ROBERTS SYNDROME: EXAMINATION OF CHROMOSOME STABILITY

罗伯茨综合症：染色体稳定性检查

• 批准号: 2025604
• 负责人: ROGER A. SCHULTZ
• 金额: $ 14.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2025604
• 关键词: autosomal recessive trait; cell fusion; chromosome aberrations; chromosome movement; computer assisted sequence analysis; cytogenetics; gene expression; genetic disorder; genetic mapping; genotype; human genetic material tag; human tissue; molecular cloning; molecular genetics; molecular pathology; northern blottings; phenotype; polymerase chain reaction; southern blotting

DESCRIPTION (Adapted from the Investigator's Abstract): Numerical chromosome anomalies account for a significant proportion of childhood diseases. Much remains to be learned about cellular mechanisms responsible for faithful chromosome segregation and maintenance of the normal genomic constitution. One approach to the elucidation of these basic cellular functions is through the characterization of heritable disorders exhibiting mutant cellular phenotypes. Given that chromosome segregation is essential for viability, few human disorders have been identified which exhibit faulty chromosome segregation. However, one such disorder is Roberts syndrome (RS). This rare autosomal recessive disease is clinically manifested by mental and growth retardation, tetraphocomelia, and variable craniofacial abnormalities. Cell lines derived from RS patients exhibit cytogenetic abnormalities which include random chromosome loss and the premature separation at metaphase of heterochromatic regions, a cytological phenomenon referred to as heterochromatic repulsion (HR). RS cells also exhibit subtle hypersensitivity to a broad spectrum of agents, including certain mutagens. Biochemical approaches have not provided insights into RS and the disorder is too rare for classic genetic linkage analysis. Somatic cell hybridizations have demonstrated complementation of both the HR and hypersensitivity phenotypes. The present application proposes to map the gene which complements these phenotypes. RS cells will be fused with microcells bearing few (1 to 4) chromosomes derived directly from normal human cells. Direct human-human transfer eliminates the need to establish the usual somatic cell hybrid intermediates used in microcell chromosome transfer and facilitates assessment of effects rendered by simultaneous transfer of several chromosomes. Automated genotyping will be used to correlate complementation with a newly introduced chromosome(s). Similarly, chromosomes transferred from cell lines bearing relevant deletions or derivatives will facilitate finer mapping of the complementing locus. Genes previously mapped to the area will be evaluated in a "candidate gene" approach or, beyond the scope of this proposal, mapping data will be used for positional cloning of the gene. Identification of a gene which corrects RS cellular phenotypes should provide new insights into mechanisms which influence numerical chromosome content and the avoidance of birth defects.

描述（改编自调查员的摘要）：数值 染色体异常占儿童比例的很大比例 疾病。 关于负责的细胞机制还有很多尚待了解 用于忠实的染色体隔离和正常基因组的维持 宪法。 阐明这些基本细胞的一种方法 功能是通过表现出的可遗传障碍的特征 突变的细胞表型。 鉴于染色体分离是必不可少的 为了生存能，很少发现人类疾病出现故障 染色体分离。 但是，罗伯茨综合症是一种疾病 （Rs）。 这种罕见的常染色体隐性疾病在临床上表现为 心理和生长迟缓，四核和可变颅面 异常。 衍生自RS患者的细胞系表现出细胞遗传学 包括随机染色体损失和过早的异常 杂色区域的中期分离，一种细胞学现象 称为异质抑制（HR）。 RS细胞也表现出微妙的 超敏反应，包括某些诱变剂。 生化方法尚未提供对RS和疾病的见解 对于经典的遗传连锁分析来说太罕见了。 体细胞 杂交已经表明了人力资源和人力资源的补充 高敏表型。 本申请提议映射 补充这些表型的基因。 RS单元将与 直接衍生自正常的染色体（1至4）染色体的微电池很少 人类细胞。 直接人类转移消除了建立的需求 通常用于微孔染色体的通常的体细胞混合中间体 转移和促进对同时产生的效果的评估 几个染色体的转移。 自动基因分型将用于 与新引入的染色体相关的互补。 相似地， 染色体从带有相关缺失的细胞系转移或 衍生物将促进补充基因座的更精细映射。 基因 以前映射到该地区的映射将在“候选基因”中进行评估 方法或除了本提案的范围之外，将使用映射数据 用于基因的位置克隆。 校正基因的识别 RS细胞表型应提供有关机制的新见解 影响数字染色体含量和避免出生缺陷。