Genetic Dissection of Trisomy 21

21 三体的基因剖析

基本信息

批准号：
8066350
负责人：
Eugene Yu
金额：
$ 43.22万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8066350
关键词：
Adult Affect Age-Months Alleles Alzheimer&apos s Disease Aneuploidy Candidate Disease Gene Cardiac Cardiovascular system Child Chromosomes Chromosomes, Human, Pair 10 Chromosomes, Human, Pair 16 Congenital Heart Defects Congenital chromosomal disease Defect Development Diagnosis Disease Dissection Down Syndrome Engineering Event Exhibits Gene Expression Generations Genes Genetic Genetic Processes Genomics Genotype Goals Hereditary Disease Human Human Chromosomes Human Genetics Individual Institutes Knock-out Knockout Mice Laboratories Lead Life Maps Mental Retardation Methodology Modeling Molecular Morphogenesis Mouse Strains Mus Mutant Strains Mice Mutate Nerve Degeneration Neurologic Newborn Infant Orthologous Gene Patients Phenotype Ploidies Prevention Process Research Resources Screening procedure Senile Plaques System Transgenic Mice United States base clinically significant congenital heart disorder disease phenotype dosage early onset gastrointestinal genetic analysis genome-wide insight leukemia malformation mouse genome mouse model mutant neuropathology novel strategies skeletal vector

项目摘要

DESCRIPTION (provided by applicant): Trisomy 21/Down syndrome (DS) is one of the most important human genetic diseases. It currently affects approximately 350,000 people in the United States and more than 2,000,000 people worldwide. It is the most frequent live-born human aneuploidy. It is the most common genetic cause of congenital heart disease and mental retardation. It is a leading cause of gastrointestinal anomalies and megakaryoblastic leukemia. It causes early-onset Alzheimer-type neurodegeneration in nearly every individual with DS. The prevailing hypothesis is that the DS phenotypes are caused by the dosage imbalances of the specific genes on human chromosome (HSA) 21, which is supported by mouse-based experimental results. Many DS phenotypes, including valvuloseptal defects, megakaryoblastic leukemia, and amyloid plaque neuropathology, are highly specific and rarely observed in other human chromosomal disorders, suggesting that these phenotypes are the consequences of the triplications of specific causative genes on HSA 21. However, the efforts to isolate these genes have not been successful due to lacking of an effective approach. In this application, we propose a new genetic analysis strategy for DS based largely on generating and analyzing mouse mutants carrying nested duplications and deletions in the HSA 21 syntenic regions. The strategy is capable of isolating the causative genes for DS phenotypes and predicted to be efficient for the following reasons: (1) We have established the first group of the mouse models of DS trisomic for all of the HSA 21 syntenic regions on mouse chromosomes 10, 16, and 17 and exhibiting DS phenotypes. (2) We have established the MICER resource which provides the ready-made targeting vectors for efficient chromosome engineering in any regions of the mouse genome. (3) The Sanger Institute has approved our request to complete the public effort in generating the knockout mice for all of the orthologs of the HSA 21 genes and has begun the process of mutating 54 of these genes. A major task of studying any human genetic diseases is genetic analysis of the disorders with the goal of isolating the causative genes for the disease phenotypes because subsequent studies on these genes may unravel the true mechanisms of the disorders which are otherwise unattainable. The aims of this discovery-driven proposal are in-depth characterization of DS-associated congenital cardiovascular malformations in our new mutant mice and genetic dissection of this phenotype to identify the critical genomic region(s) and ultimately the causative gene(s). The attainment of our objectives should unravel the entry points to the mechanistic details leading to congenital cardiovascular malformations in DS and may yield rare insights on cardiac development, which may lead to novel strategies for prevention, diagnosis, and treatment of congenital heart disease in children and adults regardless of their states of ploidy. The genetic analysis strategy refined and new mouse mutants generated through this study will have a lasting impact on DS research and will particularly benefit the efforts to isolate causative genes for other major phenotypes of DS.

描述（由申请人提供）：三体疾病/唐氏综合症（DS）是最重要的人类遗传疾病之一。目前，它影响了美国约35万人，全球有超过2,000,000人。它是最常见的现场直播人类倍倍。它是先天性心脏病和智力低下的最常见遗传原因。这是胃肠道异常和巨核细胞白血病的主要原因。它导致几乎每个患有DS的人都会引起早期发作的阿尔茨海默氏症神经变性。流行的假设是DS表型是由人类染色体（HSA）21的特定基因的剂量失衡引起的，该基因受基于小鼠的实验结果支持。许多DS表型，包括瓣膜缺陷，巨型质细胞性白血病和淀粉样菌斑神经病理学，在其他人类染色体疾病中非常具体且很少观察到，这表明这些表型是对特定遗传的疾病的影响，这些遗传是对HSA 21 21的特定遗传的影响。方法。在此应用中，我们为DS提出了一种新的遗传分析策略，主要基于生成和分析HSA 21同时区域中携带嵌套重复和缺失的小鼠突变体。该策略能够隔离DS表型的致病基因，并由于以下原因被预测：（1）我们已经在所有HSA Trisomic的小鼠模型中为所有HSA 21的HSA 21同步区域建立了小鼠染色体上的同步区域10、16，17和17，并展示了DS现象。（2）我们已经建立了米粉资源，该资源为小鼠基因组任何区域的有效染色体工程提供了现成的靶向向量。（3）Sanger Institute已批准我们的请求，以完成公众为HSA 21基因的所有直系同源物生成淘汰小鼠的努力，并开始突变这些基因的54个过程。研究任何人类遗传疾病的一项主要任务是对疾病的遗传分析，目的是隔离疾病表型的病因基因，因为随后对这些基因的研究可能会揭示疾病的真实机制，而这些机制原本是无法实现的。该发现驱动的建议的目的是在我们的新突变小鼠中对DS相关的先天性心血管畸形的深入表征以及该表型的遗传解剖，以识别关键基因组区域和最终导致基因。实现我们的目标应阐明入口指向机械细节导致先天性心血管畸形的机械细节，并可能对心脏发展产生罕见的见解，这可能会导致新的预防，诊断和治疗儿童和成人的先天性心脏病的新策略，无论其颇具友善的状态。通过这项研究产生的遗传分析策略和新的小鼠突变体将对DS研究产生持久的影响，并特别受益于隔离DS的其他主要表型的致病基因的努力。