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. 1979 Jun;76(6):2886–2889. doi: 10.1073/pnas.76.6.2886

beta 0 thalassemia, a nonsense mutation in man.

J C Chang, Y W Kan
PMCID: PMC383714  PMID: 88735

Abstract

We determined the complete nucleotide sequence of the 5' noncoding region and the first 74 amino acids of the nonfunctional beta-globin mRNA in a patient with homozygous beta 0 thalassemia. We identified the molecular defect as a single nucleotide substitution in the coding region of the mRNA. At the position corresponding to amino acid 17, replacement of an adenine by a uracil changes the triplet AAG, which codes for lysine in the normal beta chain, to an amber termination codon, UAG. This type of beta 0 thalassemia represents an example of a nonsense mutation in man.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. BAGLIONI C. The fusion of two peptide chains in hemoglobin Lepore and its interpretation as a genetic deletion. Proc Natl Acad Sci U S A. 1962 Nov 15;48:1880–1886. doi: 10.1073/pnas.48.11.1880. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benz E. J., Forget B. G., Hillman D. G., Cohen-Solal M., Pritchard J., Cavallesco C., Prensky W., Housman D. Variability in the amount of beta-globin mRNA in beta0 thalassemia. Cell. 1978 Jun;14(2):299–312. doi: 10.1016/0092-8674(78)90116-2. [DOI] [PubMed] [Google Scholar]
  3. Bolivar F., Rodriguez R. L., Greene P. J., Betlach M. C., Heyneker H. L., Boyer H. W., Crosa J. H., Falkow S. Construction and characterization of new cloning vehicles. II. A multipurpose cloning system. Gene. 1977;2(2):95–113. [PubMed] [Google Scholar]
  4. Capecchi M. R., Haar R. A., Capecchi N. E., Sveda M. M. The isolation of a suppressible nonsense mutant in mammalian cells. Cell. 1977 Oct;12(2):371–381. doi: 10.1016/0092-8674(77)90113-1. [DOI] [PubMed] [Google Scholar]
  5. Chang J. C., Poon R., Neumann K. H., Kan Y. W. The nucleotide sequence of the 5' untranslated region of human gamma-globin mRNA. Nucleic Acids Res. 1978 Oct;5(10):3515–3522. doi: 10.1093/nar/5.10.3515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chang J. C., Temple G. F., Poon R., Neumann K. H., Kan Y. W. The nucleotide sequences of the untranslated 5' regions of human alpha- and beta-globin mRNAs. Proc Natl Acad Sci U S A. 1977 Nov;74(11):5145–5149. doi: 10.1073/pnas.74.11.5145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Clegg J. B., Weatherall D. J., Contopolou-Griva I., Caroutsos K., Poungouras P., Tsevrenis H. Haemoglobin Icaria, a new chain-termination mutant with causes alpha thalassaemia. Nature. 1974 Sep 20;251(5472):245–247. doi: 10.1038/251245a0. [DOI] [PubMed] [Google Scholar]
  8. Clegg J. B., Weatherall D. J., Milner P. F. Haemoglobin Constant Spring--a chain termination mutant? Nature. 1971 Dec 10;234(5328):337–340. doi: 10.1038/234337a0. [DOI] [PubMed] [Google Scholar]
  9. Conconi F., Del Senno L., Ferrarese P., Menini C., Borgatti L., Vullo C., Labie D. Appearance of beta globin synthesis in erythroid cells of Ferrara beta -o-thalassaemic patients following blood transfusion. Nature. 1975 Mar 20;254(5497):256–259. doi: 10.1038/254256a0. [DOI] [PubMed] [Google Scholar]
  10. Cremer K. J., Bodemer M., Summers W. P., Summers W. C., Gesteland R. F. In vitro suppression of UAG and UGA mutants in the thymidine kinase gene of herpes simplex virus. Proc Natl Acad Sci U S A. 1979 Jan;76(1):430–434. doi: 10.1073/pnas.76.1.430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. De Jong W. W., Meera Khan P., Bernini L. F. Hemoglobin Koya Dora: high frequency of a chain termination mutant. Am J Hum Genet. 1975 Jan;27(1):81–90. [PMC free article] [PubMed] [Google Scholar]
  12. Forget B. G., Benz E. J., Jr, Skoultchi A., Baglioni C., Housman D. Absence of messenger RNA for beta globin chain in beta(0) thalassaemia. Nature. 1974 Feb 8;247(5440):379–381. doi: 10.1038/247379a0. [DOI] [PubMed] [Google Scholar]
  13. Gesteland R. F., Wills N., Lewis J. B., Grodzicker T. Identification of amber and ochre mutants of the human virus Ad2+ND1. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4567–4571. doi: 10.1073/pnas.74.10.4567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Godet J., Verdier G., Nigon V., Belhani M., Richard F., Colonna P., Mitchell J., Williamson R., Tolstoshev P. beta-O-thalassemia from Algeria: genetic and molecular characterization. Blood. 1977 Sep;50(3):463–470. [PubMed] [Google Scholar]
  15. Kan Y. W., Dozy A. M., Varmus H. E., Taylor J. M., Holland J. P., Lie-Injo L. E., Ganesan J., Todd D. Deletion of alpha-globin genes in haemoglobin-H disease demonstrates multiple alpha-globin structural loci. Nature. 1975 May 15;255(5505):255–256. doi: 10.1038/255255a0. [DOI] [PubMed] [Google Scholar]
