Skip to main content
SpringerLink
Log in

GenetiC Mechanisms Underlying Regulation of Hemoglobin Mass

  • Conference paper
Book cover Hypoxia and the Circulation

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 618))

Abstract

Hemoglobin, the sole carrier of oxygen to tissues, accounts for most cytoplasmic protein of the erythrocyte, an enucleate cell lacking protein synthesizing machinery and with limited energy metabolism. While a number of genetic mechanisms can result in decreased hemoglobin concentration in the blood, this review concentrates on those that lead to increased hemoglobin mass, i.e. polycythemia or erythrocytosis. Polycythemia may be due to a) mutations of the enzyme synthesizing 2, 3 BPG, a metabolic intermediate which regulates hemoglobin-oxygen affinity and thus oxygen delivery, b) mutation of the a or Ý globin genes that increase hemoglobin-oxygen affinity and thus decrease oxygen delivery, and c) mutations of the erythropoietin receptor gene or genes regulating erythropoietin production that lead to increased production of erythrocytes. Primary polycythemias are caused by inherited or acquired somatic mutations affecting the hematopoietic progenitors. In contrast, in secondary polycythemia normal progenitors are activated by external factors present in increased concentration, most commonly erythropoietin. Some hypoxia sensing disorders blur the distinction between primary and secondary polycythemias and may deserve their own category. Most polycythemias are acquired, but both primary and secondary polycythemias may be inherited. In this review we will discuss the genetic heterogeneity of individual responses to hypoxia, and the current understanding of inherited primary and secondary polycythemias.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adamson J, Fialkow PJ, Murphy S, et al. Polycythemia vera:stem-cell and probable clonal origin of the disease. N Engl J Med295: 913–916, 1976.

    Article  CAS  PubMed  Google Scholar 

  2. Ang S, Chen H, Gordeuk VR, et al. Endemic polycythemia in Russia:mutation in the VHL gene. Blood Cells Mol Dis28: 57-62, 2002.

    Article  PubMed  Google Scholar 

  3. Ang S, Chen H, Hirota K, et al. Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nat Genet32: 614-621, 2002.

    Article  CAS  PubMed  Google Scholar 

  4. Barker S, Curry J, Redford D, et al. Measurement of carboxyhemoglobin and methemoglobin by pulse oximetry: a human volunteer study. Anesthesiology105:892-897, 2006.

    Article  PubMed  Google Scholar 

  5. Bento M, Chang KT, Guan Y, et al. Congenital polycythemia with homozygous and heterozygous mutations of von Hippel-Lindau gene: five new Caucasian patients.Haematologica90: 128–129, 2005.

    CAS  PubMed  Google Scholar 

  6. Bunn H, Forget, BG. Hemoglobin: Molecular, Genetic and Clinical Aspects. Philadelphia, WB Saunders, 1986.

    Google Scholar 

  7. Cario H, Schwarz K, Jorch N, et al. Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene and VHLhaplotype analysis in patients with presumable congenital erythrocytosis. Haematologica90: 19–24, 2005.

    CAS  PubMed  Google Scholar 

  8. Cartier P, Labie D, Leroux JP, et al. Familial diphosphoglycerate mutase deficiency:hematological and biochemical study. French. Nouv Rev Fr Hematol12: 269-287,1972.

    CAS  PubMed  Google Scholar 

  9. Clifford S, Cockman ME, Smallwood AC, et al. Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease. Hum Mol Genet10: 1029–1038, 2001.

    Article  CAS  PubMed  Google Scholar 

  10. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1 alpha is essential for myeloid cellmediated inflammation.Cell112: 645–657, 2003.

    Article  CAS  PubMed  Google Scholar 

  11. D’Andrea A, Yoshimura A, Youssoufian H, et al. The cytoplasmic region of the erythropoietin receptor contains non-overlapping positive and negative growthregulatory domains. Mol Cell Biol11: 1980–1987, 1991.

    PubMed  Google Scholar 

  12. Darling R, Roughton F. The effect of methemoglobin on the equilibrium between oxygen and hemoglobin. Am J Physiol137: 56, 1942.

    CAS  Google Scholar 

  13. Emanuel P, Eaves C, Broudy V, et al. Familial and congenital polycythemia in three unrelated families. Blood79: 3019–3030, 1992.

