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. 1993 Mar;30(3):240–244. doi: 10.1136/jmg.30.3.240

Filipino beta zero thalassaemia: a high Hb A2 beta zero thalassaemia resulting from a large deletion of the 5' beta globin gene region.

P I Motum 1, A Kearney 1, T J Hamilton 1, R J Trent 1
PMCID: PMC1016308  PMID: 7682618

Abstract

A large novel deletional beta zero thalassaemia mutation associated with unusually high levels of haemoglobin (Hb) A2 in heterozygotes is described in two unrelated subjects of Filipino background. The deletion was characterised by DNA mapping including pulsed field gel electrophoresis. Filipino beta zero thalassaemia extends for approximately 45 kb beginning approximately 1.5 kb 3' to the delta globin gene. It is the largest deletion to date which gives rise to the beta zero thalassaemia phenotype. This mutation, similar to previously described deletional beta zero thalassaemias associated with high Hb A2, removes sequences 5' to the beta globin gene promoter and emphasises the functional importance of the 5' beta globin region in eliciting the unusually high level of Hb A2. This example also suggests that it is the 3' sequences which are transposed rather than the actual deletion size which are significant in the raised fetal haemoglobin (Hb F) found with some of the thalassaemias.

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Selected References

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

  1. Alperin J. B., Dow P. A., Petteway M. B. Hemoglobin A2 levels in health and various hematologic disorders. Am J Clin Pathol. 1977 Mar;67(3):219–226. doi: 10.1093/ajcp/67.3.219. [DOI] [PubMed] [Google Scholar]
  2. Anagnou N. P., Papayannopoulou T., Nienhuis A. W., Stamatoyannopoulos G. Molecular characterization of a novel form of (A gamma delta beta)zero-thalassemia deletion with a 3' breakpoint close to those of HPFH-3 and HPFH-4: insights for a common regulatory mechanism. Nucleic Acids Res. 1988 Jul 11;16(13):6057–6066. doi: 10.1093/nar/16.13.6057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anand R., Boehm C. D., Kazazian H. H., Jr, Vanin E. F. Molecular characterization of a beta zero-thalassemia resulting from a 1.4 kilobase deletion. Blood. 1988 Aug;72(2):636–641. [PubMed] [Google Scholar]
  4. Bilofsky H. S., Burks C., Fickett J. W., Goad W. B., Lewitter F. I., Rindone W. P., Swindell C. D., Tung C. S. The GenBank genetic sequence databank. Nucleic Acids Res. 1986 Jan 10;14(1):1–4. doi: 10.1093/nar/14.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bodine D. M., Ley T. J. An enhancer element lies 3' to the human A gamma globin gene. EMBO J. 1987 Oct;6(10):2997–3004. doi: 10.1002/j.1460-2075.1987.tb02605.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Codrington J. F., Li H. W., Kutlar F., Gu L. H., Ramachandran M., Huisman T. H. Observations on the levels of Hb A2 in patients with different beta-thalassemia mutations and a delta chain variant. Blood. 1990 Sep 15;76(6):1246–1249. [PubMed] [Google Scholar]
  7. Collins F. S., Cole J. L., Lockwood W. K., Iannuzzi M. C. The deletion in both common types of hereditary persistence of fetal hemoglobin is approximately 105 kilobases. Blood. 1987 Dec;70(6):1797–1803. [PubMed] [Google Scholar]
  8. Diaz-Chico J. C., Yang K. G., Kutlar A., Reese A. L., Aksoy M., Huisman T. H. An approximately 300 bp deletion involving part of the 5' beta-globin gene region is observed in members of a Turkish family with beta-thalassemia. Blood. 1987 Aug;70(2):583–586. [PubMed] [Google Scholar]
  9. Efremov G. D. An evaluation of the methods for quantitation of hemoglobin A2: results from a survey of 10,663 cases. Hemoglobin. 1977;1(8):845–860. doi: 10.3109/03630267709003911. [DOI] [PubMed] [Google Scholar]
