title: Nuclear degradation of nonsense mutated beta-globin mRNA: a post-transcriptional mechanism to protect heterozygotes from severe clinical manifestations of beta-thalassemia?
abstract: Nonsense mutations of the beta-globin gene are a common cause of beta-thalassemia. It is a hallmark of these mutations not only to cause a lack of protein synthesis but also a reduction of mRNA expression. Both the pathophysiologic significance and the underlying mechanisms for this surprising phenomenon have so far remained enigmatic. We report that the reduction of the fully spliced mutant beta-globin mRNA already manifests itself within the nucleus. In contrast, the levels of mutant pre-mRNA are normal. The promoter and the 5'-untranslated region (5'-UTR) of the herpes simplex virus type 1 thymidine kinase (HSV1 Tk) gene can independently circumvent this recognition/response mechanism in cis and restore nonsense mutated beta-globin mRNA expression to normal levels. These two genetic elements can thus exert a dominant influence on the post-transcriptional control of nonsense mutated beta-globin gene expression. While wild-type mRNA levels are restored by fusion of the HSV1 Tk 5'-UTR to the nonsense mutated beta-globin reading frame, translation of a wildtype reading frame in such a hybrid is precluded. In contrast, the HSV1 Tk promoter appears to efficiently deliver the mRNA to the translational apparatus. The 5'-UTR and the promoter sequences therefore control the nuclear fate of nonsense mutated beta-globin mRNA by separable pathways. The nuclear mRNA degradation mechanisms examined here may prevent the synthesis of C-terminally truncated beta-globin chain fragments and may protect heterozygotes from clinically relevant symptoms of beta-thalassemia.
authors.affiliation: Department Pediatrics II, University of Ulm, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Kugler
authors.forename: J
authors.initials: J
authors.lastname: Enssle
authors.forename: M W
authors.initials: MW
authors.lastname: Hentze
authors.forename: A E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D001483:Base Sequence; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000378:metabolism; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D014176:Protein Biosynthesis / Q000235:genetics; D012322:RNA Precursors / Q000032:analysis; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: D012322:RNA Precursors; D012333:RNA, Messenger; D005914:Globins; D013937:Thymidine Kinase