SCREEN FOR FRAGILE X MUTATIONS IN PRIMATES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 脆性X综合征是最常见的精神发育迟滞的遗传形式，它发生在脆性X智力低下1(FMR1)基因的5‘非翻译区有超过200个CGG重复的个体。在人类中，大约每260名女性中就有1名携带扩大的(55到200)CGG重复序列。我们已经确定了一个恒河猴家系，其中5名受试者携带了前突变范围内扩大的CGG区域。脆性X预突变的人类受试者在血液样本中表达更高水平的FMR1-mRNA，在2到10倍之间。FMR1表达的增加可导致多年来的细胞毒性，并可能是脆性X相关震颤共济失调综合征(FXTAS)的原因，FXTAS是一种新发现的神经退行性疾病。还观察到，前突变携带者通常表达较低水平的脆性X蛋白(FMRP)，据推测，FMRP可能导致社交恐惧症、自闭症样行为、焦虑、强迫症、精神病特征和学习障碍。这个系谱代表了第一个自发携带扩展重复序列的动物模型。FMR1中CGG重复序列扩增的猕猴中，FMR1的mRNA和蛋白水平尚未得到分析。通过对该家系中FMR1基因和相关蛋白的研究，我们希望在理解导致CGG重复序列在后代中扩大的分子机制以及识别参与转录-翻译调控的因素方面取得进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fragile X syndrome, the most common inherited form of mental retardation, arises in individuals with more than 200 CGG repeats in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. In humans, approximately 1 in 260 women, is a carrier of the expanded (55 to 200) CGG repeat. We have identified a rhesus macaque pedigree with 5 subject carriers of an expanded CGG region in the premutation range. Human subject carriers of fragile X premutations express higher levels of FMR1-mRNA, between 2 to 10 fold in blood samples. The increased FMR1 expression can lead to cell toxicity over the years and be the cause of Fragile X associated tremor ataxia syndrome (FXTAS) a newly described neurodegenerative disease. It has also been observed that premutation carriers often express lower levels of fragile X protein (FMRP) that presumably causes social phobia, autistic-like behavior, anxiety, OCD, psychotic traits and learning disability. This pedigree represents the first animal model that spontaneously carries an expanded repeat. FMR1 mRNA and protein levels have not yet been analyzed in macaque carriers of expansions of CGG repeats in FMR1. By examining FMR1 gene and related proteins in this pedigree we expect to make progress in the understanding of the molecular mechanisms leading to the expansion of the CGG repeats in succeeding generations, as well as identifying factors involved in transcriptional-translational regulation.