  10. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  11. Gilman J. G. The 12.6 kilobase DNA deletion in Dutch beta zero-thalassaemia. Br J Haematol. 1987 Nov;67(3):369–372. doi: 10.1111/j.1365-2141.1987.tb02360.x. [DOI] [PubMed] [Google Scholar]
  12. Grosveld F., van Assendelft G. B., Greaves D. R., Kollias G. Position-independent, high-level expression of the human beta-globin gene in transgenic mice. Cell. 1987 Dec 24;51(6):975–985. doi: 10.1016/0092-8674(87)90584-8. [DOI] [PubMed] [Google Scholar]
  13. HUISMAN T. H., PUNT K., SCHAAD J. D. Thalassemia minor associated with hemoglobin-B2 heterozygosity. A family report. Blood. 1961 Jun;17:747–757. [PubMed] [Google Scholar]
  14. Henthorn P. S., Mager D. L., Huisman T. H., Smithies O. A gene deletion ending within a complex array of repeated sequences 3' to the human beta-globin gene cluster. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5194–5198. doi: 10.1073/pnas.83.14.5194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Henthorn P. S., Smithies O., Nakatsuji T., Felice A. E., Gardiner M. B., Reese A. L., Huisman T. H. (A gamma delta beta)0-Thalassaemia in Blacks is due to a deletion of 34 kbp of DNA. Br J Haematol. 1985 Feb;59(2):343–356. doi: 10.1111/j.1365-2141.1985.tb02999.x. [DOI] [PubMed] [Google Scholar]
  16. Horikoshi M., Hai T., Lin Y. S., Green M. R., Roeder R. G. Transcription factor ATF interacts with the TATA factor to facilitate establishment of a preinitiation complex. Cell. 1988 Sep 23;54(7):1033–1042. doi: 10.1016/0092-8674(88)90118-3. [DOI] [PubMed] [Google Scholar]
  17. Kaufman R. E., Kretschmer P. J., Adams J. W., Coon H. C., Anderson W. F., Nienhuis A. W. Cloning and characterization of DNA sequences surrounding the human gamma-, delta-, and beta-globin genes. Proc Natl Acad Sci U S A. 1980 Jul;77(7):4229–4233. doi: 10.1073/pnas.77.7.4229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kazazian H. H., Jr, Dowling C. E., Boehm C. D., Warren T. C., Economou E. P., Katz J., Antonarakis S. E. Gene defects in beta-thalassemia and their prenatal diagnosis. Ann N Y Acad Sci. 1990;612:1–14. doi: 10.1111/j.1749-6632.1990.tb24285.x. [DOI] [PubMed] [Google Scholar]
  19. Kollias G., Hurst J., deBoer E., Grosveld F. The human beta-globin gene contains a downstream developmental specific enhancer. Nucleic Acids Res. 1987 Jul 24;15(14):5739–5747. doi: 10.1093/nar/15.14.5739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Losekoot M., Fodde R., Gerritsen E. J., van de Kuit I., Schreuder A., Giordano P. C., Vossen J. M., Bernini L. F. Interaction of two different disorders in the beta-globin gene cluster associated with an increased hemoglobin F production: a novel deletion type of (G) gamma + ((A) gamma delta beta)(0)-thalassemia and a delta(0)-hereditary persistence of fetal hemoglobin determinant. Blood. 1991 Feb 15;77(4):861–867. [PubMed] [Google Scholar]
  21. Lynch J. R., Brown J. M., Best S., Jennings M. W., Weatherall D. J. Characterization of the breakpoint of a 3.5-kb deletion of the beta-globin gene. Genomics. 1991 Jun;10(2):509–511. doi: 10.1016/0888-7543(91)90344-e. [DOI] [PubMed] [Google Scholar]
  22. Mager D. L., Henthorn P. S., Smithies O. A Chinese G gamma + (A gamma delta beta)zero thalassemia deletion: comparison to other deletions in the human beta-globin gene cluster and sequence analysis of the breakpoints. Nucleic Acids Res. 1985 Sep 25;13(18):6559–6575. doi: 10.1093/nar/13.18.6559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Maniatis T., Goodbourn S., Fischer J. A. Regulation of inducible and tissue-specific gene expression. Science. 1987 Jun 5;236(4806):1237–1245. doi: 10.1126/science.3296191. [DOI] [PubMed] [Google Scholar]
  24. Motum P. I., Lindeman R., Hamilton T. J., Trent R. J. Australian beta zero-thalassaemia: a high haemoglobin A2 beta zero-thalassaemia due to a 12 kb deletion commencing 5' to the beta-globin gene. Br J Haematol. 1992 Sep;82(1):107–113. doi: 10.1111/j.1365-2141.1992.tb04601.x. [DOI] [PubMed] [Google Scholar]
