Limbic System Function in Carriers of the Fragile X Premutation

描述（由申请人提供）：脆性X综合征（FXS）是由位于Xq27.3的脆性X智力迟钝1基因（FMR1）的5'未翻译区域的三核苷酸重复扩增（全突变；> 200个CGG重复）引起的，导致该基因的蛋白产物FMR1蛋白（FMRP）减少或缺失，最终导致认知和行为障碍，这是该综合征的特征。具有FMR1预突变（55-200个CGG重复序列）的个体在后代中具有扩展的全突变形式的基因传播的风险。直到最近，这些“携带者”被认为在临床上是不受影响的。然而，经过一段时间的科学辩论和争议，最近的证据表明，这些个体中有一部分有显著的社会、情感和认知问题，甚至在最受影响的患者中有自闭症和智力迟钝(Cornish, et al., 2005; Franke, et al., 1998; Goodlin-Jones, Tassone, Gane, & Hagerman, 2004; r.j. Hagerman & Hagerman, 2002; Johnston, et al., 2001; Moore, Daly, Schmitz, et al., 2004；Moore, Daly， Tassone等，2004；塔松，哈格曼，泰勒，米尔斯等，2000)。这些缺陷以前被归因于FMRP的轻度缺陷，这种缺陷可能发生在突变前携带者中，特别是那些具有较高CGG重复等位基因的携带者。此外，我们发现男性和罕见的女性携带者在成年后期患一种主要以意图性震颤和步态共济失调为特征的神经退行性疾病的风险很大，这种疾病被称为脆性x相关震颤共济失调综合征（FXTAS， R. J. Hagerman等，2001；Jacquemont等，2003）。这种疾病在FXS中未见，并且具有不同的分子机制，我们认为涉及FMR1 mRNA异常升高的功能毒性增益效应。该建议不涉及FXTAS患者，而是涉及具有先兆突变的年轻男性和女性，他们表现出精神障碍，并有后期神经退行性变的风险（Hessl等，2005）。边缘区，特别是海马和杏仁核，似乎特别受到CGG重复序列大小增加和FMR1 mRNA异常升高的影响（Abitbol等，1993；Greco等，2002；Jdkdld等，1997;Moore, Daly， Tassone等，2004），因此我们在本研究中重点关注这一区域。这项研究将阐明基因-大脑-行为与预突变相关的关联，这可能为其他包括记忆、社会情感功能障碍和更广泛的自闭症表型的疾病提供见解。考虑到预突变在251 - 813名男性中约有1名，在113 - 259名女性中约有1名（Dombrowski, et al., 2002; Rousseau, Rouillard, Morel, Khandjian, & Morgan, 1995; toledanoalhadef, et al., 2001），这项研究的潜在相关性是显著的。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) results from a trinucleotide repeat expansion (full mutation; > 200 CGG repeats) in the in the 5' untranslated region of the fragile X mental retardation 1 gene (FMR1) located at Xq27.3, leading to a reduction or absence of the gene's protein product, the FMR1 protein (FMRP), ultimately causing cognitive and behavioral impairments that are characteristic of the syndrome. Individuals with the FMR1 premutation (55-200 CGG repeats) are at risk for transmission of the gene in its expanded full mutation form in subsequent generations. Until recently, these "carriers" were believed to be clinically unaffected. However, following a period of scientific debate and controversy over this topic, recent evidence has emerged demonstrating that a proportion of these individuals have significant social, emotional, and cognitive problems, even autism and mental retardation in the most affected patients (Cornish, et al., 2005; Franke, et al., 1998; Goodlin-Jones, Tassone, Gane, & Hagerman, 2004; R. J. Hagerman & Hagerman, 2002; Johnston, et al., 2001; Moore, Daly, Schmitz, et al., 2004; Moore, Daly, Tassone, et al., 2004; Tassone, Hagerman, Taylor, Mills, et al., 2000). These deficits have previously been attributed to a mild deficit of FMRP that can occur in premutation carriers, especially those with higher CGG repeat alleles. In addition, we have discovered that male and rare female carriers are at significant risk for a neurodegenerative disease in later adulthood primarily characterized by intention tremor and gait ataxia called Fragile X-Associated Tremor Ataxia Syndrome (FXTAS, R. J. Hagerman, et al., 2001; Jacquemont, et al., 2003). This disease is not seen in FXS and has a different molecular mechanism involving, we believe, a toxic gain of function effect of abnormal elevation of FMR1 mRNA. This proposal does not involve FXTAS patients but rather younger men and women with the premutation who demonstrate psychiatric disturbances and are at risk for later neurodegeneration (Hessl, et al., 2005). The limbic region, especially the hippocampus and amygdala, appear to be especially impacted by increased CGG repeat size and the abnormal elevation of FMR1 mRNA (Abitbol, et al., 1993; Greco, et al., 2002; Jdkdld, et al., 1997; Moore, Daly, Tassone, et al., 2004) and we therefore focus on this region in the present study. This research will elucidate gene-brain-behavior associations related to the premutation that may provide insight into other disorders involving memory, social-emotional dysfunction, and the broader autism phenotype. The potential relevance of this work is significant given that the premutation occurs in an estimated 1 in 251 to 813 males and 1 in 113 to 259 females (Dombrowski, et al., 2002; Rousseau, Rouillard, Morel, Khandjian, & Morgan, 1995; Toledano-Alhadef, et al., 2001). PUBLIC HEALTH RELEVANCE: This research examines whether fragile X premutation carriers have emotional, social, or memory problems due to alterations in the structure or function of the limbic system of the brain. The premutation of the FMR1 gene is relatively common, affecting approximately 1 in 150 to 1 in 800 individuals. This research will help to clarify links between genes, brain, and behavior within this condition that may have implications for understanding of these types of mechanisms in other more common neuropsychiatric conditions.