title: 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.
abstract: 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.
authors.affiliation: 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.
authors.forename: Lucie
authors.initials: L
authors.lastname: Lanikova
authors.forename: Jana
authors.initials: J
authors.lastname: Kucerova
authors.forename: Karel
authors.initials: K
authors.lastname: Indrak
authors.forename: Martina
authors.initials: M
authors.lastname: Divoka
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Josef T
authors.initials: JT
authors.lastname: Prchal
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divoky
mesh_terms: D000328:Adult; D000483:Alleles; D017398:Alternative Splicing; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005786:Gene Expression Regulation; D023061:Gene Order; D020868:Gene Silencing; D006801:Humans; D007438:Introns; D020084:Long Interspersed Nucleotide Elements; D016254:Mutagenesis, Insertional; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D014158:Transcription, Genetic; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D055544:beta-Globins
keywords: HBB; LINE-1; epigenetic repression; β-globin; β-thalassemia