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β-Thalassemia due to intronic LINE-1 insertion in the β-globin gene (HBB): molecular mechanisms underlying reduced transcript levels of the β-globin(L1) allele [Beta-Thalassemia due to intronic LINE-1 insertion in the beta-globin gene (HBB): molecular mechanisms underlying reduced transcript levels of the beta-globin(L1) allele]

Lucie Lanikova, Jana Kucerova, Karel Indrak, Martina Divoka, Jean-Pierre Issa, Thalia Papayannopoulou, Josef T. Prchal and Vladimir Divoky

. 2013 ; 34 (10) : 1361-1365.

Language English Country United States

Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc14074709

Grant support
NT11208 MZ0 CEP Register
NT13587 MZ0 CEP Register

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.

Beta-Thalassemia due to intronic LINE-1 insertion in the beta-globin gene (HBB): molecular mechanisms underlying reduced transcript levels of the beta-globin(L1) allele

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$a Lanikova, Lucie $u Department of Biology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; Departments of Medicine, Pathology and Genetics, University of Utah and Medical Service, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah
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$a Beta-Thalassemia due to intronic LINE-1 insertion in the beta-globin gene (HBB): molecular mechanisms underlying reduced transcript levels of the beta-globin(L1) allele
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$a 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.
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