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Related Collections Red Cells Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 October 2000, Vol. 96, No. 8, pp. 2895-2901 RED CELLS Nonsense mutations in the human -globin gene lead to unexpected levels of cytoplasmic mRNA accumulation Luísa Romão, Ângela Inácio, Susana Santos, Madalena Ávila, Paula Faustino, Paula Pacheco, and João Lavinha From the Instituto Nacional de Saúde Dr Ricardo Jorge, Lisbon, Portugal. Generally, nonsense codons 50 bp or more upstream of the 3'-most intron of the human -globin gene reduce mRNA abundance. In contrast, dominantly inherited -thalassemia is frequently associated with nonsense mutations in the last exon. In this work, murine erythroleukemia (MEL) cells were stably transfected with human -globin genes mutated within each of the 3 exons, namely at codons 15 (TGGTGA), 39 (CT), or 127 (CT). Primer extension analysis after erythroid differentiation induction showed codon 127 (CT) mRNA accumulated in the cytoplasm at approximately 20% of the normal mRNA level. Codon 39 (CT) mutation did not result in significant mRNA accumulation. Unexpectedly, codon 15 (TGGTGA) mRNA accumulated at approximately 90%. Concordant results were obtained when reticulocyte mRNA from 2 carriers for this mutation was studied. High mRNA accumulation of codon 15 nonsense-mutated gene was revealed to be independent of the type of nonsense mutation and the genomic background in which this mutation occurs. To investigate the effects of other nonsense mutations located in the first exon on the mRNA level, nonsense mutations at codons 5, 17, and 26 were also cloned and stably transfected into MEL cells. After erythroid differentiation induction, mRNAs with a mutation at codon 5 or 17 were detected at high levels, whereas the mutation at codon 26 led to low mRNA levels. 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