Pathogenic consequences of expansions and deletions of CGG repeats in the FMR1 gene

FMR1 基因中 CGG 重复序列的扩增和缺失的致病后果

• 批准号: 9227113
• 负责人: JOHN H CARSON
• 金额: $ 23.93万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227113
• 关键词: 5' Untranslated Regions; Affect; Arginine; Ataxia; Binding; Binding Proteins; CGG repeat; CGG repeat expansion; Cells; Confocal Microscopy; Cytoplasmic Granules; Disease; FMR1; FXTAS; Fragile X Syndrome; Genes; Goals; Human; Image; In Vitro; Individual; Label; Mediating; Methylation; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Ovarian; Process; Proteins; RNA; Reading; Repression; Reticulocytes; Ribosomes; Surface Plasmon Resonance; Synapses; Therapeutic; Translations; Tremor; Trinucleotide Repeats; Venus; Work; in vivo; novel therapeutic intervention; premature; reproductive; research study; single molecule

The FMR1 gene encodes fragile X mental retardation protein (FMRP), which regulates translation of specific target RNAs. Normally the FMR1 gene contains 6-54 CGG repeats in the 5'UTR. Intermediate expansion of CGG repeats (55-200), referred to as premutation, results in reduced translation of FMR1 RNA associated with a neurodegenerative disorder called fragile X tremor ataxia (FXTAS) and a reproductive disorder called fragile X premature ovarian insufficiency (FXPOI). Larger expansion of CGG repeats (>200), referred to as full mutation, results in methylation and transcriptional silencing of the FMR1 gene associated with a neurodevelopmental disorder called fragile X syndrome (FXS). Deletions of CGG repeats in the FMR1 gene, are often associated with FXS or FXTAS. However the pathogenic consequences of such deletions has not been investigated. Here we will determine if CGG repeat deletions in FMR1 affect: localization of FMR1 RNA in granules, bursty translation of FMRP at synapses, and synthesis of poly-arginine FMRP by repeat associated nonAUG (RAN) translation and whether any of these phenomena affect translation of specific FMRP target RNAs. The results may identify a new pathogenic mechanism for deletion of CGG repeats in FMR1 and may also have important consequences for therapeutic strategies involving deletion of repeats in FXS, FXTAS and FXPOI, or in other trinucleotide repeat disorders.

FMR 1基因编码脆性X智力低下蛋白（FMRP），其调节 翻译特定的目标RNA。正常情况下，FMR 1基因含有6-54 CGG 在5 'UTR中重复。CGG重复（55-200）的中间扩增，称为 前突变，导致FMR 1 RNA的翻译减少， 神经退行性疾病称为脆性X震颤共济失调（FXTAS）和生殖 脆性X卵巢功能不全（FXPOI）更大规模的扩张 CGG重复序列（>200），称为完全突变，导致甲基化， 与神经发育相关的FMR 1基因的转录沉默 脆性X综合征（FXS）FMR 1基因中CGG重复序列的缺失， 通常与FXS或FXTAS有关。然而， 这种缺失尚未被研究。在这里，我们将确定CGG是否重复 FMR 1缺失影响：FMR 1 RNA在颗粒中的定位， 突触处的FMRP，以及通过重复相关nonAUG合成聚精氨酸FMRP (RAN)翻译以及这些现象是否影响特定内容的翻译 FMRP靶RNA。结果可能会发现一个新的致病机制缺失 CGG重复序列在FMR 1中的表达，也可能对治疗性疾病有重要影响。 涉及缺失FXS、FXTAS和FXPOI中的重复序列，或其他 三核苷酸重复障碍。