Moore Caroline J, Daly Eileen M, Tassone Flora, Tysoe Carolyn, Schmitz Nicole, Ng Virginia, Chitnis Xavier, McGuire Philip, Suckling John, Davies Kay E, Hagerman Randi J, Hagerman Paul J, Murphy Kieran C, Murphy Declan G M
Division of Psychological Medicine, Department of Neurology, Institute of Psychiatry, King's College London, DeCrespigny Park, UK.
Brain. 2004 Dec;127(Pt 12):2672-81. doi: 10.1093/brain/awh256. Epub 2004 Oct 13.
Expanded trinucleotide repeats are associated with several neuropsychiatric disorders, including fragile X syndrome (FraX) which is the most common inherited form of mental retardation. It is currently thought that FraX results from having >200 CGG trinucleotide repeats, with consequent methylation of the fragile X mental retardation gene (FMR1) and loss of FMR1 protein (FMRP). Pre-mutation carriers of FraX (with 55-200 CGG trinucleotide repeats) were originally considered unaffected, although recent studies challenge this view. However, there are few studies on the effect of pre-mutation trinucleotide repeat expansion on the male human brain using quantitative MRI. Also the results of prior investigations may be confounded because people were selected on the basis of clinical and neurological features, and not genetic phenotype. We compared the brain anatomy of 20 adult male pre-mutation members of known FraX families with 20 healthy male controls. The two groups did not differ significantly in age, intelligence quotient (IQ) or handedness. We also investigated whether any observed effects were associated with: (i) ageing; (ii) expansion of pre-mutation CGG trinucleotide repeats; (iii) reduction in the percentage of lymphocytes staining with anti-FMRP antibodies [%FMRP(+) lymphocytes]; and (iv) elevation of FMR1 mRNA levels. Male pre-mutation carriers of FraX, compared with matched controls, had significantly less voxel density in several brain regions, including the cerebellum, amygdalo-hippocampal complex and thalamus. Within pre-mutation carriers of FraX, ageing, increases in the number of CGG trinucleotide repeats and decreases in %FMRP(+) lymphocytes were associated with decreasing voxel density of regions previously identified as decreased relative to controls. Regional grey and white matter density is significantly affected in male pre-mutation carriers of FraX recruited on the basis of genetic, not clinical, phenotype. The association of voxel density reduction and ageing is consistent with observations of a subgroup of older pre-mutation males who present with cognitive decline. Moreover, our findings suggest, for the first time, an association between voxel density reduction and genetic variation in FraX.
扩展的三核苷酸重复序列与多种神经精神疾病相关，包括脆性X综合征（FraX），它是智力发育迟缓最常见的遗传形式。目前认为，FraX是由于CGG三核苷酸重复序列超过200次，导致脆性X智力低下基因（FMR1）甲基化，进而导致FMR1蛋白（FMRP）缺失。FraX的前突变携带者（具有55 - 200个CGG三核苷酸重复序列）最初被认为未受影响，尽管最近的研究对这一观点提出了挑战。然而，使用定量MRI研究前突变三核苷酸重复序列扩展对男性人类大脑影响的研究很少。此外，先前研究的结果可能存在混淆，因为研究对象是根据临床和神经学特征而非遗传表型选择的。我们比较了20名已知FraX家族成年男性前突变成员与20名健康男性对照的脑解剖结构。两组在年龄、智商（IQ）或利手方面没有显著差异。我们还研究了观察到的任何影响是否与以下因素相关：（i）衰老；（ii）前突变CGG三核苷酸重复序列的扩展；（iii）抗FMRP抗体染色的淋巴细胞百分比降低[％FMRP(+)淋巴细胞]；以及（iv）FMR1 mRNA水平升高。与匹配的对照组相比，FraX男性前突变携带者在包括小脑、杏仁核 - 海马复合体和丘脑在内的几个脑区的体素密度显著降低。在FraX前突变携带者中，衰老、CGG三核苷酸重复序列数量增加以及％FMRP(+)淋巴细胞减少与先前确定的相对于对照组减少的区域的体素密度降低有关。基于遗传而非临床表型招募的FraX男性前突变携带者的区域灰质和白质密度受到显著影响。体素密度降低与衰老之间的关联与一组出现认知衰退的老年前突变男性的观察结果一致。此外，我们的研究结果首次表明体素密度降低与FraX中的遗传变异之间存在关联。
