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Genetic disorders of hemoglobin oxygen affinity

Martin H Steinberg, MD
Section Editors
Donald H Mahoney, Jr, MD
Benjamin A Raby, MD, MPH
Deputy Editor
Jennifer S Tirnauer, MD


Normal adult hemoglobin is a tetramer of two pairs of globin polypeptide chains, alpha chains and beta chains. Some rare mutations in these globin chains change the affinity of the hemoglobin molecule for oxygen, thereby disturbing the normal loading of oxygen in the lungs and delivery of oxygen to the tissues. (See "Structure and function of normal hemoglobins".)

Mutations in the coding sequence of globin genes that alter hemoglobin oxygen affinity and mutations in other genes that may cause polycythemia will be discussed here [1]. Understanding these hemoglobin mutants is useful for clinicians who must diagnose and treat patients with suspected hemoglobinopathies.

The more general evaluation of patients with erythrocytosis, which may be a consequence of increased hemoglobin oxygen affinity or of other disorders that increase the production of RBCs such as polycythemia vera or smoking, is discussed separately. (See "Diagnostic approach to the patient with polycythemia".)  


The normal oxygen binding characteristics of hemoglobin are displayed by the sigmoidally-shaped hemoglobin-oxygen dissociation curve and its P50, the point on the curve where the hemoglobin molecule is half-saturated with oxygen.

When a hemoglobin's affinity for oxygen is high (ie, lowP50), oxygen delivery to tissues is impaired, stimulating erythropoietin production and increasing the red cell mass, resulting in erythrocytosis.


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Literature review current through: Sep 2016. | This topic last updated: Mar 16, 2016.
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  1. Disorders of Hemoglobin: Genetics, Pathophysiology, Clinical Management, Forget BG, Higgs DR, Nagel RL, et al. (Eds), Cambridge University Press, UK 1999.
  2. http://globin.cse.psu.edu (Accessed on April 02, 2010).
  3. Charache S, Weatherall DJ, Clegg JB. Polycythemia associated with a hemoglobinopathy. J Clin Invest 1966; 45:813.
  4. Wajcman H, Kister J, Galactéros F, et al. Hb Montefiore (126(H9)Asp-->Tyr). High oxygen affinity and loss of cooperativity secondary to C-terminal disruption. J Biol Chem 1996; 271:22990.
  5. Maniatis A, Bousios T, Nagel RL, et al. Hemoglobin Crete (beta 129 ala leads to pro): a new high-affinity variant interacting with beta o -and delta beta o -thalassemia. Blood 1979; 54:54.
  6. Lorkin PA, Stephens AD, Beard ME, et al. Haemoglobin Rahere (beta Lys-Thr): A new high affinity haemoglobin associated with decreased 2, 3-diphosphoglycerate binding and relative polycythaemia. Br Med J 1975; 4:200.
  7. Ikkala E, Koskela J, Pikkarainen P, et al. Hb Helsinki: a variant with a high oxygen affinity and a substitution at a 2,3-DPG binding site (beta82[EF6] Lys replaced by Met). Acta Haematol 1976; 56:257.
  8. Bonaventura J, Bonaventura C, Sullivan B, et al. Hemoglobin providence. Functional consequences of two alterations of the 2,3-diphosphoglycerate binding site at position beta 82. J Biol Chem 1976; 251:7563.
  9. White JM, Szur L, Gillies ID, et al. Familial polycythaemia caused by a new haemoglobin variant: Hb Heathrow, beta 103 (G5) phenylalanine leads to leucine. Br Med J 1973; 3:665.
  10. Marsh G, Marino G, Pucci P, et al. A third instance of the high oxygen affinity variant, Hb Heathrow [beta 103(G5)Phe- greater than Leu]: identification of the mutation by mass spectrometry and by DNA analysis. Hemoglobin 1991; 15:43.
  11. Percy MJ, Butt NN, Crotty GM, et al. Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis. Haematologica 2009; 94:1321.
  12. Gregg XT, Prchal JT. Erythropoietin receptor mutations and human disease. Semin Hematol 1997; 34:70.
  13. Kralovics R, Indrak K, Stopka T, et al. Two new EPO receptor mutations: truncated EPO receptors are most frequently associated with primary familial and congenital polycythemias. Blood 1997; 90:2057.
  14. Arcasoy MO, Degar BA, Harris KW, Forget BG. Familial erythrocytosis associated with a short deletion in the erythropoietin receptor gene. Blood 1997; 89:4628.
  15. Boyer SH, Charache S, Fairbanks VF, et al. Hemoglobin Malmö Beta-97 (FG-4) histidine--glutamine: a cause of polycythemia. J Clin Invest 1972; 51:666.
  16. Bard H, Peri KG, Gagnon C. The biologic implications of a rare hemoglobin mutant that decreases oxygen affinity. Pediatr Res 2001; 49:69.
  17. Valverde G, Zhou H, Lippold S, et al. A novel candidate region for genetic adaptation to high altitude in Andean populations. PLoS One 2015; 10:e0125444.
  18. Lorenzo FR, Huff C, Myllymäki M, et al. A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 2014; 46:951.
  19. Crowley MA, Mollan TL, Abdulmalik OY, et al. A hemoglobin variant associated with neonatal cyanosis and anemia. N Engl J Med 2011; 364:1837.
  20. Bonaventura J, Riggs A. Hemoglobin Kansas, a human hemoglobin with a neutral amino acid substitution and an abnormal oxygen equilibrium. J Biol Chem 1968; 243:980.
  21. Reismann KR, Ruth WE, Nomura T. A human hemoglobin with lowered oxygen affinity and impaired heme-heme interactions. J Clin Invest 1961; 40:182.
  22. Nagel RL, Lynfield J, Johnson J, et al. Hemoglobin Beth Israel. A mutant causing clinically apparent cyanosis. N Engl J Med 1976; 295:125.
  23. Arous N, Braconnier F, Thillet J, et al. Hemoglobin Saint Mandé beta 102 (G4) asn replaced by tyr: a new low oxygen affinity variant. FEBS Lett 1981; 126:114.
  24. Winslow RM, Charache S. Hemoglobin Richmond. Subunit dissociation and oxygen equilibrium properties. J Biol Chem 1975; 250:6939.