Tassone F, Hagerman P J
Department of Biological Chemistry, University of California, Davis, School of Medicine, Davis CA, USA.
Cytogenet Genome Res. 2003;100(1-4):124-8. doi: 10.1159/000072846.
Fragile X syndrome is a trinucleotide repeat disorder in which a (CGG)n element located within the 5' untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene expands to more than 200 copies (full mutation) and becomes hypermethylated. Such expansions are accompanied by the failure to produce FMR1 protein (FMRP), resulting in the fragile X phenotype. For smaller (premutation) expansions (approximately 55-200 repeats), FMR1 mRNA and FMRP levels had been assumed to be normal; however, our group and others have recently demonstrated that FMR1 mRNA levels are elevated in cells harboring premutation alleles. Moreover, mRNA levels remain elevated in fragile X males with partially methylated full mutation alleles. Finally, some fragile X males with hypermethylated, full mutation alleles continue to produce FMR1 mRNA, despite the expectation that those genes should be silent. These observations all point to a complex mechanism of expression of the FMR1 gene, one that provides a more consistent foundation for the spectrum of clinical involvement. An FMRP deficit is observed in all categories of fragile X individuals, including carriers of the premutation and partially methylated full mutation alleles. These results demonstrate that lowered FMRP levels, in the absence of methylation-coupled silencing of the FMR1 gene, are not caused by reduced transcriptional activity, but rather by a reduced efficiency of translation.
脆性X综合征是一种三核苷酸重复序列疾病，其中位于脆性X智力低下1（FMR1）基因5'非翻译区内的（CGG）n元件扩展至200多个拷贝（完全突变）并发生高度甲基化。这种扩展伴随着无法产生FMR1蛋白（FMRP），从而导致脆性X表型。对于较小的（前突变）扩展（约55 - 200个重复序列），FMR1 mRNA和FMRP水平曾被认为是正常的；然而，我们团队及其他研究人员最近证明，携带前突变等位基因的细胞中FMR1 mRNA水平会升高。此外，在具有部分甲基化完全突变等位基因的脆性X男性中，mRNA水平仍保持升高。最后，一些具有高度甲基化完全突变等位基因的脆性X男性尽管预期这些基因应该沉默，但仍继续产生FMR1 mRNA。这些观察结果都指向FMR1基因表达的复杂机制，这为临床受累谱提供了更一致的基础。在所有类型的脆性X个体中都观察到FMRP缺陷，包括前突变和部分甲基化完全突变等位基因的携带者。这些结果表明，在FMR1基因不存在甲基化偶联沉默的情况下，FMRP水平降低并非由转录活性降低引起，而是由翻译效率降低所致。
