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

FMR1基因编码脆性X智力低下蛋白(FMRP)，它调节 特定靶RNA的翻译。正常情况下，FMR1基因包含6-54个CGG 在5‘非编码区中重复。CGG重复序列的中间扩展(55-200)，称为 预突变，导致FMR1 RNA的翻译减少，与 神经退行性疾病称为脆性X震颤共济失调(FXTAS)和一种生殖器 这种疾病被称为脆性X卵巢早衰(FXPOI)。更大规模的扩展 CGG重复(&gt；200)，称为完全突变，导致甲基化和 与神经发育相关的FMR1基因转录沉默 这种疾病被称为脆性X综合征(FXS)。FMR1基因CGG重复序列的缺失， 通常与FXS或FXTAS相关联。然而，病毒的致病后果 这样的删除还没有得到调查。在这里我们将确定CGG是否会重复 FMR1中的缺失影响：FMR1 RNA在颗粒中的定位，FMR1的突然翻译 突触FMRP及重复相关非AUG合成多聚精氨酸FMRP (RAN)翻译，以及这些现象中是否有任何一种影响具体的翻译 FMRP靶向RNA。结果可能确定了一种新的缺失致病机制 在FMR1中重复CGG，并可能对治疗有重要影响 涉及FXS、FXTAS和FXPOI或其他 三核苷酸重复疾病。

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.