Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Oct;76(4):1554–1558. doi: 10.1172/JCI112136

A distant gene deletion affects beta-globin gene function in an atypical gamma delta beta-thalassemia.

P Curtin, M Pirastu, Y W Kan, J A Gobert-Jones, A D Stephens, H Lehmann
PMCID: PMC424127  PMID: 2997283

Abstract

We describe an English family with an atypical gamma delta beta-thalassemia syndrome. Heterozygosity results in a beta-thalassemia phenotype with normal hemoglobin A2. However, unlike previously described cases, no history of neonatal hemolytic anemia requiring blood transfusion was obtained. Gene mapping showed a deletion that extended from the third exon of the G gamma-globin gene upstream for approximately 100 kilobases (kb). The A gamma-globin, psi beta-, delta-, and beta-globin genes in cis remained intact. The malfunction of the beta-globin gene on a chromosome in which the deletion is located 25 kb away suggests that chromatin structure and conformation are important for globin gene expression.

Full text

PDF
1557

Images in this article

1555Image
on p.1555
1555Image
on p.1555
1555Image
on p.1555
1555Image
on p.1555
1556Image
on p.1556
1556Image
on p.1556
1556Image
on p.1556
1556Image
on p.1556
1556Image
on p.1556
1556Image
on p.1556
1557Image
on p.1557
1557Image
on p.1557
1557Image
on p.1557
1557Image
on p.1557

Selected References

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

  1. Antonarakis S. E., Boehm C. D., Giardina P. J., Kazazian H. H., Jr Nonrandom association of polymorphic restriction sites in the beta-globin gene cluster. Proc Natl Acad Sci U S A. 1982 Jan;79(1):137–141. doi: 10.1073/pnas.79.1.137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bernards R., Flavell R. A. Physical mapping of the globin gene deletion in hereditary persistence of foetal haemoglobin (HPFH). Nucleic Acids Res. 1980 Apr 11;8(7):1521–1534. doi: 10.1093/nar/8.7.1521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Collins F. S., Weissman S. M. The molecular genetics of human hemoglobin. Prog Nucleic Acid Res Mol Biol. 1984;31:315–462. doi: 10.1016/s0079-6603(08)60382-7. [DOI] [PubMed] [Google Scholar]
  4. Fritsch E. F., Lawn R. M., Maniatis T. Characterisation of deletions which affect the expression of fetal globin genes in man. Nature. 1979 Jun 14;279(5714):598–603. doi: 10.1038/279598a0. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Huisman T. H., Wilson J. B. Recent advances in the quantitation of human fetal hemoglobins with different gamma chains. Am J Hematol. 1980;9(2):225–235. doi: 10.1002/ajh.2830090211. [DOI] [PubMed] [Google Scholar]
  7. Kan Y. W., Forget B. G., Nathan D. G. Gamma-beta thalassemia: a cause of hemolytic disease of the newborn. N Engl J Med. 1972 Jan 20;286(3):129–134. doi: 10.1056/NEJM197201202860304. [DOI] [PubMed] [Google Scholar]
  8. Kan Y. W., Lee K. Y., Furbetta M., Angius A., Cao A. Polymorphism of DNA sequence in the beta-globin gene region. Application to prenatal diagnosis of beta 0 thalassemia in Sardinia. N Engl J Med. 1980 Jan 24;302(4):185–188. doi: 10.1056/NEJM198001243020401. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Kioussis D., Vanin E., deLange T., Flavell R. A., Grosveld F. G. Beta-globin gene inactivation by DNA translocation in gamma beta-thalassaemia. Nature. 1983 Dec 15;306(5944):662–666. doi: 10.1038/306662a0. [DOI] [PubMed] [Google Scholar]
  11. Kohen G., Philippe N., Godet J. Polymorphism of the Hinf I restriction site located 1 Kb 5' to the human beta-globin gene. Hum Genet. 1982;62(2):121–123. doi: 10.1007/BF00282298. [DOI] [PubMed] [Google Scholar]
  12. Nienhuis A. W., Anagnou N. P., Ley T. J. Advances in thalassemia research. Blood. 1984 Apr;63(4):738–758. [PubMed] [Google Scholar]
  13. Orkin S. H., Goff S. C., Nathan D. G. Heterogeneity of DNA deletion in gamma delta beta-thalassemia. J Clin Invest. 1981 Mar;67(3):878–884. doi: 10.1172/JCI110105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Orkin S. H., Kazazian H. H., Jr The mutation and polymorphism of the human beta-globin gene and its surrounding DNA. Annu Rev Genet. 1984;18:131–171. doi: 10.1146/annurev.ge.18.120184.001023. [DOI] [PubMed] [Google Scholar]
  15. Orkin S. H., Kolodner R., Michelson A., Husson R. Cloning and direct examination of a structurally abnormal human beta 0-thalassemia globin gene. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3558–3562. doi: 10.1073/pnas.77.6.3558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ottolenghi S., Giglioni B., Comi P., Gianni A. M., Polli E., Acquaye C. T., Oldham J. H., Masera G. Globin gene deletion in HPFH, delta (o) beta (o) thalassaemia and Hb Lepore disease. Nature. 1979 Apr 12;278(5705):654–657. doi: 10.1038/278654a0. [DOI] [PubMed] [Google Scholar]
  17. Pirastu M., Kan Y. W., Galanello R., Cao A. Multiple mutations produce delta beta 0 thalassemia in Sardinia. Science. 1984 Mar 2;223(4639):929–930. doi: 10.1126/science.6198720. [DOI] [PubMed] [Google Scholar]
  18. Pirastu M., Kan Y. W., Lin C. C., Baine R. M., Holbrook C. T. Hemolytic disease of the newborn caused by a new deletion of the entire beta-globin cluster. J Clin Invest. 1983 Aug;72(2):602–609. doi: 10.1172/JCI111008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Tuan D., Murnane M. J., deRiel J. L., Forget B. G. Heterogeneity in the molecular basis of hereditary persistence of fetal haemoglobin. Nature. 1980 May 29;285(5763):335–337. doi: 10.1038/285335a0. [DOI] [PubMed] [Google Scholar]
  21. Van der Ploeg L. H., Konings A., Oort M., Roos D., Bernini L., Flavell R. A. gamma-beta-Thalassaemia studies showing that deletion of the gamma- and delta-genes influences beta-globin gene expression in man. Nature. 1980 Feb 14;283(5748):637–642. doi: 10.1038/283637a0. [DOI] [PubMed] [Google Scholar]
  22. Vanin E. F., Henthorn P. S., Kioussis D., Grosveld F., Smithies O. Unexpected relationships between four large deletions in the human beta-globin gene cluster. Cell. 1983 Dec;35(3 Pt 2):701–709. doi: 10.1016/0092-8674(83)90103-4. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES