Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Hum Mol Genet. 2011 Feb 1;20(3):580-8. doi: 10.1093/hmg/ddq501. Epub 2010 Nov 18.
More than 12 neurogenetic disorders are caused by unstable expansions of (CTG)•(CAG) repeats. The expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have shown that contractions of (CAG)(95) are more frequent when the repeat tract is transcribed. Here we determined whether transcription can promote repeat expansion, using (CTG)•(CAG) repeat tracts in the size range that is typical for myotonic dystrophy type 1. We derived normal human fibroblasts having single-copy genomic integrations of 800 CTG repeats. The repeat tract showed modest instability when it was not transcribed, yielding an estimated mutation rate of 0.28% per generation. Instability was enhanced several-fold by transcription in the forward or reverse transcription, and 30-fold by bidirectional transcription, yielding many expansions and contractions of more than 200 repeats. These results suggest that convergent bidirectional transcription, which has been reported at several disease loci, could contribute to somatic instability of highly expanded (CTG)•(CAG) repeats.
超过 12 种神经遗传疾病是由不稳定的（CTG）•（CAG）重复序列扩展引起的。扩展的重复序列在生殖细胞和体细胞中不稳定，可能导致疾病严重程度的变化。先前的研究表明，当重复序列转录时，（CAG）（95）的收缩更为频繁。在这里，我们使用肌萎缩性侧索硬化症 1 型中典型的大小范围的（CTG）•（CAG）重复序列来确定转录是否可以促进重复序列的扩展。我们从具有 800 个 CTG 重复的单拷贝基因组整合的正常人成纤维细胞中分离出来。当重复序列不转录时，它表现出适度的不稳定性，估计每个世代的突变率为 0.28%。正向或反向转录的转录增强了几倍的不稳定性，而双向转录增强了 30 倍，产生了许多超过 200 个重复的扩展和收缩。这些结果表明，已经在几个疾病位点报道的会聚双向转录可能导致高度扩展的（CTG）•（CAG）重复序列的体细胞不稳定性。
