Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation.
Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation.
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强直性肌营养不良：可能存在显性失活 RNA 突变的证据。
DOI：
10.1093/hmg/4.4.599
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发表时间：
1995
影响因子：
3.5
通讯作者：
Hoffman,EP
中科院分区：
文献类型：
--
作者：
Wang,J;Pegoraro,E;Menegazzo,E;Gennarelli,M;Hoop,RC;Angelini,C;Hoffman,EP
引起强直性肌营养不良的三核苷酸扩增突变位于蛋白激酶基因的3'非翻译区。扩增的重复序列引起临床上可变的多系统疾病强直性肌营养不良的分子机制尚不清楚。由于扩展突变位于编码蛋白质的基因元件之外，并且不应该被翻译成蛋白质，因此使显性遗传合理化特别困难。在这里，我们使用肌肉活检从经典的成人发病的强直性肌营养不良症患者的研究从正常和扩大DM激酶基因在患者肌肉中的转录物的积累，并比较结果正常和肌病对照。我们发现肌肉总RNA库中DM激酶RNA相对较小的减少;然而，这些减少不是疾病特异性的。poly（A）+RNA的分析显示突变和正常DM激酶RNA均显著减少，并且这些变化具有疾病特异性。我们的研究结果与强直性肌营养不良的一种新的分子发病机制相一致：正常和扩增的DM激酶基因在患者肌肉中都有转录，但含有异常扩增的RNA通过阻止poly（A）+RNA的积累对RNA代谢具有主导作用。扩增突变改变poly（A）+RNAin积累的能力反式表明强直性肌营养不良可能是在RNA水平上表现的显性负突变的第一个例子。
The trinucleotide expansion mutation causing myotonic dystrophy is in the 3' untranslated region of a protein kinase gene. The molecular mechanisms by which the expanded repeat causes the clinically variable and multisystemic disease, myotonic dystrophy, are not understood. It has been particularly difficult to rationalize the dominant inheritance with the fact that the expansion mutation lies outside of the protein-encoding gene elements, and should not be translated into protein. Here we use muscle biopsies from classical adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the normal and expanded DM kinase genes in patient muscle, and compare the results to normal and myopathic controls. We found relatively small decreases of DM kinase RNA in the total RNA pool from muscle; however, these reductions were not disease specific. Analysis of poly(A)+RNA showed dramatic decreases of both the mutant and normal DM kinase RNAs, and these changes were disease-specific. Our findings are consistent with a novel molecular pathogenetic mechanism for myotonic dystrophy: both the normal and expanded DM kinase genes are transcribed in patient muscle, but the abnormal expansion-containing RNA has a dominant effect on RNA metabolism by preventing the accumulation of poly(A)+RNA. The ability of the expansion mutation to alter accumulation of poly(A)+RNAin transsuggests that myotonic dystrophy may be the first example of a dominant-negative mutation manifested at the RNA level.