Fragile X Related Genes Mental Retardation/Development

描述（由申请人提供）：本申请为Nelson， Oostra和Paylor小组之间的联合项目寻求新的资金，以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和执行小鼠基因组中存在的3个fmr1样基因中每个携带条件（Cre-lox）等位基因的小鼠的初始特征。进展非常好；对Fxr2基因敲除进行了表征，并为Fmr1和Fxr1创建了携带条件等位基因的模型。已经创建了Fmr1和Fxr2的双敲除；这些突变体表现出比单突变体更强的表型。此外，在双敲除中观察到一种独特的昼夜节律缺陷——这些动物过度活跃，在光/暗或暗/暗循环中没有节律。Fxr1功能丧失导致新生儿死亡，而Fxr1水平降低的动物受到影响，但可以存活。人类脆性X预突变相关震颤共济失调综合征（称为FXTAS）的小鼠模型也已开发并正在进行表征。这些模型概括了这种晚发性神经退行性疾病的几个方面。这些研究提供了创建和表征遗传疾病（脆性X综合征和FXTAS）小鼠模型的机会，这些疾病是由人类常见突变引起的。这些模型将允许确定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有关FMR1功能及其缺失后果的假设以及新描述的FXTAS疾病的团队提供资源。本次更新申请旨在通过以下具体目标继续这些研究：1)开发用于测试小鼠FMR1和类似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预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允许定义脆性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.