GENETIC AND CYTOGENETIC STUDIES OF MENTAL RETARDATION

智力低下的遗传和细胞遗传学研究

• 批准号: 3096852
• 负责人: SAMUEL A. LATT
• 金额: $ 47.85万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3096852
• 关键词: chromosome disorders; cytogenetics; gene expression

We propose a program of research on the localization and analysis of genetic determinants on human chromosomes, as well as subchromosomal structural changes underlying diseases, with emphasis on the human X, #15, #21, and other regions of the genome in which abnormalities can be associated with mental retardation and/or developmental defects. The research planned utilizes techniques which allow intense study of subchromosomal regions, such as fluorescence activated chromosome sorting and phenol-enhanced differential hybridization, recombinant DNA methodology, cytogenetics, somatic cell genetics and pedigree analysis. The goal is to obtain, localize, and characterize cloned DNA segments, as well as deleted, duplicated, rearranged, or labile subchromosomal regions associated with specific diseases. Using Xp21 deletions in DMD as a prototype and starting point, we will explore adjacent regions and deletions responsible for glycerol kinase deficiency, the McCloud phenotype, as well as X- linked eye diseases such as retinitis pigmentosa, retinoschisis, and choroideremia, the last associated with a deletion in proximal Xq. Structural analysis of Xp21, as well as distal Xp and Xp will be used to study normal and abnormal meiosis and the role of the latter in deletion-related diseases, insertion of a Yp segment into Xp in 46,XX males, and aneusomy. Recombination based screening will be used to obtain molecular probes near the fragile site in distal Xq to study its structural features and unusual mode of mutation. Existing and newly sought molecular probes will be used to analyze MR-associated diseases in 12p and proximal 15q1, in the case to understand better the nature and causes of structural changes associated with the Prader-Willi syndrome, as well as to refine diagnosis of this disease. Other genomic probes, as well as antibodies, will be used to isolate cDNA sequences mapping to chromosome #21 to investigate abnormalities, related to Down syndrome, of tissue-specific #21 DNA expression, e.g. as regards neuronal organization and cell surface changes underlying developmental defects. Of particular interest will be #21-linked amyloid beta protein cDNA and the relationship of amyloid to premature aging in Down syndrome and to Alzheimer disease. The information sought should both be of basic mechanistic interest, and it should translate readily into practical molecular genetic diagnostic applications.

我们提出了一个关于本地化和分析的研究计划 人类染色体上的遗传决定因素，以及 潜在疾病的亚染色体结构变化， 强调人类 X、#15、#21 和其他区域 基因组中异常可能与精神相关 发育迟缓和/或发育缺陷。 研究计划 利用可深入研究亚染色体的技术 区域，例如荧光激活染色体分选和 酚增强差异杂交、重组DNA 方法学、细胞遗传学、体细胞遗传学和谱系 分析。 目标是获取、本地化和表征克隆 DNA 片段，以及删除、复制、重新排列或 与特定疾病相关的不稳定亚染色体区域。 使用 DMD 中的 Xp21 缺失作为原型和起点， 我们将探索相邻区域和删除的原因 甘油激酶缺乏症、McCloud 表型以及 X- 相关眼部疾病，如色素性视网膜炎、视网膜劈裂等 无脉络膜血症，最后一种与近端 Xq 缺失相关。 Xp21 以及远端 Xp 和 Xp 的结构分析将 用于研究正常和异常减数分裂及其作用 后者在缺失相关疾病中，将 Yp 片段插入 Xp 为 46，XX 男性，且异型。 基于重组 筛选将用于获得易碎附近的分子探针 远端Xq位点，研究其结构特征和异常模式 的突变。 现有的和新寻找的分子探针将 用于分析 12p 和近端 15q1 的 MR 相关疾病， 以便更好地了解事件的性质和原因 与普瑞德威利综合征相关的结构变化，如 以及完善该疾病的诊断。 其他基因组探针， 以及抗体，将用于分离 cDNA 序列 映射至 21 号染色体以调查相关异常 唐氏综合症，组织特异性 #21 DNA 表达，例如作为 考虑神经元组织和细胞表面的潜在变化 发育缺陷。 特别感兴趣的是#21-linked β淀粉样蛋白cDNA及其与淀粉样蛋白的关系 唐氏综合症和阿尔茨海默病的过早衰老。 寻求的信息应该是基本的机械信息 兴趣，并且它应该很容易转化为实用的分子 遗传诊断应用。