Limbic System Function in Carriers of the Fragile X Premutation

描述（由申请人提供）：本研究的目的是研究具有脆性X基因前置突变的成年男性社会情感和认知功能的分子遗传与大脑异常之间的关系。脆弱的X前兆突变与X染色体上的FMR1基因的CGG重复扩增55到200有关，是一种相对常见的遗传病，估计每813名男性和250名女性中就有1名。直到最近，人们还认为，基因突变的携带者在临床上是不受影响的。然而，最近的证据表明，这些人中有一部分人有明显的社交、情感和认知缺陷，甚至有自闭症和智力迟钝。我们发现，有些人在晚年会患上一种新发现的进行性神经系统疾病，即脆性X相关震颤共济失调综合征（FXTAS）。我们有证据表明，FXTAS，甚至成年早期的心理障碍，与突变前CGG重复序列范围内FMR1-mRNA升高引起的功能毒性增益效应有关。我们假设边缘功能障碍是具有这种前兆的年轻成年个体的社会情感和记忆缺陷的基础。在目前的研究中，我们将使用结构和功能MRI来确定与年龄和智商匹配的男性相比，18至45岁的男性是否在边缘脑区域表现出异常的大脑形态和功能，重点是海马体和杏仁核，以及与记忆和社交情感功能障碍相关的大脑区域。我们还将检查这些受试者中与情绪障碍、社会认知和互惠相关的精神症状，并检查FMR1基因功能的测量，包括mRNA的升高，是否与这些边缘脑区域的形态和功能相关。这项研究将有助于更好地理解与FMR1预突变相关的基因-脑-行为关系。此外，从这项工作中产生的参与预突变的多个系统的知识将为未来更有针对性的精神药理学，行为和可能的遗传干预研究奠定基础。对一个相对同质的单基因条件的研究，如脆性X预突变，为理解更复杂疾病的分子遗传、大脑和精神特征之间的联系提供了一个模型系统。

DESCRIPTION (provided by applicant): The aim of this study is to investigate relations between molecular genetic and brain abnormalities underlying social-emotional and cognitive functioning in adult males with the fragile X premutation. The fragile X premutation, associated with a CGG repeat expansion of 55 to 200 in the FMR1 gene on the X chromosome, is a relatively common genetic condition, present in an estimated 1 per 813 men and 1 per 250 women. Until recently, it was believed that carriers of the premutation were clinically unaffected. Recent evidence, however shows that a proportion of these individuals have significant social, emotional, and cognitive deficits, and even autism and mental retardation. We have found that some will go on to develop in their later years a newly discovered, progressive neurological disorder, fragile X associated tremor ataxia syndrome (FXTAS). We have evidence that FXTAS, and even psychological disturbance in earlier adulthood, is related to a toxic gain of function effect from elevated FMR1-mRNA in the premutation CGG repeat range. We hypothesize that limbic dysfunction underlies social-emotional and memory deficits in young adult individuals with the premutation. In the current study, we will use structural and functional MRI to determine whether men with the premutation (ages 18 to 45 years), in comparison to an age and IQmatched group of men, demonstrate abnormal brain morphology and function in limbic brain regions, focusing on the hippocampus and amygdala, and related brain regions associated with memory and socialemotional dysfunction. We will also examine psychiatric symptoms related to mood disorder and social cognition and reciprocity in these subjects, and examine whether measures of FMR1 gene function, including elevated mRNA, are associated with the morphology and function of these limbic brain regions. This research will lead to a better understanding of gene-brain-behavior relations associated with the FMR1 premutation. In addition, the knowledge of multiple systems of involvement in the premutation generated from this work will lay the groundwork for more targeted psychopharmacological, behavioral, and perhaps genetic intervention studies in the future. The study of a relatively homogeneous single gene condition such as the fragile X premutation provides a model system for understanding links between molecular genetic, brain, and psychiatric features of more complex disorders.