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7 - Hemoglobins of the Embryo, Fetus, and Adult

from SECTION ONE - THE MOLECULAR, CELLULAR, AND GENETIC BASIS OF HEMOGLOBIN DISORDERS

Published online by Cambridge University Press:  03 May 2010

Martin H. Steinberg ,
Bernard G. Forget ,
Douglas R. Higgs  and
David J. Weatherall
By
Martin H. Steinberg  and
Ronald L. Nagel
Martin H. Steinberg
Affiliation:
Boston University
Bernard G. Forget
Affiliation:
Yale University, Connecticut
Douglas R. Higgs
Affiliation:
MRC Institute of Molecular Medicine, University of Oxford
David J. Weatherall
Affiliation:
Albert Einstein College of Medicine, New York
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Summary

INTRODUCTION

During development, humans express six different hemoglobin types, the products of eight different globin genes (Fig. 3.1, Chapter 3). Hb Gower I (ς2ε2), Gower II (α2ε2), and Portland (ς2γ2) are found in the embryo, fetal hemoglobin (HbF; α2γ2) is present mainly in the fetus but also in the embryo and adult, whereas HbA (α2β2) and HbA2 (α2δ2) are seen primarily in adults. All hemoglobins undergo posttranslational modifications forming minor hemoglobins. Globin genes are discussed in Chapter 3, hemoglobin switching in Chapter 5, and the structure and function of hemoglobin in Chapter 6 and. In this chapter we discuss the clinical and physiological attributes of HbF, HbA2, embryonic hemoglobins, and their posttranslational modifications.

HEMOGLOBIN F

The observation that hemoglobin in newborns' erythrocytes was resistant to alkaline denaturation provided the first suggestion that a hemoglobin existed that differed from normal HbA.

Structure of the γ-Globin Genes and γ-Globin

γ-Globin chains differ from β-globin chains in either 39 or 40 amino acid residues, depending on whether a glycine or alanine residue is present at γ136. γ-Globin is the product of two nearly identical γ-globin genes. A glycine codon is present in the 5′ or Gγ gene (HBG2) and an alanine codon characterizes the 3′, or Aγ gene (HBG1). Also, a common polymorphism is found in the Aγ gene, where threonine (AγT) replaces isoleucine (AγI) at codon γ75 (HbF-Sardinia). This striking similarity in protein sequence and structure of the γ-globin genes reflect their concerted evolution from gene duplication and gene conversion.

Type
Chapter
Information
Disorders of Hemoglobin
Genetics, Pathophysiology, and Clinical Management
 , pp. 119 - 136
Publisher: Cambridge University Press
Print publication year: 2009

