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），一种遗传性精神疾病， FMR 1基因的缺失是由于FMR 1 X-连锁基因的沉默。在超过 在98%的病例中，突变是由于不稳定的CGG重复序列的扩增所致。 序列位于5？基因的非翻译区。一旦超过两百 重复（全突变），FMR 1基因是高甲基化的，因此没有 消息已转录。最初，认为没有显著的表型 与一般人群中6%的携带者有关 长的、未甲基化的FMR 1重复轨道，即，41-199重复的等位基因 产生FMR 1 mRNA和蛋白质（FMRP）。然而，现在有令人信服的 相关表型的证据：21%携带前突变的女性 等位基因（6 1-199重复）是卵巢早衰（POF）的风险， 携带完全突变基因的人与一般人有同样的风险。 此外，来自男性的初步证据表明， FMR 1 mRNA和FMRP水平降低与重复序列增加相关 number.根据申请人？她以前的工作和其他人的工作，她有 这表明FMR 1重复序列数量的增加可能会影响 个人？的认知和行为表现。由于FMR 1基因是 已知在正常大脑功能中发挥作用，检查认知和 FMR 1高重复等位基因的行为后果是重要的下一步。 申请人提出测定高表达的FMR 1 mRNA和FMRP水平。 重复携带者，以更好地定义长CGG重复序列的影响， 相关表型具体来说，她计划评估650人， 包括高重复携带者和对照组， 神经心理学特征此外，她计划证实或反驳一项 最近的报告表明，突变前的男性可能有迟发性 小脑震颤最后，她认为当务之急是开始翻译 这一重要的遗传信息的FXS，最常见的遗传形式 进入公共卫生竞技场。因为携带前突变的女性 不仅有风险与FXS生孩子，而且有风险 POF，她计划调查筛查女性的可行性， 前突变等位基因的生育年龄。这项提案将采取第一 步骤，以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。