Fragile X Related Genes Mental Retardation/Development

描述(由申请人提供)：本申请寻求为Nelson、Oostra和Payler小组之间的一个联合项目寻求新的资金，该项目旨在创建和研究人类脆性X综合征的小鼠模型。该项目的先前目标是开发并对携带条件(Cre-lox)等位基因的小鼠进行初步鉴定，这些等位基因存在于小鼠基因组中的3个FMR1样基因中的每一个。进展很好；已经确定了Fxr2基因敲除的特征，并为Fmr1和Fxr1创建了携带条件等位基因的模型。Fmr1和Fxr2的双基因敲除已经被创建；这些基因表现出比单一突变体中发现的更强的表型。此外，在双基因敲除中观察到了一个独特的昼夜节律缺陷--这些动物非常活跃，在明/暗或暗/暗周期中没有节律。Fxr1功能丧失会导致新生儿死亡，而Fxr1水平降低的动物会受到影响，但仍能存活。人类脆性X前突变相关震颤共济失调综合征(简称FXTAS)的小鼠模型也已经开发出来，并正在进行表征。这些模型概括了这种迟发性神经退行性疾病的几个方面。这些研究为建立和描述由人类常见突变引起的遗传疾病(脆性X综合征和FXTAS)的小鼠模型提供了机会。这样的模型将允许确定Fmr1类蛋白质的许多功能，并为其他有兴趣利用这些模型来测试关于Fmr1功能及其缺失的后果以及新描述的FXTAS障碍的假说提供资源。这项更新请求寻求通过追求以下具体目标来继续这些研究：1)开发在小鼠身上测试FMR1和Paralog功能的模型和分析方法。2)建立和使用小鼠模型以确定脆性X-前突变相关震颤共济失调综合征的机制基础。这些目标的成功完成将使人们能够定义脆性X综合征和FXTAS的功能和功能障碍。

DESCRIPTION (provided by applicant): This application seeks renewed funding for a joint project between the Nelson, Oostra and Paylor groups to create and study mouse models for human Fragile X syndrome. Prior aims of the project sought to develop and perform initial characterization of mice carrying conditional (Cre-lox) alleles at each of the 3 FMR1-like genes present in the mouse genome. Progress has been excellent; Fxr2 knockouts have been characterized, and models carrying conditional alleles have been created for Fmr1 and Fxr1. Double knockouts of Fmr1 and Fxr2 have been created; these show enhanced phenotypes beyond those found in the single mutants. Moreover, a unique circadian rhythm defect has been observed in double knockouts-these animals are hyperactive and show no rhythm in light/dark or dark/dark cycles. Fxr1 loss of function results in neonatal lethality, while animals with reduced levels of Fxr1 are affected, but viable. Mouse models for the human Fragile X premutation-associated tremor ataxia syndrome (termed FXTAS) have also been developed and are being characterized. These models recapitulate several aspects of this late onset neurodegenerative disorder. These studies offer the opportunity to create and characterize mouse models for genetic disorders (Fragile X syndrome and FXTAS) that result from a common human mutation. Such models will allow the determination of a number of the functions of the FMR1 class of proteins, and provide a resource for other groups interested in utilizing such models to test hypotheses regarding Fmr1 function and the consequences of its absence, as well as the newly described FXTAS disorder. This renewal request seeks to continue these studies through the pursuit of the following specific aims: 1) Development of models and assays for testing FMR1 and paralog functions in mice. 2) Development and use of mouse models to determine the mechanistic basis of Fragile X-premutation-associated tremor ataxia syndrome. Successful completion of these aims will allow the definition of function and dysfunction in Fragile X syndrome and FXTAS.