Processing of human β-globin mRNA precursor to mRNA is defective in three patients with β +-thalassemia

Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/1980; 77(7):4287-91. DOI: 10.1073/pnas.77.7.4287
Source: PubMed


Nucleated bone marrow cells from normal individuals and from three patients with homozygous beta+-thalassemia were pulse-labeled with tritiated nucleosides. The processing of the newly synthesized globin mRNA precursors was monitored by inhibiting additional transcription with actinomycin D for 30 min. Human beta-globin mRNA is derived from its precursor via a series of reactions that generate processing intermediates. In nonthalassemic cells the precursor is processed efficiently to mature mRNA during the chase. In contrast, in beta+-thalassemic cells the processing of beta-globin RNA is defective. In one patient the beta-globin mRNA precursor turns over during the chase, but some of the intermediate RNAs accumulate and are not processed to mRNA. In two other patients a large fraction of the precursor and intermediate RNAs is not processed to mRNA. The alpha-globin mRNA precursor and intermediates are processed efficiently to mRNA-sized molecules in thalassemic and normal cells. The reduction in the rate of beta-globin but not alpha-globin RNA processing accounts for the alpha/beta globin mRNA imbalance in thalassemic erythroid cells. We discuss the possibility that the genetic lesions in beta+-thalassemia are at splicing signal sites within intervening sequences of the beta-globin gene.

Download full-text


Available from: George R Honig, Oct 16, 2014
  • Source
    • "of splicing defects that cause a disease, in this case P+thalassemia (Kantor et al. 1980; Maquat et al. 1980). Over the years, it has become clear that sequence elements important for proper intron removal reside in the immediate vicinity of the exon-intron borders (fig. "

    Preview · Article · Sep 1996 · The American Journal of Human Genetics
  • Source
    • "Indeed , Beserga and Benz (1988) showed that no reduction in mRNA levels occurred when translatable missense mutations were made in the human beta globin gene in vitro. However, defective RNA processing, such as occurs in human Beta+-thalassemia (Maquat et al ., 1980) can account for decreased mRNA levels (Housman et al., 1973) . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mice homozygous for the nb mutation (Chromosome 8) have a severe hemolytic anemia and develop a psychomotor disorder at 6 mo of age. The nb/nb mice are deficient in erythroid ankyrin (Ank-1) but, until the present study, the role of Ank-1 and of Ank-2 (brain ankyrin) in disease genesis was unknown. In normal erythroid tissues, we show that two major transcripts are expressed from Ank-1, and one of these is also present at high levels in the cerebellum. By in situ hybridization and immunocytochemistry, Ank-1 localizes to the cerebellar Purkinje cells and, to a lesser extent, the granule cells. In nb/nb mice, Ank-1 transcripts are markedly reduced in both erythroid and neural tissue, and nb/nb Purkinje cells and granule cells are nearly devoid of Ank-1. The neurological syndrome appears concurrently with a dramatic loss of Purkinje cells. Ank-2 maps to Chromosome 3 and its expression is unaffected by the nb mutation. We conclude that Ank-1 is specifically required for Purkinje cell stability and, in its absence, Purkinje cell loss and neurological symptoms appear.
    Full-text · Article · Oct 1991 · The Journal of Cell Biology
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ɑ-like and β-like subunits of human hemoglobin are encoded by a small family of genes that are differentially expressed during development. Through the use of molecular cloning procedures, each member of this gene family has been isolated and extensively characterized. Although the ɑ-like and β-like globin genes are located on different chromosomes, both sets of genes are arranged in closely linked clusters. In both clusters, each of the genes is transcribed from the same DNA strand, and the genes are arranged in the order of their expressions during development. Structural comparisons of immediately adjacent genes within each cluster have provided evidence for the occurrence of gene duplication and correction during evolution and have led to the discovery of pseudogenes, genes that have acquired numerous mutations that prevent their normal expression. Recently, in vivo and in vitro systems for studying the expression of cloned eukaryotic genes have been developed as a means of identifying DNA sequences that are necessary for normal gene function. This article describes the application of an in vitro transcription procedure to the study of human globin gene expression.
    No preview · Article · Oct 1980 · Science
Show more