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. 1987 Nov;80(5):1416–1421. doi: 10.1172/JCI113220

An initiation codon mutation (AUG----GUG) of the human alpha 1-globin gene. Structural characterization and evidence for a mild thalassemic phenotype.

P Moi 1, F E Cash 1, S A Liebhaber 1, A Cao 1, M Pirastu 1
PMCID: PMC442398  PMID: 3680504

Abstract

alpha-globin is encoded by two adjacent genes, alpha 1 and alpha 2. Recent evidence suggests that these genes are not equally expressed and that the alpha 2-globin gene encodes the majority of alpha-globin. This finding would predict that a thalassemic mutation of the alpha 2-globin gene would result in a more severe loss of alpha-chain synthesis than a similar mutation in the alpha 1-globin gene. In a previous study we described a nondeletion alpha-thalassemia defect in the alpha 2-globin gene resulting from an AUG----ACG initiation codon mutation. In the present study we describe a different initiation codon mutation, AUG----GUG, present in the alpha 1-globin gene. The alpha 1- and alpha 2-globin gene initiation codon mutations result in similarly lowered levels of encoded mRNA. Despite the similarity of these two mutations, the alpha 2 mutant results in a more severe loss of alpha-globin synthesis and a more severe clinical alpha-thalassemia phenotype than the corresponding alpha 1-globin gene mutation. This difference reflects the dominant role of alpha 2-globin gene in overall alpha-globin synthesis.

