CHARACTERIZATION OF THE FRAGILE X MUTATION

脆性 X 突变的特征

• 批准号: 6613925
• 负责人: Stephanie L. Sherman
• 金额: $ 17.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6613925
• 关键词: behavioral /social science research tag; behavioral genetics; biomarker; family genetics; fragile X syndromes; gene expression; genetic disorder diagnosis; genetic markers; genetic polymorphism; genetic screening; genetic susceptibility; human data; human genetic material tag; human subject; immunologic assay /test; molecular pathology; nerve /myelin protein; neural degeneration; neuropsychological tests; neuropsychology; nucleic acid quantitation /detection; nucleic acid repetitive sequence; patient oriented research; protein structure function; sex linked trait; statistics /biometry

Description: The fragile X syndrome (FXS), a type of inherited mental retardation (MR), is due to the silencing of the FMR1 X-linked gene. In over 98% of cases, the mutation is due to an expansion of an unstable CGG repeat sequence located in the 5? untranslated region of the gene. Once over 200 repeats (full mutations), the FMR1 gene is hypermethylated and consequently no message is transcribed. Originally, no significant phenotype was thought to be associated with the 6% of individuals in the general population who carry long, unmethylated FMR1 repeat tracks, i.e., those alleles with 41-199 repeats that produce FMR1 mRNA and protein (FMRP). However, there is now convincing evidence for an associated phenotype: 21% of women who carry the premutation allele (6 1-199 repeats) are at risk for premature ovarian failure (POF) while those who carry full mutations have the same risk as the general population. Moreover, preliminary evidence from males indicates that increased levels of FMR1 mRNA and reduced levels of FMRP are associated with increasing repeat number. Based on the applicant?s previous work and that of others, she has suggested that an increased number of FMR1 repeats may influence an individual?s cognitive and behavioral performance. Given the FMR1 gene is known to play a role in normal brain function, examination of a cognitive and behavioral consequence of FMR1 high repeat alleles is an important next step. The applicant proposes to determine the FMR1 mRNA and FMRP levels of high repeat carriers to better define the affect of long CGG repeat tracts and associated phenotypes. Specifically, she plans to assess 650 individuals, including high repeat carriers and controls, on whom she has neuropsychological profiles. In addition, she plans to confirm or refute a recent report suggesting that premutation males may be at risk for late onset cerebellar tremors. Lastly, she thinks it is imperative to begin to translate this important genetic information on the FXS, the most common inherited form of MR, into the public health arena. Because women who carry the premutation are not only at risk for having a child with the FXS but also are at risk for POF, she plans to investigate the feasibility of screening women of reproductive age for premutation alleles. This proposal will take the first step to rigorously assess the consequence of high repeat alleles at the molecular and phenotypic level and then determine if these data can be applied at the public health level.

描述：脆性 X 综合征 (FXS)，一种遗传性心理疾病 迟缓 (MR) 是由于 FMR1 X 连锁基因的沉默所致。在结束 98% 的情况下，突变是由于不稳定的 CGG 重复序列的扩展造成的 序列位于5?基因的非翻译区。一旦超过200 重复（完全突变），FMR1 基因高度甲基化，因此没有 消息已转录。最初，人们认为没有显着的表型 与普通人群中 6% 的携带者相关 长的、未甲基化的 FMR1 重复序列，即具有 41-199 次重复的等位基因 产生 FMR1 mRNA 和蛋白质 (FMRP)。然而现在有令人信服的 相关表型的证据：21% 的女性携带前突变 等位基因（6 个 1-199 重复）有卵巢早衰 (POF) 的风险，而 那些携带完全突变的人与普通人群具有相同的风险。 此外，来自男性的初步证据表明， FMR1 mRNA 和 FMRP 水平降低与重复次数增加相关 数字。根据申请人之前的工作和其他人的工作，她已经 表明 FMR1 重复次数的增加可能会影响 个人的认知和行为表现。鉴于 FMR1 基因是 已知在正常大脑功能、认知和认知检查中发挥作用 FMR1 高重复等位基因的行为后果是重要的下一步。 申请人建议测定高水平的FMR1 mRNA和FMRP水平 重复携带者可以更好地定义长 CGG 重复束的影响 相关的表型。具体来说，她计划评估 650 人， 包括高重复携带者和对照，她对他们有 神经心理学概况。此外，她还计划确认或反驳 最近的报告表明，突变前的男性可能有晚发的风险 小脑震颤。最后，她认为有必要开始翻译 FXS（最常见的遗传形式）上的这一重要遗传信息 MR 进入公共卫生领域。因为携带前突变的女性 不仅面临生育患有 FXS 的孩子的风险，而且还面临以下风险： POF，她计划调查对女性进行筛查的可行性 前突变等位基因的生育年龄。该提案将优先考虑 步骤严格评估高重复等位基因的后果 分子和表型水平，然后确定这些数据是否可以应用 在公共卫生层面。