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References

Singer, K, Chernoff, AI, Singer, L. Studies on abnormal hemoglobins. I. Their demonstration in sickle cell anemia and other hematologic disorders by means of alkali denaturation. Blood. 1951;6:413–428.Google ScholarPubMed
Schroeder, WA, Shelton, JR, Shelton, JB, Cormick, J, Jones, RT. The amino acid sequence of the gamma chain of human fetal hemoglobin. Biochemistry. 1963;2:992–1008.CrossRefGoogle ScholarPubMed
Slightom, JL, Blechl, AE, Smithies, O. Human fetal G-gamma and A-gamma globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell. 1980;21:627–638.CrossRefGoogle ScholarPubMed
Bouhassira, EE, Lachman, H, Krishnamoorthy, R, Labie, D, Nagel, RL. A gene conversion located 5′ to the A gamma gene in linkage disequilibrium with the Bantu haplotype in sickle cell anemia. J Clin Invest. 1989;83:2070–2073.CrossRefGoogle ScholarPubMed
Adachi, K, Yang, Y, Lakka, V, Wehrli, S, Reddy, KS, Surrey, S. Significance of β116 His (G18) at α1β1 contact sites for αβ assembly and autoxidation of hemoglobin. Biochemistry. 2003;42(34):10252–10259.CrossRefGoogle ScholarPubMed
Yagami, T, Ballard, BT, Padovan, JC, Chait, BT, Popowicz, AM, Manning, JM. N-terminal contributions of the gamma-subunit of fetal hemoglobin to its tetramer strength: remote effects at subunit contacts. Protein Sci. 2002;11(1):27–35.CrossRefGoogle ScholarPubMed
Frier, JA, Perutz, MF. Structure of human foetal deoxyhaemoglobin. J Mol Biol. 1977;112(1):97–112.CrossRefGoogle ScholarPubMed
Dumoulin, A, Manning, LR, Jenkins, WT, Winslow, RM, Manning, JM. Exchange of subunit interfaces between recombinant adult and fetal hemoglobins. Evidence for a functional inter-relationship among regions of the tetramer. J Biol Chem. 1997;272(50):31326–31332.CrossRefGoogle ScholarPubMed
Charache, S, Catalano, P, Burns, S, et al. Pregnancy in carriers of high-affinity hemoglobins. Blood. 1985;65(3):713–718.Google ScholarPubMed
Giardina, B, Messana, I, Scatena, R, Castagnola, M. The multiple functions of hemoglobin. Crit Rev Biochem Mol Biol. 1995;30(3):165–196.CrossRefGoogle ScholarPubMed
Brittain, T. Molecular aspects of embryonic hemoglobin function. Mol Aspects Med. 2002;23(4):293–342.CrossRefGoogle ScholarPubMed
Miyoshi, K, Kaneto, Y, Kawai, H, et al. X-linked dominant control of F-cells in normal adult life: characterization of the Swiss type as hereditary persistence of fetal hemoglobin regulated dominantly by gene(s) on X chromosome. Blood. 1988;72:1854–1860.Google ScholarPubMed
Nagel, RL. Severity, pathobiology, epistatic effects, and genetic markers in sickle cell anemia. Semin Hematol. 1991; 28(3):180–201.Google ScholarPubMed
Morris, J, Dunn, D, Beckford, M, et al. The haematology of homozygous sickle cell disease after the age of 40 years. Br J Haematol. 1991;77:382.CrossRefGoogle ScholarPubMed
Steinberg, MH, Hsu, H, Nagel, RL, et al. Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia. Am J Hematol. 1995;48(3):175–181.CrossRefGoogle ScholarPubMed
Stamatoyannopoulos, G. Control of globin gene expression during development and erythroid differentiation. Exp Hematol. 2005;33(3):259–271.CrossRefGoogle ScholarPubMed
Bank, A. Regulation of human fetal hemoglobin: new players, new complexities. Blood. 2006;107(2):435–443.CrossRefGoogle ScholarPubMed
Sebastiani, P, Wang, L, Nolan, VG, et al. Fetal hemoglobin in sickle cell anemia: Bayesian modeling of genetic associations. Am J Hematol. 2008;83:189–195.CrossRefGoogle ScholarPubMed