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Selected References

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

  1. Adirojnanon P., Wasi P. Levels of haemoglobin H and proportions of red cells with inclusion bodies in the two types of haemoglobin H disease. Br J Haematol. 1980 Nov;46(3):507–509. doi: 10.1111/j.1365-2141.1980.tb06002.x. [DOI] [PubMed] [Google Scholar]
  2. Alter B. P. The G gamma:A gamma composition of fetal hemoglobin in fetuses and newborns. Blood. 1979 Nov;54(5):1158–1163. [PubMed] [Google Scholar]
  3. Becerra S. P., Rose J. A., Hardy M., Baroudy B. M., Anderson C. W. Direct mapping of adeno-associated virus capsid proteins B and C: a possible ACG initiation codon. Proc Natl Acad Sci U S A. 1985 Dec;82(23):7919–7923. doi: 10.1073/pnas.82.23.7919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brown J. C., Smith A. E. Initiator codons in eukaryotes. Nature. 1970 May 16;226(5246):610–612. doi: 10.1038/226610a0. [DOI] [PubMed] [Google Scholar]
  5. Chen E. Y., Seeburg P. H. Supercoil sequencing: a fast and simple method for sequencing plasmid DNA. DNA. 1985 Apr;4(2):165–170. doi: 10.1089/dna.1985.4.165. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Deisseroth A., Nienhuis A., Turner P., Velez R., Anderson W. F., Ruddle F., Lawrence J., Creagan R., Kucherlapati R. Localization of the human alpha-globin structural gene to chromosome 16 in somatic cell hybrids by molecular hybridization assay. Cell. 1977 Sep;12(1):205–218. doi: 10.1016/0092-8674(77)90198-2. [DOI] [PubMed] [Google Scholar]
  8. Embury S. H., Lebo R. V., Dozy A. M., Kan Y. W. Organization of the alpha-globin genes in the Chinese alpha-thalassemia syndromes. J Clin Invest. 1979 Jun;63(6):1307–1310. doi: 10.1172/JCI109426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goossens M., Kan Y. Y. DNA analysis in the diagnosis of hemoglobin disorders. Methods Enzymol. 1981;76:805–817. doi: 10.1016/0076-6879(81)76159-7. [DOI] [PubMed] [Google Scholar]
  10. Goossens M., Lee K. Y., Liebhaber S. A., Kan Y. W. Globin structural mutant alpha 125Leu leads to Pro is a novel cause of alpha-thalassaemia. Nature. 1982 Apr 29;296(5860):864–865. doi: 10.1038/296864a0. [DOI] [PubMed] [Google Scholar]
  11. Higgs D. R., Goodbourn S. E., Lamb J., Clegg J. B., Weatherall D. J., Proudfoot N. J. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983 Nov 24;306(5941):398–400. doi: 10.1038/306398a0. [DOI] [PubMed] [Google Scholar]
  12. Higgs D. R., Pressley L., Aldridge B., Clegg J. B., Weatherall D. J., Cao A., Hadjiminas M. G., Kattamis C., Metaxatou-Mavromati A., Rachmilewitz E. A. Genetic and molecular diversity in nondeletion Hb H disease. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5833–5837. doi: 10.1073/pnas.78.9.5833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Higgs D. R., Weatherall D. J. Alpha-thalassemia. Curr Top Hematol. 1983;4:37–97. [PubMed] [Google Scholar]
  14. Huisman T. H., Schroeder W. A., Brodie A. N., Mayson S. M., Jakway J. Microchromatography of hemoglobins. II. A simplified procedure for the determination of hemoglobin A2. J Lab Clin Med. 1975 Oct;86(4):700–702. [PubMed] [Google Scholar]
  15. Kan Y. W., Dozy A. M., Stamatoyannopoulos G., Hadjiminas M. G., Zachariades Z., Furbetta M., Cao A. Molecular basis of hemoglobin-H disease in the Mediterranean population. Blood. 1979 Dec;54(6):1434–1438. [PubMed] [Google Scholar]
  16. Kan Y. W., Dozy A. M., Trecartin R., Todd D. Identification of a nondeletion defect in alpha-thalassemia. N Engl J Med. 1977 Nov 17;297(20):1081–1084. doi: 10.1056/NEJM197711172972002. [DOI] [PubMed] [Google Scholar]
  17. Kan Y. W., Schwartz E., Nathan D. G. Globin chain synthesis in the alpha thalassemia syndromes. J Clin Invest. 1969 Nov;47(11):2512–2522. doi: 10.1172/JCI105933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kozak M. Comparison of initiation of protein synthesis in procaryotes, eucaryotes, and organelles. Microbiol Rev. 1983 Mar;47(1):1–45. doi: 10.1128/mr.47.1.1-45.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lauer J., Shen C. K., Maniatis T. The chromosomal arrangement of human alpha-like globin genes: sequence homology and alpha-globin gene deletions. Cell. 1980 May;20(1):119–130. doi: 10.1016/0092-8674(80)90240-8. [DOI] [PubMed] [Google Scholar]
  20. Liebhaber S. A., Cash F. E., Ballas S. K. Human alpha-globin gene expression. The dominant role of the alpha 2-locus in mRNA and protein synthesis. J Biol Chem. 1986 Nov 15;261(32):15327–15333. [PubMed] [Google Scholar]
  21. Liebhaber S. A., Cash F. E., Main D. M. Compensatory increase in alpha 1-globin gene expression in individuals heterozygous for the alpha-thalassemia-2 deletion. J Clin Invest. 1985 Sep;76(3):1057–1064. doi: 10.1172/JCI112058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Liebhaber S. A., Cash F. E., Shakin S. H. Translationally associated helix-destabilizing activity in rabbit reticulocyte lysate. J Biol Chem. 1984 Dec 25;259(24):15597–15602. [PubMed] [Google Scholar]