    CAS  PubMed  Google Scholar 

  14. Evelyn K, Malloy H. Microdetermination of oxyhemoglobin, methemoglobin,and sulfhemoglobin in a single sample of blood. J Biol Chem126: 655, 1938.

    CAS  Google Scholar 

  15. Forget B, Degar BA, Arcasoy MO. Familial polycythemia due to truncations of the erythropoietin receptor.Trans Am Clin Climatol Assoc111: 38-44, 2000.

    CAS  PubMed  Google Scholar 

  16. Friedrich C. Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum Mol Genet10: 763-767, 2001.

    Article  CAS  PubMed  Google Scholar 

  17. Giardine B, van Baal S, Kaimakis P, et al. HbVar database of human hemoglobin variants and thalassemia mutations: 2007 update. Hum Mutat28: 206, 2007.

    Article  PubMed  Google Scholar 

  18. Gordeuk V, Prchal JT. Vascular complications in Chuvash polycythemia.Semin Thromb Hemost32: 289-294, 2006.

    Article  PubMed  Google Scholar 

  19. Gordeuk V, Sergueeva AI, Miasnikova GY, et al. Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors. Blood103: 3924-3932, 2004.

    Article  CAS  PubMed  Google Scholar 

  20. Gordeuk V, Stockton DW, Prchal JT. Congenital polycythemias/erythrocytoses. Haematologica90: 109-116 , 2005.

    CAS  PubMed  Google Scholar 

  21. Gregg X, Prchal JT. Recent advances in the molecular biology of congenital polycythemias and polycythemia vera. Curr Hematol Rep4: 238-242, 2005.

    CAS  PubMed  Google Scholar 

  22. Horton J, Harsh GR 4th, Fisher JW, et al. Von Hippel-Lindau disease and erythrocytosis: radioimmunoassay of erythropoietin in cyst fluid from a brainstem hemangioblastoma. Neurology41: 753-754, 1991.

    CAS  PubMed  Google Scholar 

  23. Ivan M, Kondo K, Yang H, et al. HIF alpha targeted for VHL-mediated destruction by proline hydroxylation:implications for O2 sensing. Science292: 464–468, 2001.

    Article  CAS  PubMed  Google Scholar 

  24. Iwai K, Yamanaka K, Kamura T, et al. Identification of the von Hippel-lindau tumorsuppressor protein as part of an active E3 ubiquitin ligase complex. Proc Natl Acad Sci USA96: 12436–12441, 1999.

    Article  CAS  PubMed  Google Scholar 

  25. Iyanagi T, Watanabe S, Anan KF. One-electron oxidation-reduction properties of hepatic NADH-cytochrome b5 reductase. Biochemistry23: 1418-1425, 1984.

    Article  CAS  PubMed  Google Scholar 

  26. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel- Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science292: 468–472, 2001.

    Article  CAS  PubMed  Google Scholar 

  27. Jedlickova K, Stockton DW, Prchal, JT. Possible primary familial and congenital polycythemia locus at 7q22.1-7q22.2. Blood Cells Mol Dis31: 327-331, 2003.

    Article  CAS  PubMed  Google Scholar 

  28. Juvonen E, Ikkala E, Fyhrquist F, et al. Autosomal dominant erythrocytosis causes by increased sensitivity to erythropoietin. Blood78: 3066–3069, 1991.

    CAS  PubMed  Google Scholar 

  29. Kelner M, Bailey D. Mismeasurement of methemoglobin (“methemoglobin revisited”). Clin Chem31: 168, 1985.

    Google Scholar 

  30. Kondo K, Klco J, Nakamura E, et al. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein. Cancer Cell1: 237–246, 2002.

    Article  CAS  PubMed  Google Scholar 

  31. Kralovics R, Prchal JT. Genetic heterogeneity of primary familial and congenital polycythemia. Am J Hematol68: 115–121, 2001.

    Article  CAS  PubMed  Google Scholar 

  32. Kralovics R, Stockton DW, Prchal JT. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood102: 3793–3796, 2003.

    Article  CAS  PubMed  Google Scholar 

  33. Kuma F, Ishizawa S, Hirayama K, et al. Studies on methemoglobin reductase. I. Comparative studies of diaphorases from normal and methemoglobinemic erythrocytes. J Biol Chem247: 550, 1972.

