resequencing technology. We have designed a bait tiling library using 120 base-pair bait lengths for the 24.6 Mb ETM2 (48,054 baits) and the 14.4 Mb ETM3 (30,796 baits) loci to include all regulatory regions, exons, splice sites, enhancer, and conserved intergenic regions. A power analysis estimates that the sample size required to detect mutations with 95% confidence are 10 affected individuals with a disease haplotype and 10 unaffected individuals without the disease haplotype from each family linked to the ETM2 and ETM3 loci. Sanger sequencing will reconfirm the ETM2 and ETM3 mutations identified in the 20 affected individuals from the two families. These candidate genes will be Sanger sequenced in 73 additional, unrelated families with ET to identify other ETM2 and ETM3 mutations. Future experiments using in vitro and in vivo models will analyze the functional consequences of ET gene mutations during aging and development. PUBLIC HEALTH RELEVANCE: The identification of ET genes will improve diagnostic accuracy, refine the classification of tremor, and is a pivotal step toward finding effective treatments. Studying the untoward effects of mutant ET genes will increase our knowledge of ET and other movement disorders such as Parkinson disease.

描述（由申请人提供）：特发性震颤（ET）是人类最常见的神经系统疾病之一，患病率接近百分之四。 ET 作为显性性状遗传，在大多数家族病例中外显率不完全，但复杂的多基因传播是可能的。家族性 ET 的三个遗传易感位点存在于染色体 3p13.1 (ETM1)、2p24 (ETM2) 和 6p23 (ETM3) 上，但在与这些位点相关的家族中尚未鉴定出致病基因。 16 个冰岛家族中的多态性 ETM1 位点和 23 个法国家族中多巴胺受体 D3 基因的变异与 ET 表型相关。 ETM2 基因座与四个美国家庭的疾病等位基因相关。进一步的研究表明，在美国、新加坡和韩国人群中，ETM2 与 ET 表型之间存在紧密的等位关联。两个北美家族与 ETM3 基因座相关，其中最大的家族表现出混合表型，除了 ET 之外还包括肌张力障碍。由于表型的存在、不完全外显率和 ET 的高患病率，导致遗传模式不明确，阻碍了对致病基因的寻找。固相微阵列和仪器的进步允许大规模 DNA 测序，部分缓解了这些障碍。基因组生物信息学的进步和经过验证的规范群体数据库（例如 1000 Genomes SNP 数据库、dbSNP 和 HapMap）的可用性提供了从假定突变中过滤遗传变异的能力。通过使用这项技术，我们最近通过对 4.2 兆碱基 (Mb) 候选区域的高密度测序，在三个不相关的家族中发现了一种新基因（猫白血病病毒亚组 C 受体 1 基因）的错义突变，该突变是导致孟德尔紊乱、后柱共济失调和色素性视网膜炎的原因。这一发现证实了我们在进行拟议的遗传研究所需的所有特定技术方面的专业知识，并为特定目标 1 提供了原理证明，即使用高通量重测序技术识别与 ETM2 和 ETM3 位点相关的两个信息丰富的大家族中导致 ET 的基因。我们为 24.6 Mb ETM2（48,054 个诱饵）和 14.4 Mb ETM3（30,796 个诱饵）基因座使用 120 个碱基对诱饵长度设计了诱饵平铺库，以包括所有调控区、外显子、剪接位点、增强子和保守基因间区域。功效分析估计，以 95% 的置信度检测突变所需的样本量是来自与 ETM2 和 ETM3 基因座相关的每个家族的 10 个具有疾病单倍型的受影响个体和 10 个不具有疾病单倍型的未受影响个体。桑格测序将再次确认这两个家族的 20 名受影响个体中发现的 ETM2 和 ETM3 突变。这些候选基因将在 73 个其他不相关的 ET 家族中进行 Sanger 测序，以鉴定其他 ETM2 和 ETM3 突变。未来使用体外和体内模型的实验将分析 ET 基因突变在衰老和发育过程中的功能后果。公共健康相关性：ET 基因的鉴定将提高诊断准确性，完善震颤的分类，并且是寻找有效治疗方法的关键一步。研究突变 ET 基因的不良影响将增加我们对 ET 和其他运动障碍（如帕金森病）的了解。