Genetic Dissection of Trisomy 21

21 三体的基因剖析

• 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
• 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' 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

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（申请人提供）：21三体/唐氏综合症（DS）是最重要的人类遗传病之一。目前，美国约有 35 万人受到影响，全球范围内有超过 200 万人受到影响。它是最常见的活产人类非整倍体。它是先天性心脏病和智力低下最常见的遗传原因。它是胃肠道异常和巨核细胞白血病的主要原因。它会导致几乎所有 DS 患者出现早发性阿尔茨海默型神经变性。普遍的假设是 DS 表型是由人类 21 号染色体 (HSA) 上特定基因的剂量不平衡引起的，这一点得到了基于小鼠的实验结果的支持。许多 DS 表型，包括瓣膜间隔缺陷、巨核细胞白血病和淀粉样斑块神经病理学，具有高度特异性，在其他人类染色体疾病中很少观察到，表明这些表型是 HSA 21 上特定致病基因三倍体的结果。然而，由于缺乏有效的方法，分离这些基因的努力并未成功。 方法。在此应用中，我们提出了一种新的 DS 遗传分析策略，主要基于生成和分析在 HSA 21 同线性区域中携带嵌套重复和缺失的小鼠突变体。该策略能够分离DS表型的致病基因，并预计是有效的，原因如下：（1）我们建立了第一组DS三体小鼠模型，其小鼠10、16和17号染色​​体上的所有HSA 21同线区域均表现出DS表型。 (2) 我们建立了MICER资源，为小鼠基因组任何区域的高效染色体工程提供现成的靶向载体。 (3) 桑格研究所已批准我们的请求，完成公共努力，生成 HSA 21 基因所有直系同源基因的敲除小鼠，并已开始对其中 54 个基因进行突变。研究任何人类遗传疾病的一个主要任务是对疾病进行遗传分析，目的是分离疾病表型的致病基因，因为对这些基因的后续研究可能会揭示疾病的真正机制，而这是其他方法无法实现的。这一发现驱动的提案的目的是深入表征我们的新突变小鼠中与 DS 相关的先天性心血管畸形，并对这种表型进行遗传解剖，以确定关键的基因组区域和最终的致病基因。我们的目标的实现应该揭示导致 DS 先天性心血管畸形的机制细节的切入点，并可能产生关于心脏发育的罕见见解，这可能会导致儿童和成人先天性心脏病的预防、诊断和治疗的新策略，无论其倍性状态如何。通过这项研究改进的遗传分析策略和产生的新小鼠突变体将对 DS 研究产生持久影响，并将特别有利于分离 DS 其他主要表型的致病基因。