Limbic System Function in Carriers of the Fragile X Premutation

描述（申请人提供）：脆性X综合征（FXS）由三核苷酸重复扩增引起（完全突变;> 200个CGG重复），导致该基因的蛋白产物FMR 1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FMR 1前突变（55-200 CGG重复）的个体有将该基因以其扩展的完全突变形式传递给后代的风险。直到最近，这些“携带者”被认为是临床上不受影响的。然而，在关于该主题的一段时间的科学辩论和争议之后，最近的证据已经出现，表明这些个体中的一部分具有显著的社会、情感和认知问题，甚至在最受影响的患者中具有自闭症和精神发育迟滞（康沃尔语，et al.，2005; Franke等人，Goodlin-Jones，Tassone，Gane，& Hagerman，2004; R. J. Hagerman & Hagerman，2002;约翰斯顿等人，2001;摩尔，戴利，施米茨等人，2004;摩尔，戴利，Tassone等人，2004; Tassone，Hagerman，Taylor，米尔斯等人，2000年）。这些缺陷以前被归因于FMRP的轻度缺陷，其可发生在前突变携带者中，特别是具有较高CGG重复等位基因的那些携带者。此外，我们发现男性和罕见的女性携带者在成年后期患神经退行性疾病的风险很大，主要特征是意图震颤和步态共济失调，称为脆性X相关震颤共济失调综合征（FXTAS，R. J. Hagerman等人，2001; Jacquemont等人，2003年）。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FMR 1 mRNA异常升高的功能效应的毒性获得。该提议不涉及FXTAS患者，而是涉及具有前突变的年轻男性和女性，其表现出精神障碍并处于后期神经变性的风险中（Hessl等人，2005年）。边缘区，特别是海马和杏仁核，似乎特别受到CGG重复大小增加和FMR 1 mRNA异常升高的影响（Abitbol，et al.，1993; Greco等人，2002; Jdkdld等人，1997;摩尔，戴利，Tassone等人，2004年），因此，我们在本研究中重点关注这一地区。这项研究将阐明与前突变相关的基因-大脑-行为关联，这可能会为涉及记忆、社交情感功能障碍和更广泛的自闭症表型的其他疾病提供深入了解。鉴于前突变发生在估计的1/251至813的男性和1/113至259的女性中，该工作的潜在相关性是显著的（Dombrowski等人，2002; Rousseau，Rouillard，Morel，Khandjian，& Morgan，1995; Toledano-Alhadef，et al.，2001年）。 公共卫生相关性：这项研究旨在检查脆性X基因前突变携带者是否因大脑边缘系统的结构或功能改变而出现情感、社交或记忆问题。FMR 1基因的前突变相对常见，约为1/150至1/800。这项研究将有助于澄清这种情况下基因，大脑和行为之间的联系，这可能对理解其他更常见的神经精神疾病中的这些类型的机制有影响。

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.