SCREEN FOR FRAGILE X MUTATIONS IN PRIMATES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 脆性X综合征是最常见的遗传性精神发育迟滞形式，发生在脆性X智力低下1（FMR 1）基因5'非翻译区中具有超过200个CGG重复的个体中。在人类中，大约每260名女性中就有1名携带CGG重复序列扩增（55至200）。我们已经确定了一个恒河猴家系与5个受试者的扩展CGG区域的前突变范围内的运营商。脆性X前突变的人类受试者携带者在血液样品中表达更高水平的FMR 1-mRNA，在2至10倍之间。FMR 1表达的增加可导致细胞毒性，并且是脆性X相关震颤共济失调综合征（FXTAS）的原因，FXTAS是一种新描述的神经退行性疾病。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），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。这个谱系代表了第一个自发携带扩增重复序列的动物模型。FMR 1 mRNA和蛋白水平尚未在FMR 1中CGG重复扩增的猕猴携带者中进行分析。通过研究FMR 1基因和相关蛋白质在这个谱系中，我们希望取得进展的分子机制的理解，导致CGG重复序列在后代中的扩展，以及确定参与转录-翻译调控的因素。

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.