Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Introduction to hemoglobin mutations

Stanley L Schrier, MD
Section Editors
William C Mentzer, MD
Donald H Mahoney, Jr, MD
Deputy Editor
Jennifer S Tirnauer, MD


Over 1000 different mutations of the globin chains of the human hemoglobin molecule have been discovered [1,2]. They are classified according to the type of mutation (eg, insertion, deletion, base change), the affected globin subunit (eg, alpha chain, beta chain), and by the clinical and hematologic phenotype (table 1 and table 2). This topic review will present an introduction to the most common of these hemoglobin mutations.

The hemoglobins found in normal adults (ie, hemoglobins A [adult], A2, and F [fetal]) are discussed separately. (See "Structure and function of normal hemoglobins".)

Sickle hemoglobin (HbS) and the thalassemias are discussed in depth separately. (See "Diagnosis of sickle cell disorders" and "Clinical manifestations and diagnosis of the thalassemias".)

Laboratory and DNA-based methods for separation and detection of hemoglobin mutations are discussed separately. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)


It has been estimated that in excess of 300,000 children are born in the world each year with a severe inherited disorder of hemoglobin (eg, the thalassemic and sickle cell disorders), and that approximately 80 percent of these births occur in low- or middle-income countries [3]. Accordingly, these disorders are presenting an increasing global health burden. (See "Public health issues in the thalassemic syndromes".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Apr 13, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Hardison RC, Chui DH, Riemer C, et al. Databases of human hemoglobin variants and other resources at the globin gene server. Hemoglobin 2001; 25:183.
  2. Hardison RC, Chui DH, Giardine B, et al. HbVar: A relational database of human hemoglobin variants and thalassemia mutations at the globin gene server. Hum Mutat 2002; 19:225.
  3. Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood 2010; 115:4331.
  4. Wilson JB, Chen SS, Webber BB, et al. The identification of five rare beta-chain abnormal hemoglobins by high performance liquid chromatographic procedures. Hemoglobin 1986; 10:49.
  5. Lubin BH, Witkowska HE, Kleman K. Laboratory diagnosis of hemoglobinopathies. Clin Biochem 1991; 24:363.
  6. Schnee J, Aulehla-Scholz C, Eigel A, Horst J. Hb D Los Angeles (D-Punjab) and Hb Presbyterian: analysis of the defect at the DNA level. Hum Genet 1990; 84:365.
  7. Codrington JF, Kutlar F, Harris HF, et al. Hb A2-Wrens or alpha 2 delta 2 98(FG5) Val----Met, an unstable delta chain variant identified by sequence analysis of amplified DNA. Biochim Biophys Acta 1989; 1009:87.
  8. Camaschella C, Saglio G. Recent advances in diagnosis of hemoglobinopathies. Crit Rev Oncol Hematol 1993; 14:89.
  9. Cash FE, Monplaisir N, Goossens M, Liebhaber SA. Locus assignment of two alpha-globin structural mutants from the Caribbean basin: alpha Fort de France (alpha 45 Arg) and alpha Spanish Town (alpha 27 Val). Blood 1989; 74:833.
  10. Bunn HF, McDonald MJ. Electrostatic interactions in the assembly of haemoglobin. Nature 1983; 306:498.
  11. Bunn HF. Subunit assembly of hemoglobin: an important determinant of hematologic phenotype. Blood 1987; 69:1.
  12. Liebhaber SA, Cash FE, Cornfield DB. Evidence for posttranslational control of Hb C synthesis in an individual with Hb C trait and alpha-thalassemia. Blood 1988; 71:502.