    CAS  PubMed  Google Scholar 

  34. Labie D, Leroux JP, Najman A, et al. Familial diphosphoglyceratemutase deficiency. Influence on the oxygen affinity curves of hemoglobin. FEBS Lett9: 37–40, 1970.

    Article  CAS  PubMed  Google Scholar 

  35. Laughner E, Taghavi P, Chiles K, et al. HER2 (neu) signaling increases the rate of hypoxia inducible factor 1a (HIF-1a) synthesis:novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol21: 3995-4004, 2001.

    Article  CAS  PubMed  Google Scholar 

  36. Lichtman M, Murphy MS, Adamson JW. Detection of mutant hemoglobins with altered affinity for oxygen. A simplified technique. Ann Intern Med84: 517–520, 1976.

    CAS  PubMed  Google Scholar 

  37. Liu E, Percy MJ, Amos CI, et al. The worldwide distribution of the VHL 598C>T mutation indicates a single founding event. Blood103: 1937-1940, 2004.

    Article  CAS  PubMed  Google Scholar 

  38. Luttun A, Carmeliet P. Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered? J Clin Invest111: 600–602, 2003.

    CAS  PubMed  Google Scholar 

  39. Maher E. Von Hippel-Lindau disease. Curr Mol Med4: 833–842, 2004.

    Article  CAS  PubMed  Google Scholar 

  40. Maher E, Webster, AR, Richards FM, et al. Phenotypic expression in von Hippel- Lindau disease: correlations with germline VHL gene mutations. J Med Genet33: 328–332, 1996.

    Article  CAS  PubMed  Google Scholar 

  41. Maran J, Jedlickova K, Stockton D, et al. Finding the novel molecular defect in a family with high erythropoietin autosomal dominant polycythemia. Blood102: 162b, 2003.

    Google Scholar 

  42. Maxwell P, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature399: 271–275, 1999.

    Article  CAS  PubMed  Google Scholar 

  43. Molthrop D, Wheeler R, Hall K, et al. Evaluation of the methemoglobinemia associated with sulofenur. Invest New Drugs12: 99, 1994.

    Article  CAS  PubMed  Google Scholar 

  44. Nagel R, Steinberg MH. Hemoglobins of the embryo and fetus and minor hemoglobins of adults.UK: Cambridge University Press, 2001.

    Google Scholar 

  45. Passon P, Hultquist D. Soluble cytochrome b5 reductase from human erythrocytes. Biochim Biophys Acta275: 62, 1972.

    Article  CAS  PubMed  Google Scholar 

  46. Pastore Y, Jedlickova K, Guan Y, et al. Mutations of von Hippel-Lindau tumorsuppressor gene and congenital polycythemia. Am J Hum Genet73: 412–419, 2003.

    Article  CAS  PubMed  Google Scholar 

  47. Pastore Y, Jelinek J, Ang S, et al. Mutations in the VHL gene in sporadic apparently congenital polycythemia. Blood101: 1591–1595, 2003.

    Article  CAS  PubMed  Google Scholar 

  48. Percy M, McMullin MF, Jowitt SN, et al. Chuvash-type congenital polycythemia in four families of Asian and Western European ancestry. Blood102: 1097–1099, 2003.

    Article  CAS  PubMed  Google Scholar 

  49. Percy M, Zhao Q, Flores A, et al. A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. Proc Natl Acad Sci U S A 103: 654-659, 2006.

    Article  CAS  PubMed  Google Scholar 

  50. Perrine G, Prchal JT, Prchal JF. Study of a polycythemic family. Blood50: 134, 1977.

    Google Scholar 

  51. Perrotta S, Nobili B, Ferraro M, et al. Von Hippel Lindau-dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster. Blood107: 514-519, 2006.

    Article  CAS  PubMed  Google Scholar 

  52. Poliakova L. Familial erythrocytosis among the residents of the Chuvash ASSR [published in Russian only]. Probl Gematol Pereliv Krovi19: 30–33, 1974.

    CAS  PubMed  Google Scholar 

  53. Prchal J. Pathogenetic mechanisms of polycythemia vera and congenital polycythemic disorders. Semin Hematol38: 10–20, 2001.