Boyer, SH, Belding, TK, Margolet, L, Noyes, AN. Fetal hemoglobin restriction to a few erythrocytes (F cells) in normal human adults. Science. 1975;188(4186):361–363.CrossRefGoogle Scholar
Dover, GJ, Boyer, SH, Pembrey, ME. F cell production in sickle cell anemia: regulation by genes linked to beta-hemoglobin locus. Science. 1981;211(4489):1441–1444.CrossRefGoogle ScholarPubMed
Tsantes, A, Androutsos, G, Bonovas, S, et al. Assessment of a new immunocytochemical technique in HbF-cell counting by a novel objective evaluation method. Br J Haematol. 2003;123(5):948–951.CrossRefGoogle ScholarPubMed
Amoyal, I, Fibach, E. Flow cytometric analysis of fetal hemoglobin in erythroid precursors of beta-thalassemia. Clin Lab Haematol. 2004;26(3):187–193.CrossRefGoogle ScholarPubMed
Italia, KY, Colah, R, Mohanty, D. Evaluation of F cells in sickle cell disorders by flow cytometry – comparison with the Kleihauer-Betke's slide method. Intl J Lab Hematol. 2007; 29(6):409–414.CrossRefGoogle ScholarPubMed
Horiuchi, K, Osterhout, ML, Kamma, H, Bekoe, NA, Hirokawa, KJ. Estimation of fetal hemoglobin levels in individual red cells via fluorescence image cytometry. Cytometry. 1995; 20:261–267.CrossRefGoogle ScholarPubMed
Franco, RS, Yasin, Z, Palascak, MB, Ciraolo, P, Joiner, CH, Rucknagel, DL. The effect of fetal hemoglobin on the survival characteristics of sickle cells. Blood. 2006;108(3):1073–1076.CrossRefGoogle ScholarPubMed
Leonova, JY, Kazanetz, EG, Smetanina, NS, Adekile, AD, Efremov, GD, Huisman, THJ. Variability in the fetal hemoglobin level of the normal adult. Am J Hematol. 1996;53:59–65.3.0.CO;2-2>CrossRefGoogle ScholarPubMed
Wood, WG. Hereditary persistence of fetal hemoglobin and δ thalassemia. In: Steinberg, MH, Forget, BG, Higgs, DR, Nagel, RL, eds. Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. 1st ed. Cambridge: Cambridge University Press; 2001:356–388.Google Scholar
Perry, GW, Vargas-Cuba, R, Vertes, RP. Fetal hemoglobin levels in sudden infant death syndrome. Arch Pathol Lab Med. 1997;121:1084–1054.Google ScholarPubMed
Bard, H, Cote, A, Praud, JP, Infante-Rivard, C, Gagnon, C. Fetal hemoglobin synthesis determined by gamma-mRNA/ gamma-mRNA + beta-mRNA quantitation in infants at risk for sudden infant death syndrome being monitored at home for apnea. Pediatrics. 2003;112(4):e285.CrossRefGoogle ScholarPubMed
Krous, HF, Haas, EA, Chadwick, AE, Masoumi, H, Stanley, C, Perry, GW. Hemoglobin F in sudden infant death syndrome: a San Diego SIDS/SUDC Research Project report. J Forensic Leg Med. 2007;14(8):456–460.CrossRefGoogle Scholar
Wolk, M, Martin, JE, Constantin, R. Blood cells with fetal haemoglobin (F cells) detected by immunohistochemistry as indicators of solid tumours. J Clin Pathol. 2004;57(7):740–745.CrossRefGoogle ScholarPubMed
Wolk, M, Martin, JE, Reinus, C. Development of fetal haemoglobin-blood cells (F cells) within colorectal tumour tissues. J Clin Pathol. 2006;59(6):598–602.CrossRefGoogle ScholarPubMed
Adams, JG, Morrison, WT, Steinberg, MH. Hemoglobin Parchman: double crossover within a single human gene. Science. 1982;218:291–293.CrossRefGoogle ScholarPubMed
Petes, TD. Evidence that structural variants within the human δ-globin protein may reflect genetic inteactions between the δ- and β-globin genes. Am J Hum Genet. 1982;34:820–823.Google Scholar
Sen, U, Dasgupta, J, Choudhury, D, et al. Crystal structures of HbA2 and HbE and modeling of hemoglobin delta 4: interpretation of the thermal stability and the antisickling effect of HbA2 and identification of the ferrocyanide binding site in Hb. Biochemistry. 2004;43(39):12477–12488.CrossRefGoogle ScholarPubMed
