Bhagavati S, Ghatpande A, Leung B
Department of Neurology, State University of New York, Brooklyn 11203, USA.
Biochem Biophys Res Commun. 1996 Nov 1;228(1):55-62. doi: 10.1006/bbrc.1996.1615.
Myotonic dystrophy is caused by a trinucleotide repeat expansion (CTG)n, located in the 3' untranslated region of the DM-protein kinase gene. The cellular effects of the CTG expansion and how they lead to the diverse, multi-system clinical phenotype of DM are unknown. Studies on the expression of the DM gene in affected tissue have not yielded consistent results, leading to the suggestion that alterations of DM-PK may not be the sole molecular basis for DM. We explored the hypothesis that the expanded repeat in mutant DM RNA (CUG)n binds and titrates out nuclear RNA binding proteins. Alterations in the normal function of these proteins could result in the disruption of important cellular processes. We report here the identification and magnetic bead affinity purification of two nuclear proteins, 35 and 25 kD in size, which bind to RNA (CUG)n repeats and to a varying extent with other pyrimidine rich sequences. Sequence analysis of the 35 kD protein shows that it is a novel protein. Both these proteins are widely expressed, including human brain and skeletal muscle. We speculate that these proteins may play a role in DM pre-mRNA processing or nuclear cytoplasmic trafficking of RNA. Studies into the function of these proteins should yield important insights into the complex pathogenesis of myotonic dystrophy.
强直性肌营养不良由位于DM蛋白激酶基因3'非翻译区的三核苷酸重复序列扩增（CTG）n引起。CTG扩增的细胞效应以及它们如何导致DM多样的多系统临床表型尚不清楚。对受累组织中DM基因表达的研究尚未得出一致结果，这表明DM-PK的改变可能不是DM的唯一分子基础。我们探讨了这样一个假说：突变的DM RNA中的扩增重复序列（CUG）n结合并耗尽核RNA结合蛋白。这些蛋白质正常功能的改变可能导致重要细胞过程的破坏。我们在此报告了两种大小分别为35 kD和25 kD的核蛋白的鉴定及磁珠亲和纯化，它们与RNA（CUG）n重复序列结合，并在不同程度上与其他富含嘧啶的序列结合。对35 kD蛋白的序列分析表明它是一种新蛋白。这两种蛋白均广泛表达，包括在人脑和骨骼肌中。我们推测这些蛋白可能在DM前体mRNA加工或RNA的核质运输中起作用。对这些蛋白功能的研究应能为强直性肌营养不良复杂的发病机制提供重要见解。
