CRYPTIC TELOMERE ABNORMALITIES IN MENTAL RETARDATION

智力低下的隐性端粒异常

• 批准号: 2676089
• 负责人: David H. Ledbetter
• 金额: $ 17.58万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-05 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2676089
• 关键词: African American; Asian Americans; animal genetic material tag; autism; biochemical evolution; caucasian American; chromosome disorders; clinical research; cytogenetics; family genetics; fluorescent in situ hybridization; gene rearrangement; genetic mapping; genetic polymorphism; human genetic material tag; human subject; mental retardation; pregnancy loss; telomere

DESCRIPTION: (Adapted from the applicant's abstract) Visible cytogenetic abnormalities are detected in approximately 10-20 percent of children with mild to severe mental retardation (including autism) and approximately 2-5 percent of couples with recurrent pregnancy loss. As current cytogenetic banding resolution only detects imbalances greater than 2 million basepairs of DNA, it is likely that submicroscopic abnormalities affecting the ends of chromosomes, the telomeres, may play a role in a significant proportion of unexplained ("idiopathic") mental retardation and pregnancy loss. The hypothesis to be tested is that submicroscopic gene dosage imbalances at human telomeres contribute significantly and disproportionately to idiopathic mental retardation and recurrent pregnancy loss. Special features of human telomeres which suggest they may be disproportionately represented compared to other regions of the genome include the fact that telomeres are the most gene rich regions of the human genome, and therefore very small imbalances are likely to have significant genetic consequences. Aspects of telomere structure and polymorphism may mediate nonhomologous chromosome pairing and unequal cross-over events leading to gene dosage imbalance. Studies to address these hypotheses only recently have become possible due to development of a complete set of specific human telomere probes. Of 41 human telomeres, unique probes within 300 kb of the end of the chromosome are available for 40. This probe set provides an entree into more detailed biological studies of the architecture of human telomeres, as well as the frequency, mechanisms, and consequences of telomeric rearrangements in idiopathic mental retardation, autism, pregnancy loss, birth defects and cancer. Specific aims are: (1) Molecular characterization of polymorphism and recent evolutionary duplications/rearrangements of subtelomeric transition zones by analysis of human populations and nonhuman primates, (2) Determination of the frequency and pattern of cryptic deletions and translocations in unexplained mental retardation/autism probands with a family history suggestive of chromosomal translocation, and (3) Determination of the mechanisms and consequences of telomere imbalance by detailed molecular analysis of the size of the imbalance, breakpoints, gene/EST content, and parental origin.

描述：（改编自申请人的摘要）可见 大约10-20％检测到细胞遗传学异常 患有轻度至重度智力低下的儿童（包括自闭症） 大约有2-5％的夫妻复发妊娠丧失。 由于当前的细胞遗传学带分辨率仅检测失衡 大于200万底座DNA，很可能 影响染色体末端的亚显微镜异常， 端粒可能会在很大一部分无法解释的地方发挥作用 （“特发性”）智力低下和妊娠丧失。 要检验的假设是亚镜基因剂量 人类端粒失衡的贡献很大，并且 与特发性智力低下和经常性不成比例 怀孕丧失。 人类端粒的特殊功能，暗示他们 与其他地区相比，可能是不成比例的 基因组包括端粒是最富基因的区域 人类的基因组，因此很小的失衡很可能 具有重大的遗传后果。 端粒结构的各个方面 和多态性可能介导非同源染色体配对，并 导致基因剂量失衡的不平等跨界事件。 研究 由于最近仅解决这些假设，由于 开发一组特定的人端粒探针。 41 人类端粒，独特的探针在末端的300公里以内 染色体可用于40。此探针集为 对人端粒结构的更详细的生物学研究， 以及端粒的频率，机制和后果 特发性智力低下，自闭症，怀孕丧失的重排， 出生缺陷和癌症。 具体目的是：（1）多态性和 近最新的进化重复/重排 通过分析人类和非人类灵长类动物的过渡区， （2）确定隐秘缺失的频率和模式和模式 无法解释的智力低下/自闭症易位的易位。 一份有关染色体易位的家族史，（3） 确定端粒失衡的机制和后果 通过详细的分子分析不平衡的大小 断点，基因/EST内容和父母的起源。