Elevated levels of FMR1 mRNA in carrier males:: A new mechanism of involvement in the fragile-X syndrome
Elevated levels of FMR1 mRNA in carrier males:: A new mechanism of involvement in the fragile-X syndrome
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DOI：
10.1086/302720
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发表时间：
2000-01-01
影响因子：
9.8
通讯作者：
Hagerman, PJ
中科院分区：
文献类型：
--
作者：
Tassone, F;Hagerman, RJ;Hagerman, PJ
脆性- x综合征是一种三核苷酸重复扩展障碍，其临床表型被认为是由于脆性- x智力迟钝1 （FMR1）基因的转录沉默，因为CGG重复数超过200。对于突变前等位基因（类似于55-200重复），尽管越来越多的临床证据表明突变前携带者涉及fmr1基因表达异常。为了解决这个（明显的）悖论，我们确定了16名携带者男性（55-192次重复），白细胞FMR1 mRNA的相对水平，通过使用自动荧光检测逆转录- pcr，以及对FMR1蛋白（FMRP）免疫反应的淋巴细胞的百分比。对于一些重复bbb100次的等位基因，fmrp阳性细胞的数量减少。出乎意料的是，FMR1 mRNA水平在相同范围内升高了至少五倍。在一个携带雄性的淋巴母细胞样细胞系（160次重复）中，FMR1 mRNA的稳定性没有显著增加，这表明增加的信息水平是由于转录速率增加。目前的结果支持一种参与突变前载体的机制，其中降低的翻译效率至少部分通过增加的转录活性得到补偿。因此，随着FMR1基因沉默，在全突变范围内发生机制转换，翻译效率的降低可能在大部分突变前范围内都很重要。
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 similar to 200. For premutation alleles (similar to 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.