  25. Padanilam B. J., Felice A. E., Huisman T. H. Partial deletion of the 5' beta-globin gene region causes beta zero-thalassemia in members of an American black family. Blood. 1984 Oct;64(4):941–944. [PubMed] [Google Scholar]
  26. Pembrey M. E., McWade P., Weatherall D. J. Reliable routine estimation of small amounts of foetal haemoglobin by alkali denaturation. J Clin Pathol. 1972 Aug;25(8):738–740. doi: 10.1136/jcp.25.8.738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Popovich B. W., Rosenblatt D. S., Kendall A. G., Nishioka Y. Molecular characterization of an atypical beta-thalassemia caused by a large deletion in the 5' beta-globin gene region. Am J Hum Genet. 1986 Dec;39(6):797–810. [PMC free article] [PubMed] [Google Scholar]
  28. Saglio G., Camaschella C., Serra A., Bertero T., Rege Cambrin G., Guerrasio A., Mazza U., Izzo P., Terragni F., Giglioni B. Italian type of deletional hereditary persistence of fetal hemoglobin. Blood. 1986 Sep;68(3):646–651. [PubMed] [Google Scholar]
  29. Salkie M. L., Gordon P. A., Rigal W. M., Lam H., Wilson J. B., Headlee M. E., Huisman T. H. Hb A2-Canada or alpha 2 delta 2 99(G1) Asp replaced by Asn, a newly discovered delta chain variant with increased oxygen affinity occurring in cis to beta-thalassemia. Hemoglobin. 1982;6(3):223–231. doi: 10.3109/03630268208991698. [DOI] [PubMed] [Google Scholar]
  30. Sanguansermsri T., Pape M., Laig M., Hundrieser J., Flatz G. Beta zero-thalassemia in a Thai family is caused by a 3.4 kb deletion including the entire beta-globin gene. Hemoglobin. 1990;14(2):157–168. doi: 10.3109/03630269009046957. [DOI] [PubMed] [Google Scholar]
  31. Schiffer C. A. Prevention of alloimmunization against platelets. Blood. 1991 Jan 1;77(1):1–4. [PubMed] [Google Scholar]
  32. Smith C. L., Lawrance S. K., Gillespie G. A., Cantor C. R., Weissman S. M., Collins F. S. Strategies for mapping and cloning macroregions of mammalian genomes. Methods Enzymol. 1987;151:461–489. doi: 10.1016/s0076-6879(87)51038-2. [DOI] [PubMed] [Google Scholar]
  33. Sorrentino B. P., Ney P. A., Nienhuis A. W. Localization and characterization of the DNase I-hypersensitive site II (HS II) enhancer. A critical regulatory element within the beta-globin locus-activating region. Ann N Y Acad Sci. 1990;612:141–151. doi: 10.1111/j.1749-6632.1990.tb24300.x. [DOI] [PubMed] [Google Scholar]
  34. Spiegelberg R., Aulehla-Scholz C., Erlich H., Horst J. A beta-thalassemia gene caused by a 290-base pair deletion: analysis by direct sequencing of enzymatically amplified DNA. Blood. 1989 May 1;73(6):1695–1698. [PubMed] [Google Scholar]
  35. Spritz R. A., Orkin S. H. Duplication followed by deletion accounts for the structure of an Indian deletion beta (0)-thalassemia gene. Nucleic Acids Res. 1982 Dec 20;10(24):8025–8029. doi: 10.1093/nar/10.24.8025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Steinberg M. H., Adams J. G., 3rd Hemoglobin A2: origin, evolution, and aftermath. Blood. 1991 Nov 1;78(9):2165–2177. [PubMed] [Google Scholar]
  37. Thein S. L., Hesketh C., Brown J. M., Anstey A. V., Weatherall D. J. Molecular characterization of a high A2 beta thalassemia by direct sequencing of single strand enriched amplified genomic DNA. Blood. 1989 Mar;73(4):924–930. [PubMed] [Google Scholar]
  38. Tuan D., Feingold E., Newman M., Weissman S. M., Forget B. G. Different 3' end points of deletions causing delta beta-thalassemia and hereditary persistence of fetal hemoglobin: implications for the control of gamma-globin gene expression in man. Proc Natl Acad Sci U S A. 1983 Nov;80(22):6937–6941. doi: 10.1073/pnas.80.22.6937. [DOI] [PMC free article] [PubMed] [Google Scholar]

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