  23. Liebhaber S. A., Coleman M. B., Adams J. G., 3rd, Cash F. E., Steinberg M. H. Molecular basis for nondeletion alpha-thalassemia in American blacks. Alpha 2(116GAG----UAG). J Clin Invest. 1987 Jul;80(1):154–159. doi: 10.1172/JCI113041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Liebhaber S. A., Kan Y. W. Differentiation of the mRNA transcripts originating from the alpha 1- and alpha 2-globin loci in normals and alpha-thalassemics. J Clin Invest. 1981 Aug;68(2):439–446. doi: 10.1172/JCI110273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Liebhaber S. A., Kan Y. W. alpha-Thalassemia caused by an unstable alpha-globin mutant. J Clin Invest. 1983 Mar;71(3):461–466. doi: 10.1172/JCI110790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Morlé F., Lopez B., Henni T., Godet J. alpha-Thalassaemia associated with the deletion of two nucleotides at position -2 and -3 preceding the AUG codon. EMBO J. 1985 May;4(5):1245–1250. doi: 10.1002/j.1460-2075.1985.tb03767.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Nicholls R. D., Higgs D. R., Clegg J. B., Weatherall D. J. Alpha zero-thalassemia due to recombination between the alpha 1-globin gene and an AluI repeat. Blood. 1985 Jun;65(6):1434–1438. [PubMed] [Google Scholar]
  28. Orkin S. H., Goff S. C., Hechtman R. L. Mutation in an intervening sequence splice junction in man. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5041–5045. doi: 10.1073/pnas.78.8.5041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Orkin S. H., Goff S. C. The duplicated human alpha-globin genes: their relative expression as measured by RNA analysis. Cell. 1981 May;24(2):345–351. doi: 10.1016/0092-8674(81)90324-x. [DOI] [PubMed] [Google Scholar]
  30. Orkin S. H., Michelson A. Partial deletion of the alpha-globin structural gene in human alpha-thalassaemia. Nature. 1980 Jul 31;286(5772):538–540. doi: 10.1038/286538a0. [DOI] [PubMed] [Google Scholar]
  31. Orkin S. H., Old J., Lazarus H., Altay C., Gurgey A., Weatherall D. J., Nathan D. G. The molecular basis of alpha-thalassemias: frequent occurrence of dysfunctional alpha loci among non-Asians with Hb H disease. Cell. 1979 May;17(1):33–42. doi: 10.1016/0092-8674(79)90292-7. [DOI] [PubMed] [Google Scholar]
  32. Paglietti E., Galanello R., Moi P., Pirastu M., Cao A. Molecular pathology of haemoglobin H disease in Sardinians. Br J Haematol. 1986 Jul;63(3):485–496. doi: 10.1111/j.1365-2141.1986.tb07525.x. [DOI] [PubMed] [Google Scholar]
  33. Phillips J. A., 3rd, Scott A. F., Smith K. D., Young K. E., Lightbody K. L., Jiji R. M., Kazazian H. H., Jr A molecular basis for hemoglobin-H disease in American blacks. Blood. 1979 Dec;54(6):1439–1445. [PubMed] [Google Scholar]
  34. Phillips J. A., 3rd, Vik T. A., Scott A. F., Young K. E., Kazazian H. H., Jr, Smith K. D., Fairbanks V. F., Koenig H. M. Unequal crossing-over: a common basis of single alpha-globin genes in Asians and American blacks with hemoglobin-H disease. Blood. 1980 Jun;55(6):1066–1069. [PubMed] [Google Scholar]
  35. Pirastu M., Lee K. Y., Dozy A. M., Kan Y. W., Stamatoyannopoulos G., Hadjiminas M. G., Zachariades Z., Angius A., Furbetta M., Rosatelli C. Alpha-thalassemia in two Mediterranean populations. Blood. 1982 Aug;60(2):509–512. [PubMed] [Google Scholar]
  36. Pirastu M., Saglio G., Chang J. C., Cao A., Kan Y. W. Initiation codon mutation as a cause of alpha thalassemia. J Biol Chem. 1984 Oct 25;259(20):12315–12317. [PubMed] [Google Scholar]
  37. Pongsamart S., Pootrakul S., Wasi P., Na-Nakorn S. Hemoglobin Constant Spring: hemoglobin synthesis in heterozygous and homozygous states. Biochem Biophys Res Commun. 1975 May 19;64(2):681–686. doi: 10.1016/0006-291x(75)90374-5. [DOI] [PubMed] [Google Scholar]
  38. Pressley L., Higgs D. R., Aldridge B., Metaxatou-Mavromati A., Clegg J. B., Weatherall D. J. Characterisation of a new alpha thalassemia 1 defect due to a partial deletion of the alpha globin gene complex. Nucleic Acids Res. 1980 Nov 11;8(21):4889–4898. doi: 10.1093/nar/8.21.4889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Proudfoot N. J., Gil A., Maniatis T. The structure of the human zeta-globin gene and a closely linked, nearly identical pseudogene. Cell. 1982 Dec;31(3 Pt 2):553–563. doi: 10.1016/0092-8674(82)90311-7. [DOI] [PubMed] [Google Scholar]
  40. Proudfoot N. J., Maniatis T. The structure of a human alpha-globin pseudogene and its relationship to alpha-globin gene duplication. Cell. 1980 Sep;21(2):537–544. doi: 10.1016/0092-8674(80)90491-2. [DOI] [PubMed] [Google Scholar]
  41. Rovera G., Magarian C., Borun T. W. Resolution of hemoglobin subunits by electrophoresis in acid urea polyacrylamide gels containing Triton X-100. Anal Biochem. 1978 Apr;85(2):506–518. doi: 10.1016/0003-2697(78)90248-8. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. Shakin S. H., Liebhaber S. A. Translational profiles of alpha 1-, alpha 2-, and beta-globin messenger ribonucleic acids in human reticulocytes. J Clin Invest. 1986 Oct;78(4):1125–1129. doi: 10.1172/JCI112670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sophocleous T., Higgs D. R., Aldridge B., Trent R. J., Pressley L., Clegg J. B., Weatherall D. J. The molecular basis for the haemoglobin Bart's hydrops fetalis syndrome in Cyprus. Br J Haematol. 1981 Jan;47(1):153–156. doi: 10.1111/j.1365-2141.1981.tb02770.x. [DOI] [PubMed] [Google Scholar]

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