  16. Kan Y. W., Holland J. P., Dozy A. M., Varmus H. E. Demonstration of non-functional beta-globin mRNA in homozygous beta (0) thalassemia. Proc Natl Acad Sci U S A. 1975 Dec;72(12):5140–5144. doi: 10.1073/pnas.72.12.5140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Marotta C. A., Wilson J. T., Forget B. G., Weissman S. M. Human beta-globin messenger RNA. III. Nucleotide sequences derived from complementary DNA. J Biol Chem. 1977 Jul 25;252(14):5040–5053. [PubMed] [Google Scholar]
  18. Maxam A. M., Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. doi: 10.1073/pnas.74.2.560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Milner P. F., Clegg J. B., Weatherall D. J. Haemoglobin-H disease due to a unique haemoglobin variant with an elongated alpha-chain. Lancet. 1971 Apr 10;1(7702):729–732. doi: 10.1016/s0140-6736(71)91992-1. [DOI] [PubMed] [Google Scholar]
  20. Old J. M., Proudfoot N. J., Wood W. G., Longley J. I., Clegg J. B., Weatherall D. J. Characterization of beta-globin mRNA in the beta0 thalassemias. Cell. 1978 Jun;14(2):289–298. doi: 10.1016/0092-8674(78)90115-0. [DOI] [PubMed] [Google Scholar]
  21. Ottolenghi S., Comi P., Giglioni B., Tolstoshev P., Lanyon W. G., Mitchell G. J., Williamson R., Russo G., Musumeci S., Schillro G. Delta-beta-thalassemia is due to a gene deletion. Cell. 1976 Sep;9(1):71–80. doi: 10.1016/0092-8674(76)90053-2. [DOI] [PubMed] [Google Scholar]
  22. Ottolenghi S., Comi P., Giglioni B., Williamson R., Vullo G., Conconi F. Direct demonstration of beta-globin mRNA in homozygous Ferrara betaO-thalassaemia patients. Nature. 1977 Mar 17;266(5599):231–234. doi: 10.1038/266231a0. [DOI] [PubMed] [Google Scholar]
  23. Ottolenghi S., Lanyon W. G., Paul J., Williamson R., Weatherall D. J., Clegg J. B., Pritchard J., Pootrakul S., Boon W. H. The severe form of alpha thalassaemia is caused by a haemoglobin gene deletion. Nature. 1974 Oct 4;251(5474):389–392. doi: 10.1038/251389a0. [DOI] [PubMed] [Google Scholar]
  24. Ottolenghi S., Lanyon W. G., Williamson R., Weatherall D. J., Clegg J. B., Pitcher C. S. Human globin gene analysis for a patient with beta-o/delta beta-thalassemia. Proc Natl Acad Sci U S A. 1975 Jun;72(6):2294–2299. doi: 10.1073/pnas.72.6.2294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Philipson L., Andersson P., Olshevsky U., Weinberg R., Baltimore D., Gesteland R. Translation of MuLV and MSV RNAs in nuclease-treated reticulocyte extracts: enhancement of the gag-pol polypeptide with yeast suppressor tRNA. Cell. 1978 Jan;13(1):189–199. doi: 10.1016/0092-8674(78)90149-6. [DOI] [PubMed] [Google Scholar]
  26. Polsky F., Edgell M. H., Seidman J. G., Leder P. High capacity gel preparative electrophoresis for purification of fragments of genomic DNA. Anal Biochem. 1978 Jul 1;87(2):397–410. doi: 10.1016/0003-2697(78)90689-9. [DOI] [PubMed] [Google Scholar]
  27. Ramirez F., Natta C., O'Donnell J. V., Canale V., Bailey G., Sanguensermsri T., Maniatis G. M., Marks P. A., Bank A. Relative numbers of human globin genes assayed with purified alpha and beta complementary human DNA. Proc Natl Acad Sci U S A. 1975 Apr;72(4):1550–1554. doi: 10.1073/pnas.72.4.1550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ramirez F., O'Donnell J. V., Marks P. A., Bank A., Musumeci S., Schilirò G., Pizzarelli G., Russo G., Luppis B., Gambino R. Abnormal or absent beta mRNA in betao Ferrara and gene deletion in delta beta thalassaemia. Nature. 1976 Oct 7;263(5577):471–475. doi: 10.1038/263471a0. [DOI] [PubMed] [Google Scholar]
  29. Sanger F., Coulson A. R. The use of thin acrylamide gels for DNA sequencing. FEBS Lett. 1978 Mar 1;87(1):107–110. doi: 10.1016/0014-5793(78)80145-8. [DOI] [PubMed] [Google Scholar]
  30. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Taylor J. M., Dozy A., Kan Y. W., Varmus H. E., Lie-Injo L. E., Ganesan J., Todd D. Genetic lesion in homozygous alpha thalassaemia (hydrops fetalis). Nature. 1974 Oct 4;251(5474):392–393. doi: 10.1038/251392a0. [DOI] [PubMed] [Google Scholar]
  32. Temple G. F., Chang J. C., Kan Y. W. Authentic beta-globin mRNA sequences in homozygous betaO-thalassemia. Proc Natl Acad Sci U S A. 1977 Jul;74(7):3047–3051. doi: 10.1073/pnas.74.7.3047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Tolstoshev P., Mitchell J., Lanyon G., Williamson R., Ottolenghi S., Comi P., Giglioni B., Masera G., Modell B., Weatherall D. J. Presence of gene for beta globin in homozygous beta0 thalassaemia. Nature. 1976 Jan 15;259(5539):95–98. doi: 10.1038/259095a0. [DOI] [PubMed] [Google Scholar]
  34. Wilson J. T., Wilson L. B., deRiel J. K., Villa-komaroff L., Efstratiadis A., Forget B. G., Weissman S. M. Insertion of synthetic copies of human globin genes into bacterial plasmids. Nucleic Acids Res. 1978 Feb;5(2):563–581. doi: 10.1093/nar/5.2.563. [DOI] [PMC free article] [PubMed] [Google Scholar]

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