Department of Biology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; Departments of Medicine, Pathology and Genetics, University of Utah and Medical Service, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
Hum Mutat. 2013 Oct;34(10):1361-5. doi: 10.1002/humu.22383. Epub 2013 Aug 13.
We describe the molecular etiology of β(+)-thalassemia that is caused by the insertion of the full-length transposable element LINE-1 (L1) into the intron-2 of the β-globin gene (HBB). The transcript level of the affected β-globin gene was severely reduced. The remaining transcripts consisted of full-length, correctly processed β-globin mRNA and a minute amount of three aberrantly spliced transcripts with a decreased half-life due to activation of the nonsense-mediated decay pathway. The lower steady-state amount of mRNA produced by the β-globin(L1) allele also resulted from a reduced rate of transcription and decreased production of full-length β-globin primary transcripts. The promoter and enhancer sequences of the β-globin(L1) allele were hypermethylated; however, treatment with a demethylating agent did not restore the impaired transcription. A histone deacetylase inhibitor partially reactivated the β-globin(L1) transcription despite permanent β-globin(L1) promoter CpG methylation. This result indicates that the decreased rate of transcription from the β-globin(L1) allele is associated with an altered chromatin structure. Therefore, the molecular defect caused by intronic L1 insertion in the β-globin gene represents a novel etiology of β-thalassemia.
我们描述了β(+)-地中海贫血的分子病因，该病是由全长转座元件 LINE-1（L1）插入β-珠蛋白基因（HBB）的内含子 2 引起的。受影响的β-珠蛋白基因的转录本水平严重降低。剩余的转录本包括全长、正确加工的β-珠蛋白 mRNA 和少量三种异常剪接的转录本，由于无意义介导的衰变途径的激活，半衰期缩短。β-珠蛋白（L1）等位基因产生的 mRNA 稳态量较低也归因于转录率降低和全长β-珠蛋白初级转录本产量减少。β-珠蛋白（L1）等位基因的启动子和增强子序列发生超甲基化；然而，用去甲基化剂处理并没有恢复受损的转录。尽管β-珠蛋白（L1）启动子 CpG 永久甲基化，但组蛋白去乙酰化酶抑制剂部分重新激活了β-珠蛋白（L1）的转录。该结果表明，β-珠蛋白（L1）等位基因转录率降低与染色质结构改变有关。因此，β-珠蛋白基因内含子 L1 插入引起的分子缺陷代表了β-地中海贫血的一种新病因。
