Tassone F, Hagerman R J, Taylor A K, Gane L W, Godfrey T E, Hagerman P J
Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Denver, CO 80262, USA.
Am J Hum Genet. 2000 Jan;66(1):6-15. doi: 10.1086/302720.
Fragile-X syndrome is a trinucleotide-repeat-expansion disorder in which the clinical phenotype is believed to result from transcriptional silencing of the fragile-X mental retardation 1 (FMR1) gene as the number of CGG repeats exceeds approximately 200. For premutation alleles ( approximately 55-200 repeats), no abnormalities in FMR1-gene expression have been described, despite growing evidence of clinical involvement in premutation carriers. To address this (apparent) paradox, we have determined, for 16 carrier males (55-192 repeats), the relative levels of leukocyte FMR1 mRNA, by use of automated fluorescence-detection reverse transcriptase-PCR, and the percent of lymphocytes that are immunoreactive for FMR1 protein (FMRP). For some alleles with>100 repeats, there was a reduction in the number of FMRP-positive cells. Unexpectedly, FMR1 mRNA levels were elevated at least fivefold within this same range. No significant increase in FMR1 mRNA stability was observed in a lymphoblastoid cell line (160 repeats) derived from one of the carrier males, suggesting that the increased message levels are due to an increased rate of transcription. Current results support a mechanism of involvement in premutation carriers, in which reduced translational efficiency is at least partially compensated through increased transcriptional activity. Thus, diminished translational efficiency may be important throughout much of the premutation range, with a mechanistic switch occurring in the full-mutation range as the FMR1 gene is silenced.
脆性X综合征是一种三核苷酸重复扩增疾病，据信当CGG重复序列的数量超过约200个时，临床表型是由脆性X智力低下1（FMR1）基因的转录沉默所致。对于前突变等位基因（约55 - 200个重复序列），尽管越来越多的证据表明前突变携带者存在临床受累情况，但尚未发现FMR1基因表达有异常。为了解决这一（明显的）矛盾，我们使用自动荧光检测逆转录酶PCR技术，测定了16名男性携带者（55 - 192个重复序列）白细胞中FMR1 mRNA的相对水平，以及对FMR1蛋白（FMRP）呈免疫反应的淋巴细胞百分比。对于一些重复序列>100的等位基因，FMRP阳性细胞数量减少。出乎意料的是，在同一范围内FMR1 mRNA水平至少升高了五倍。在源自一名携带者男性的淋巴母细胞系（160个重复序列）中未观察到FMR1 mRNA稳定性的显著增加，这表明mRNA水平的升高是由于转录速率增加所致。目前的结果支持一种在前突变携带者中起作用的机制，即翻译效率降低至少部分通过转录活性增加得到补偿。因此，在很大一部分前突变范围内，翻译效率降低可能很重要，而当FMR1基因沉默时，在全突变范围内会发生机制转换。
