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. 1983 Mar;71(3):461–466. doi: 10.1172/JCI110790

alpha-Thalassemia caused by an unstable alpha-globin mutant.

S A Liebhaber, Y W Kan
PMCID: PMC436893  PMID: 6826718

Abstract

In a previous study, molecular cloning of the alpha-globin genes from a patient with nondeletion Hb-H disease (genotype--/alpha alpha) showed that a single nucleotide mutation (CTG to CCG) in one of the genes resulted in a leucine to proline substitution. This paper describes the approach we used to detect the abnormal alpha-globin chain. The chain was identified using a cell-free translation system. It turned over rapidly both in vitro and in vivo in the patient's reticulocytes. The unusual feature of this unstable alpha-globin is that the alpha-globin deficiency causes alpha-thalassemia. Simple heterozygotes for this lesion (alpha Pro alpha/alpha alpha) resemble alpha-thalassemia carriers and do not exhibit the hemolytic anemia usually associated with unstable hemoglobins.

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Selected References

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

  1. Adams J. G., 3rd, Boxer L. A., Baehner R. L., Forget B. G., Tsistrakis G. A., Steinberg M. H. Hemoglobin Indianapolis (beta 112[G14] arginine). An unstable beta-chain variant producing the phenotype of severe beta-thalassemia. J Clin Invest. 1979 May;63(5):931–938. doi: 10.1172/JCI109393. [DOI] [PMC free article] [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. Basset P., Beuzard Y., Garel M. C., Rosa J. Isoelectric focusing of human hemoglobin: its application to screening, to the characterization of 70 variants, and to the study of modified fractions of normal hemoglobins. Blood. 1978 May;51(5):971–982. [PubMed] [Google Scholar]
  4. Busslinger M., Moschonas N., Flavell R. A. Beta + thalassemia: aberrant splicing results from a single point mutation in an intron. Cell. 1981 Dec;27(2 Pt 1):289–298. doi: 10.1016/0092-8674(81)90412-8. [DOI] [PubMed] [Google Scholar]
  5. Chang J. C., Kan Y. W. beta 0 thalassemia, a nonsense mutation in man. Proc Natl Acad Sci U S A. 1979 Jun;76(6):2886–2889. doi: 10.1073/pnas.76.6.2886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. Kleihauer E. F., Reynolds C. A., Dozy A. M., Wilson J. B., Moores R. R., Berenson M. P., Wright C. S., Huisman T. H. Hemoglobin-Bibba or alpha-2-136Pro-beta 2, an unstable alpha chain abnormal hemoglobin. Biochim Biophys Acta. 1968 Jan 22;154(1):220–222. doi: 10.1016/0005-2795(68)90274-2. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Liebhaber S. A., Goossens M., Kan Y. W. Homology and concerted evolution at the alpha 1 and alpha 2 loci of human alpha-globin. Nature. 1981 Mar 5;290(5801):26–29. doi: 10.1038/290026a0. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. 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]
  15. Orkin S. H., Kazazian H. H., Jr, Antonarakis S. E., Goff S. C., Boehm C. D., Sexton J. P., Waber P. G., Giardina P. J. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982 Apr 15;296(5858):627–631. doi: 10.1038/296627a0. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Orkin S. H. The duplicated human alpha globin genes lie close together in cellular DNA. Proc Natl Acad Sci U S A. 1978 Dec;75(12):5950–5954. doi: 10.1073/pnas.75.12.5950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Paterson B. M., Roberts B. E., Kuff E. L. Structural gene identification and mapping by DNA-mRNA hybrid-arrested cell-free translation. Proc Natl Acad Sci U S A. 1977 Oct;74(10):4370–4374. doi: 10.1073/pnas.74.10.4370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pelham H. R., Jackson R. J. An efficient mRNA-dependent translation system from reticulocyte lysates. Eur J Biochem. 1976 Aug 1;67(1):247–256. doi: 10.1111/j.1432-1033.1976.tb10656.x. [DOI] [PubMed] [Google Scholar]
  20. Pergolizzi R., Spritz R. A., Spence S., Goossens M., Kan Y. W., Bank A. Two cloned beta thalassemia genes are associated with amber mutations at codon 39. Nucleic Acids Res. 1981 Dec 21;9(24):7065–7072. doi: 10.1093/nar/9.24.7065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Poncz M., Ballantine M., Solowiejczyk D., Barak I., Schwartz E., Surrey S. beta-Thalassemia in a Kurdish Jew. Single base changes in the T-A-T-A box. J Biol Chem. 1982 Jun 10;257(11):5994–5996. [PubMed] [Google Scholar]
  23. Pressley L., Higgs D. R., Clegg J. B., Perrine R. P., Pembrey M. E., Weatherall D. J. A new genetic basis for hemoglobin-H disease. N Engl J Med. 1980 Dec 11;303(24):1383–1388. doi: 10.1056/NEJM198012113032402. [DOI] [PubMed] [Google Scholar]
  24. Roberts B. E., Paterson B. M. Efficient translation of tobacco mosaic virus RNA and rabbit globin 9S RNA in a cell-free system from commercial wheat germ. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2330–2334. doi: 10.1073/pnas.70.8.2330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Schibler U., Kelley D. E., Perry R. P. Comparison of methylated sequences in messenger RNA and heterogeneous nuclear RNA from mouse L cells. J Mol Biol. 1977 Oct 5;115(4):695–714. doi: 10.1016/0022-2836(77)90110-3. [DOI] [PubMed] [Google Scholar]
  27. Spritz R. A., Jagadeeswaran P., Choudary P. V., Biro P. A., Elder J. T., deRiel J. K., Manley J. L., Gefter M. L., Forget B. G., Weissman S. M. Base substitution in an intervening sequence of a beta+-thalassemic human globin gene. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2455–2459. doi: 10.1073/pnas.78.4.2455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Trecartin R. F., Liebhaber S. A., Chang J. C., Lee K. Y., Kan Y. W., Furbetta M., Angius A., Cao A. beta zero thalassemia in Sardinia is caused by a nonsense mutation. J Clin Invest. 1981 Oct;68(4):1012–1017. doi: 10.1172/JCI110323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vettore L., De Matteis M. C., Zampini P. A new density gradient system for the separation of human red blood cells. Am J Hematol. 1980;8(3):291–297. doi: 10.1002/ajh.2830080307. [DOI] [PubMed] [Google Scholar]
  31. Westaway D., Williamson R. An intron nucleotide sequence variant in a cloned beta +-thalassaemia globin gene. Nucleic Acids Res. 1981 Apr 24;9(8):1777–1788. doi: 10.1093/nar/9.8.1777. [DOI] [PMC free article] [PubMed] [Google Scholar]

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