    Article  CAS  PubMed  Google Scholar 

  54. Prchal J. Primary polycythemias. Curr Opinion Hematol2: 146–152,

    Google Scholar 

  55. Prchal J, Crist W, Goldwasser E, et al. Autosomal dominant polycythemia. Blood66: 1208–1214, 1985.

    CAS  PubMed  Google Scholar 

  56. Prchal J, Semenza GL, Prchal J, et al. Familial polycythemia. Science268: 1831– 1832, 1995.

    Article  CAS  PubMed  Google Scholar 

  57. Prchal J, Sokol, L. Benign erythrocytosis” and other familial and congenital polycythemias. Eur J Haematol57: 263-268, 1996.

    Article  CAS  PubMed  Google Scholar 

  58. Queisser W, Heim ME, Schmitz JM, et al. Idiopathic familial erythrocytosis. Report on a family with autosomal dominant inheritance. Dtsch Med Wochenschr113: 851–856, 1988.

    Article  CAS  PubMed  Google Scholar 

  59. Scott E, McGraw J. Purification and properties of diphoshpopyridine nucleotide diaphorase of human erythrocytes. J Biol Chem237: 249, 1962.

    CAS  PubMed  Google Scholar 

  60. Semenza G. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol13: 167- 171, 2001.

    Article  CAS  PubMed  Google Scholar 

  61. Sergeyeva A, Gordeuk VR, Tokarev YN, et al. Congenital polycythemia in Chuvashia. Blood89: 2148-2154, 1997.

    CAS  PubMed  Google Scholar 

  62. Sokol L, Kralovics R, Hubbell GL, et al. A novel erythropoietin receptor mutation associated with primary familial polycythemia and severe cardiovascular and peripheral vascular disease. Blood98: [abstract #937]. 2001.

    Google Scholar 

  63. Spivak J. Polycythemia vera: myths, mechanisms, and management. Blood100: 4272- 4290, 2002.

    Article  CAS  PubMed  Google Scholar 

  64. Strittmatter P. The reaction sequence in electron transfer in the reduced nicotinamide adenine dinucleotide-cytochrome b5 reductase system. J Biol Chem240: 4481, 1965.

    CAS  PubMed  Google Scholar 

  65. Turner K, Moore JW, Jones A, et al. Expression of hypoxia inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res62: 2957–2961, 2002.

    CAS  PubMed  Google Scholar 

  66. Van Wijk M, Kublickiene K, Boer K, et al. Vascular function in preeclampsia. Cardiovasc Res47: 38-48, 2000.

    Article  Google Scholar 

  67. Wajcman H, Galacteros, F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin29: 91-106, 2005.

    Article  CAS  PubMed  Google Scholar 

  68. Wang G, Jiang, BH, Rue, EA, et al. Hypoxia-inducible factor 1 is a basic-helix-loophelix- PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA92: 5510–5514, 1995.

    Article  CAS  PubMed  Google Scholar 

  69. Winkelmann J, Penny L, Deaven L, et al. The gene for the human erythropoietin receptor: Analysis of the coding sequence and assignment to chromosome 19q. Blood76: 24, 1990.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Utah, Salt Lake City, Utah, USA

    Neeraj Agarwal & Josef T. Prchal

  2. Howard University, Center for Sickle Cell Disease, Washington DC, USA

    Victor R. Gordeuk

Authors
  1. Neeraj Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor R. Gordeuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Josef T. Prchal
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Altitude Research Center, University of Colorado, Health Sciences Center, Mail Stop F524, PO Box 6508, Aurora, Colorado, 80045-0508, USA

    Robert C. Roach Ph.D. (Research Director) (Research Director)

  2. UCSD Dept Medicine, 0623, 9500 Gilman Avenue, La Jolla, CA, 92093-0623, USA

    Peter D. Wagner

  3. Institute for Altitude Medicine, Telluride Medical Center, 500 W. Pacific, Telluride, Colorado, 81435, USA

    Peter H. Hackett

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer Science+Business Media, LLC

About this paper

Cite this paper

Agarwal, N., Gordeuk, V.R., Prchal, J.T. (2007). GenetiC Mechanisms Underlying Regulation of Hemoglobin Mass. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia and the Circulation. Advances in Experimental Medicine and Biology, vol 618. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-75434-5_15

Download citation

Publish with us

Policies and ethics

Search

Navigation