SCREEN FOR FRAGILE X MUTATION EXPANSION IN A PRIMATE MODEL

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（FXS）是最常见的遗传性精神发育迟滞形式，发生于脆性X精神发育迟滞1（FMR 1）基因5'非翻译区中具有超过200个CGG重复的个体。在人类中，大约每260名女性中就有1名是CGG重复序列扩展（55至200）的携带者。我们已经确定了一个恒河猴家系与7个受试者的扩展CGG区域的前突变范围内的载体。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。FXTAS通常涉及意向性震颤、步态共济失调和痴呆，并且影响至少1/3的50岁以上携带脆性X智力低下1（FMR 1）基因的小（前突变，CGGrepeat）扩增的男性。FXTAS的神经病理学标志是神经细胞中存在核内包涵体，在迄今为止检查的患有神经退行性疾病的所有个体的大脑中发现。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。该谱系代表了第一个自发携带扩增的三联体重复序列的动物模型。通过研究FMR 1基因和相关蛋白在这个非人灵长类动物谱系中的表达，我们期望在理解导致CGG重复序列在后代中扩增的分子机制方面取得进展，这在人类中导致神经发育受损（FXS），以及识别参与前突变携带者转录调控的因素，这可能导致FMR 1-mRNA的毒性水平，已知FMR 1-mRNA易患迟发性神经变性 （FXTAS）.

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 (FXS), 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 7 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. FXTAS often involves intention tremor, gait ataxia, and dementia, and affects at least 1/3 of males over 50 years of age who carry small (premutation, CGGrepeat) expansions of the fragile X mental retardation 1 (FMR1) gene. The neuropathological hallmark of FXTAS is the presence of intranuclear inclusions in neural cells, found in the brains of all individuals examined to date who had suffered from the neurodegenerative disorder. 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 expanded triplet repeats. By examining the expression of the FMR1 gene and related proteins in this pedigree of non human primates, we expect to make progress in the understanding of the molecular mechanisms leading to the expansion of the CGG repeats in succeeding generations, which in humans leads to impaired neurodevelopment (FXS) as well as identifying factors involved in transcriptional regulation in premutation carriers, which can result in a toxic levels of FMR1-mRNA that are known to predispose to late onset neurodegeneration (FXTAS).