TRISOMY 21 MOSAICISM, APP GENE MUTATIONS AND DEMENTIA IN DOWN'S SYNDROME ADULTS

成人唐氏综合症患者的 21 三体嵌合体、APP 基因突变和痴呆

• 批准号: 6234434
• 负责人: NICOLE SCHUPF
• 金额: $ 17.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234434
• 关键词: Alzheimer's disease; Downs syndrome; adult human (21+); age difference; amyloid proteins; behavior test; blood chemistry; chromosome 21; chromosome translocation; data collection; dementia; disease /disorder proneness /risk; family genetics; gene mutation; genetic polymorphism; genetic promoter element; human population study; human subject; interview; karyotype; neuropsychological tests; nucleic acid sequence; polymerase chain reaction; questionnaires; statistics /biometry; trisomy

This study will investigate genetic risk factors for dementia in individuals with Down syndrome (DS) and their relatives. The brains of virtually all adults with Down syndrome show high densities of senile plaques and neurofibrillary tangles characteristic of the pathological changes of Alzheimer disease (AD), and individuals with DS are at increased risk for clinical dementia. A shared genetic susceptibility to DS and AD is supported by the findings of increased prevalence of DS births to women who themselves have AD or whose relatives have AD, by findings of increased frequency of AD in relatives of individuals with DS, and by linkage of early-onset familial AD to chromosome 21. The gene for beta-amyloid precursor protein (APP) has been localized to chromosome 21 and the early occurrence of AD pathology in adults with DS has been attributed to increased expression of beta-amyloid. However, not all individuals with DS and AD pathology dement. Mosaicism for trisomy 21 may be associated with reduced expression of beta-amyloid and later age of onset of AD. In addition, mutations in the gene for APP have been shown to cosegregate with AD in several families with early onset AD. We will determine if these or related mutations in the APP gene are associated with increased expression of clinical dementia in individuals with Down syndrome or with a history of early-onset AD in their families. Subjects for this study will be drawn from a larger ongoing study of the familial aggregation of Down syndrome and Alzheimer disease. We will study the first 150 individuals with DS and their parents. Data from the larger study will provide information on the occurrence of AD and related disorders in first- and second-degree relatives of DS probands, on the medical status and functional skills level of DS probands and on the occurrence of clinically significant regression in DS probands consistent with a diagnosis of dementia. We will determine DS karyotype (trisomy, translocation, mosaicism) and estimate the age-specific prevalence of mosaicism for trisomy 21. We will determine whether the risk for dementia and age of onset of dementia is correlated with the level of mosaicism. We will screen all individuals with DS and their parents for mutations in the coding region and promoter sequences of the APP gene and estimate the prevalence of APP mutations. We will determine whether increased risk for clinical dementia in adults with DS is associated with APP mutations by comparing DS cases with and without mutations in terms of the lifetime cumulative incidence of dementia. We will determine whether increased risk for AD in relatives of DS probands is associated with APP mutations by comparing DS cases with and without mutations in the APP gene in terms of the cumulative incidence of AD in their first- and second-degree relatives.

这项研究将研究痴呆症的遗传危险因素 患有唐氏综合症（DS）及其亲戚的人。 大脑 几乎所有患有唐氏综合症的成年人都表现出很高的老年人 病理的斑块和神经纤维缠结特征 阿尔茨海默氏病（AD）的变化和DS的个体正在增加 临床痴呆症的风险。 共同对DS和AD的遗传敏感性 受到女性DS出生的患病率增加的结果支持 通过增加的发现，谁自己拥有广告或亲戚拥有广告 AD的频率在患有DS的个体的亲属中，并通过联系 早发染色体21的家族性广告。β-淀粉样蛋白的基因 前体蛋白（APP）已定位为21染色体和早期 DS成年人中AD病理的发生已归因于 β-淀粉样蛋白的表达增加。 但是，并非所有患有DS的人 和AD病理痴呆。 三体第21三体的镶嵌可能与 β-淀粉样蛋白的表达降低，后来的AD发作年龄。 在 此外，已显示APP基因中的突变与 几个有早期广告的家庭的广告。 我们将确定这些是或 应用基因中的相关突变与表达增加有关 唐氏综合症患者的临床痴呆或病史 他们家人的早期发作广告。 这项研究的受试者将从更大的正在进行的研究中提取 唐氏综合症和阿尔茨海默氏病的家族聚集。 我们将学习 头150个人及其父母。 来自较大的数据 研究将提供有关AD和相关发生的信息 DS概率的一级和二级亲属的疾病， 医疗状况和功能技能水平的DS概率以及 DS概率的临床重大回归的发生 诊断为痴呆症。 我们将确定DS核型（三体型，易位，镶嵌）和 估计三体术21的镶嵌性特异性患病率。我们将 确定痴呆症的风险和痴呆症发作年龄是 与镶嵌水平相关。 我们将筛选所有个人 DS及其父母在编码区域和启动子中进行突变 应用基因的序列并估计应用突变的流行率。 我们 将确定成年人患有临床痴呆症的风险是否增加 DS通过在没有和没有的情况下比较DS案例与应用程序突变有关 根据痴呆症的寿命累积发生率的突变。 我们 将确定DS概率亲属中AD的风险是否增加是 与应用程序突变相关 APP基因的突变根据AD的累积发生率而言 他们的一级和二级亲戚。