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: 6098468
• 负责人: NICOLE SCHUPF
• 金额: --
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098468
• 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.

这项研究将调查痴呆症的遗传风险因素 唐氏综合症 (DS) 患者及其亲属。 的大脑 几乎所有患有唐氏综合症的成年人都表现出高密度的老年性 病理特征的斑块和神经原纤维缠结 阿尔茨海默病 (AD) 的变化以及患有 DS 的个体的患病率增加 临床痴呆的风险。 DS 和 AD 具有共同的遗传易感性 女性 DS 分娩患病率增加的研究结果支持了这一点 自己患有 AD 或其亲属患有 AD 的人，根据增加的发现 DS 患者的亲属中 AD 的频率，以及与 21 号染色体上的早发性家族性 AD。β-淀粉样蛋白基因 前体蛋白（APP）已定位于21号染色体，早期 患有 DS 的成人中 AD 病理的发生归因于 β-淀粉样蛋白的表达增加。 然而，并非所有 DS 患者 和 AD 病理学元件。 21 三体的嵌合现象可能与 β-淀粉样蛋白表达减少，AD 发病年龄较晚。 在 此外，APP 基因突变已被证明与 AD 存在于几个早发 AD 的家庭中。 我们将确定这些或 APP 基因的相关突变与表达增加有关 患有唐氏综合症或有唐氏综合症病史的人患临床痴呆的风险 他们的家族中有早发性 AD 患者。 这项研究的主题将从一项正在进行的更大的研究中选取 唐氏综合症和阿尔茨海默病有家族聚集性。 我们将学习 前 150 名 DS 患者及其父母。 数据来自较大 研究将提供有关 AD 和相关疾病发生的信息 DS先证者的一级和二级亲属的疾病， DS 先证者的医疗状况和功能技能水平以及 DS 先证者出现临床显着回归的情况一致 诊断为痴呆症。 我们将确定 DS 核型（三体性、易位、嵌合体）和 估计 21 三体性嵌合体的特定年龄患病率。我们将 确定痴呆症的风险和痴呆症的发病年龄是否 与嵌合体水平相关。 我们将对所有个人进行筛查 与 DS 及其父母一起了解编码区和启动子的突变 APP 基因序列并估计 APP 突变的发生率。 我们 将确定患有以下疾病的成年人患临床痴呆的风险是否增加 通过比较有和没有 DS 病例，DS 与 APP 突变相关 痴呆症终生累积发病率的突变。 我们 将确定 DS 先证者亲属患 AD 的风险是否增加 通过比较 DS 病例与 APP 突变的相关性 APP基因突变与AD累积发病率的关系 他们的一级和二级亲属。