  13. Huisman TH. Percentages of abnormal hemoglobins in adults with a heterozygosity for an alpha-chain and/or a beta-chain variant. Am J Hematol 1983; 14:393.
  14. Steinberg MH, Embury SH. Alpha-thalassemia in blacks: genetic and clinical aspects and interactions with the sickle hemoglobin gene. Blood 1986; 68:985.
  15. Mrabet NT, McDonald MJ, Turci S, et al. Electrostatic attraction governs the dimer assembly of human hemoglobin. J Biol Chem 1986; 261:5222.
  16. Adachi K, Yamaguchi T, Pang J, Surrey S. Effects of increased anionic charge in the beta-globin chain on assembly of hemoglobin in vitro. Blood 1998; 91:1438.
  17. Bunn HF, Noguchi CT, Hofrichter J, et al. Molecular and cellular pathogenesis of hemoglobin SC disease. Proc Natl Acad Sci U S A 1982; 79:7527.
  18. Huisman TH. Trimodality in the percentages of beta chain variants in heterozygotes: the effect of the number of active Hbalpha structural loci. Hemoglobin 1977; 1:349.
  19. Adams JG 3rd, Coleman MB, Hayes J, et al. Modulation of fetal hemoglobin synthesis by iron deficiency. N Engl J Med 1985; 313:1402.
  20. Chui DH, Patterson M, Dowling CE, et al. Hemoglobin Bart's disease in an Italian boy. Interaction between alpha-thalassemia and hereditary persistence of fetal hemoglobin. N Engl J Med 1990; 323:179.
  21. Macdonald VW, Charache S. Differences in the reaction sequences associated with drug-induced oxidation of hemoglobins E, S, A, and F. J Lab Clin Med 1983; 102:762.
  22. Lachant NA, Tanaka KR. Dapsone-associated Heinz body hemolytic anemia in a Cambodian woman with hemoglobin E trait. Am J Med Sci 1987; 294:364.
  23. Vichinsky E. Hemoglobin e syndromes. Hematology Am Soc Hematol Educ Program 2007; :79.
  24. Joutovsky A, Nardi M. Hemoglobin C and hemoglobin O-Arab variants can be diagnosed using the Bio-Rad Variant II high-performance liquid chromatography system without further confirmatory tests. Arch Pathol Lab Med 2004; 128:435.
  25. Carnley BP, Prior JF, Gilbert A, et al. The prevalence and molecular basis of hemoglobinopathies in Cambodia. Hemoglobin 2006; 30:463.
  26. Tritipsombut J, Sanchaisuriya K, Phollarp P, et al. Micromapping of thalassemia and hemoglobinopathies in diferent regions of northeast Thailand and Vientiane, Laos People's Democratic Republic. Hemoglobin 2012; 36:47.
  27. Hirsch RE, Raventos-Suarez C, Olson JA, Nagel RL. Ligand state of intraerythrocytic circulating HbC crystals in homozygote CC patients. Blood 1985; 66:775.
  28. Fabry ME, Kaul DK, Raventos-Suarez C, et al. SC erythrocytes have an abnormally high intracellular hemoglobin concentration. Pathophysiological consequences. J Clin Invest 1982; 70:1315.
  29. Brugnara C, Kopin AS, Bunn HF, Tosteson DC. Regulation of cation content and cell volume in hemoglobin erythrocytes from patients with homozygous hemoglobin C disease. J Clin Invest 1985; 75:1608.
  30. Agarwal A, Guindo A, Cissoko Y, et al. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 2000; 96:2358.
  31. Bookchin RM, Davis RP, Ranney HM. Clinical features of Hemoglobin C Harlem, a new sickling hemoglobin variant. Ann Intern Med 1968; 68:8.
  32. Steinberg MH, Chui DH. HbC disorders. Blood 2013; 122:3698.
  33. Adekile AD, Kazanetz EG, Leonova JY, et al. Co-inheritance of Hb D-Punjab (codon 121; GAA-->CAA) and beta (0) -thalassemia (IVS-II-1;G-->A). J Pediatr Hematol Oncol 1996; 18:151.
  34. The Globin Gene Server is available at http://globin.cse.psu.edu/ (Accessed on September 19, 2013).