Brouwer J R, Severijnen E, de Jong F H, Hessl D, Hagerman R J, Oostra B A, Willemsen R
Department of Clinical Genetics, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Psychoneuroendocrinology. 2008 Jul;33(6):863-73. doi: 10.1016/j.psyneuen.2008.03.011. Epub 2008 May 12.
The human FMR1 gene contains an unstable CGG-repeat in its 5' untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamic-pituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGG-repeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week-old animals. In addition, we demonstrate ubiquitin-positive inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.
人类FMR1基因在其5'非翻译区含有一个不稳定的CGG重复序列。正常人群中的重复长度具有多态性（5 - 54个CGG重复序列）。携带超过200个CGG重复序列（即完全突变）的个体表现出高甲基化，进而导致FMR1基因沉默。基因产物FMRP的缺失会导致脆性X综合征，这是最常见的遗传性智力障碍形式。前突变（PM）携带者（定义为重复长度在55至200个CGG之间）在老年时可能会发展为一种进行性神经退行性综合征：脆性X相关震颤/共济失调综合征（FXTAS）。在前突变携带者的细胞中观察到的高FMR1 mRNA水平引发了这样一种假说，即FXTAS是由致病性RNA功能获得机制引起的。除了震颤/共济失调外，已在前突变携带者中描述了有无FXTAS的特定精神症状。由于这些症状可能源于应激激素水平升高，我们使用一种基因敲入小鼠模型研究下丘脑 - 垂体 - 肾上腺（HPA）轴调节，该模型在Fmr1基因中具有PM范围内（>98个重复序列）的扩展CGG重复序列，表现出重复序列不稳定性，并呈现FXTAS的生化、表型和神经病理学特征。我们发现100周龄动物的血清皮质酮水平升高，垂体和肾上腺中存在泛素阳性包涵体。此外，我们在老年扩展CGG重复序列小鼠的杏仁核中也发现了泛素阳性包涵体。我们推测，FXTAS小鼠模型中HPA轴和杏仁核调节的改变以及更高的应激激素水平可能解释了人类相关的心理症状。