Donze, D, Jeancake, PH, Townes, TM. Activation of d-globin gene expression by erythroid Krupple-like factor: a potential approach for gene therapy of sickle cell disease. Blood. 1996;88:4051–4057.Google Scholar
Tang, DC, Ebb, D, Hardison, RC, Rodgers, GP. Restoration of the CCAAT box or insertion of the CACCC motif activate d-globin gene expression. Blood. 1997;90:421–427.Google ScholarPubMed
Nagel, RL, Bookchin, RM, Labie, D, Wajcman, H, Isaac-Sadeye, WA, Honig, GR. Structural basis for the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S. Proc Natl Acad Sci USA. 1979;76:670–672.CrossRefGoogle Scholar
Adachi, K, Pang, JA, Reddy, LR, et al. Polymerization of three hemoglobin A2 variants containing Val<6< and inhibition of hemoglobin S polymerization by hemoglobin A2. J Biol Chem. 1996;271:24557–24563.CrossRefGoogle Scholar
Kirk, R, Sandhaus, LM, Hoyer, JD. The detection and diagnosis of hemoglobin A2′ by high-performance liquid chromatography. Am J Clin Pathol. 2005;123(5):657–661.CrossRefGoogle ScholarPubMed
Head, CE, Conroy, M, Jarvis, M, Phelan, L, Bain, BJ. Some observations on the measurement of haemoglobin A2 and S percentages by high performance liquid chromatography in the presence and absence of alpha thalassaemia. J Clin Pathol. 2004;57(3):276–280.CrossRefGoogle ScholarPubMed
Zurbriggen, K, Schmugge, M, Schmid, M, et al. Analysis of minor hemoglobins by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Clin Chem. 2005;51(6):989–996.CrossRefGoogle ScholarPubMed
Pavlou, E, Phylactides, M, Kyrri, A, et al. delta-Thalassemia in Cyprus. Hemoglobin. 2006;30(4):455–462.CrossRefGoogle ScholarPubMed
Bouva, MJ, Harteveld, CL, , DP, Giordano, PC. Known and new delta globin gene mutations and their diagnostic significance. Haematologica. 2006;91(1):129–132.Google ScholarPubMed
Bunn, HF. Subunit assembly of hemoglobin: an important determinant of hematologic phenotype. Blood. 1987;69:1–6.Google ScholarPubMed
Mrabet, NT, McDonald, MJ, Turci, S, Sarkar, R, Szabo, A, Bunn, HF. Electrostatic attraction governs the dimer assembly of human hemoglobin. J Biol Chem. 1986;261:5222–5228.Google ScholarPubMed
McDonald, MJ, Turci, SM, Mrabet, NT, Himelstein, BP, Bunn, HF. The kinetics of assembly of normal and variant human oxyhemoglobins. J Biol Chem. 1987;262:5951–5956.Google ScholarPubMed
Harthoorn-Lasthuizen, EJ, Lindemans, J, Langenhuijsen, MMAC. Influence of iron deficiency anaemia on haemoglobin A2 levels: possible consequences for b-thalassaemia screening. Scand J Clin Lab Invest. 1999;59(1):65–70.CrossRefGoogle Scholar
El-Agouza, I, Abu, SA, Sirdah, M. The effect of iron deficiency anaemia on the levels of haemoglobin subtypes: possible consequences for clinical diagnosis. Clin Lab Haematol. 2002;24(5):285–289.CrossRefGoogle ScholarPubMed
Kutlar, F, Gonzalez-Redondo, JM, Kutlar, A, et al. The levels of zand d chains in patients with Hb H disease. Hum Genet. 1989;82:179–186.CrossRefGoogle Scholar
Loudianos, G, Cao, A, Ristaldi, MS, et al. Molecular basis of delta beta-thalassemia with normal fetal hemoglobin level. Blood. 1990;75:526–528. [Letter].Google ScholarPubMed
Oggiano, L, Guiso, L, Frogheri, L, et al. A novel Mediterranean “δ-thalassemia” determinant containing the δ+27 and β039 point mutations in cis. Am J Hematol. 1994;45:81–84.CrossRefGoogle Scholar
Steinberg, MH, Coleman, MB, Adams, JG. Beta-thalassemia with exceptionally high hemoglobin A2. Differential expression of the delta-globin gene in the presence of beta-thalassemia. J Lab Clin Med. 1982;100:548–557.Google ScholarPubMed
Weatherall, DJ, Clegg, JB. The Thalassaemia Syndromes. 4th ed. Oxford: Blackwell Science; 2001.CrossRefGoogle Scholar
Huisman, TH. Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations: Influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter. Acta Haematol. 1997;98(4):187–194.CrossRefGoogle ScholarPubMed
Codrington, JF, Li, HW, Kutlar, F, Gu, LH, Ramachandran, M, Huisman, TH. Observations on the levels of Hb A2 in patients with different b-thalassemia mutations and a d chain variant. Blood. 1990;76:1246–1249.Google Scholar
Kendall, AG, Bastomsky, CH. Hemoglobin A2 in hyperthyroidism. Hemoglobin. 1981;5:571–577.CrossRefGoogle ScholarPubMed
Martin, L, Pissard, S, Blanc, P, et al. [Increased haemoglobin A2 levels in pseudoxanthoma elasticum]. Ann Dermatol Venereol. 2006;133(8–9 Pt 1):645–651.CrossRefGoogle Scholar
Luo, HY, Liang, XL, Frye, C, et al. Embryonic hemoglobins are expressed in definitive cells. Blood. 1999;94(1):359–361.Google ScholarPubMed
He, Z, Russell, JE. Expression, purification, and characterization of human hemoglobins Gower-1 (zeta(2) epsilon(2)), Gower-2 (alpha(2)epsilon(2)), and Portland-2 (zeta(2)beta(2)) assembled in complex transgenic-knockout mice. Blood. 2001;97(4):1099–1105.CrossRefGoogle ScholarPubMed
Chui, DH, Wong, SC, Chung, SW, Patterson, M, Bhargava, S, Poon, MC. Embryonic zeta-globin chains in adults: a marker for alpha- thalassemia-1 haplotype due to a greater than 17.5-kb deletion. N Engl J Med. 1986;314:76–79.CrossRefGoogle ScholarPubMed
Chui, DH, Mentzer, WC, Patterson, M, et al. Human embryonic zeta-globin chains in fetal and newborn blood. Blood. 1989;74:1409–1414.Google ScholarPubMed
Lafferty, JD, Crowther, MA, Waye, JS, Chui, DHK. A reliable screening test to identify adult carriers of the (–SEA) alpha0-thalassemia deletion – Detection of embryonic zeta-globin chains by enzyme-linked immunosorbent assay. Am J Clin Pathol. 2000;114(6):927–931.CrossRefGoogle Scholar
Ma, SK, Ma, V, Chan, AY, Chan, LC, Chui, DH. Routine screening of (–(SEA)) alpha-thalassemia deletion by an enzyme-linked immunosorbent assay for embryonic zeta-globin chains. Acta Haematol. 2002;108(1):8–12.CrossRefGoogle ScholarPubMed
He, Z, Russell, JE. A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease. Proc Natl Acad Sci USA. 2002;99(16):10635–10640.CrossRefGoogle ScholarPubMed
Hofmann, OM, Brittain, T, Wells, RM. The control of oxygen affinity in the three human embryonic haemoglobins by respiration linked metabolites. Biochem Mol Biol Int. 1997;42(3):553–566.Google ScholarPubMed
Hofmann, O, Brittain, T. Ligand binding kinetics and dissociation of the human embryonic haemoglobins. Biochem J. 1996;315(Pt 1):65–70.CrossRefGoogle ScholarPubMed
Hofmann, O, Carrucan, G, Robson, N, Brittain, T. The chloride effect in the human embryonic haemoglobins. Biochem J. 1995;309(Pt 3):959–962.CrossRefGoogle ScholarPubMed
Hofmann, O, Mould, R, Brittain, T. Allosteric modulation of oxygen binding to the three human embryonic haemoglobins. Biochem J. 1995;306(Pt 2):367–370.CrossRefGoogle ScholarPubMed
Mathews, AJ, Brittain, T. Haem disorder in recombinant- and reticulocyte-derived haemoglobins: evidence for stereoselective haem insertion in eukaryotes. Biochem J. 2001;357(Pt 1):305–311.CrossRefGoogle ScholarPubMed
Robson, N, Brittain, T. Heme stability in the human embryonic hemoglobins. J Inorg Biochem. 1996;64(3):137–147.CrossRefGoogle ScholarPubMed
Robson, N, Brittain, T. Conformational relaxation and ligand binding to singly reduced human embryonic haemoglobins. Biochem Mol Biol Int. 1996;38(6):1245–1253.Google ScholarPubMed
Kidd, RD, Baker, HM, Mathews, AJ, Brittain, T, Baker, EN. Oligomerization and ligand binding in a homotetrameric hemoglobin: two high-resolution crystal structures of hemoglobin Bart's (gamma(4)), a marker for alpha-thalassemia. Protein Sci. 2001;10(9):1739–1749.CrossRefGoogle Scholar
Kidd, RD, Mathews, A, Baker, HM, Brittain, T, Baker, EN. Subunit dissociation and reassociation leads to preferential crystallization of haemoglobin Bart's (γ4) from solutions of human embryonic haemoglobin Portland (ς2γ2) at low pH. Acta Crystallogr D Biol Crystallogr. 2001;57(Pt 6):921–924.CrossRefGoogle Scholar
Sutherland-Smith, AJ, Baker, HM, Hofmann, OM, Brittain, T, Baker, EN. Crystal structure of a human embryonic haemoglobin: the carbonmonoxy form of Gower II (α2ε2) haemoglobin at 2.9 A resolution. J Mol Biol. 1998;280(3):475–484.CrossRefGoogle Scholar
Papachatzopoulou, A, Menounos, PG, Kolonelou, C, Patrinos, GP. Mutation screening in the human epsilon-globin gene using single-strand conformation polymorphism analysis. Am J Hematol. 2006;81(2):136–138.CrossRefGoogle ScholarPubMed
Kabadi, UM, Gopal, V, Hood, L, Kabadi, MU, Platt, K. Elevated glycosylated hemoglobin concentrations in AIDS. AIDS. 1992;6(2):236–238.Google Scholar
Wautier, JL, Schmidt, AM. Protein glycation: a firm link to endothelial cell dysfunction. Circ Res. 2004;95(3):233–238.CrossRefGoogle ScholarPubMed
Peterson, KP, Pavlovich, JG, Goldstein, D, Little, R, England, J, Peterson, CM. What is hemoglobin A1C? An analysis of glycated hemoglobins by electrospray ionization mass spectrometry. Clin Chem. 1998;44(9):1951–1958.Google ScholarPubMed
Rosa, MC, Sanna, MT, Messana, I, et al. Glycated human hemoglobin (HbA1C): functional characteristics and molecular modeling studies. Biophys Chem. 1998;72(3):323–335.CrossRefGoogle ScholarPubMed
Bry, L, Chen, PC, Sacks, DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem. 2001;47(2):153–163.Google ScholarPubMed
Manley, SE, Round, RA, Smith, JM. Calibration of HbA1C and its measurement in the presence of variant haemoglobins: report on questionnaire to manufacturers. Ann Clin Biochem. 2006;43(Pt 2):135–145.CrossRefGoogle ScholarPubMed
Prome, D, Blouquit, Y, Ponthus, C, Prome, JC, Rosa, J. Structure of the human adult hemoglobin minor fraction A1b by electrospray and secondary ion mass spectrometry. Pyruvic acid as amino-terminal blocking group. J Biol Chem. 1991; 266(20):13050–13054.Google ScholarPubMed
Sampathkumar, R, Balasubramanyam, M, Sudarslal, S, Rema, M, Mohan, V, Balaram, P. Increased glutathionylated hemoglobin (HbSSG) in type 2 diabetes subjects with microangiopathy. Clin Biochem. 2005;38(10):892–899.CrossRefGoogle ScholarPubMed
Abraham, EC, Abraham, A, Stallings, M. High-pressure liquid chromatographic separation of glycosylated and acetylated minor hemoglobins in newborn infants and in patients with sickle cell disease. J Lab Clin Med. 1984;104(6):1027–1034.Google ScholarPubMed
Abraham, EC, Cameron, BF, Abraham, A, Stallings, M. Glycosylated hemoglobins in heterozygotes and homozygotes for hemoglobin C with or without diabetes. J Lab Clin Med. 1984;104(4):602–609.Google ScholarPubMed

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