Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Classification of the Disorders of Hemoglobin Bernard G. Forget1 and H. Franklin Bunn2 1Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut 06520-8028 2Hematology Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 Correspondence: [email protected] Over the years, study of the disorders of hemoglobin has served as a paradigm for gaining insights into the cellular and molecular biology, as well as the pathophysiology, of inherited genetic disorders. To date, more than 1000 disorders of hemoglobin synthesis and/or struc- ture have been identified and characterized. Study of these disorders has established the principle of how a mutant genotype can alter the function of the encoded protein, which in turn can lead to a distinct clinical phenotype. Genotype/phenotype correlations have provided important understanding of pathophysiological mechanisms of disease. Before presenting a brief overview of these disorders, we provide a summary of the struc- ture and function of hemoglobin, along with the mechanism of assembly of its subunits, as background for the rationale and basis of the different categories of disorders in the classification. n impressive degree of molecular “engineer- tion to Fe3þ, which is incapable of binding ox- Aing” was necessary for the evolution of a ygen.3 Delicate noncovalent interactions be- multisubunit protein that higher organisms re- tween unlike globin subunits are required for www.perspectivesinmedicine.org quire for optimal oxygen homeostasis and buf- the hemoglobin tetramer a2b2 to bind and un- fering of acidic metabolic waste products. Each load oxygen in a cooperative manner, thereby globin subunit must form a stable linkage with assuring maximal transport to actively metab- heme (ferroprotoporphyrin IX) situated on the olizing cells. This phenomenon is reflected by external surface of the protein so that oxygen a sigmoid oxygen-binding curve that depends in the RBC cytosol can bind reversibly to the on hemoglobin tetramer having two quaternary hemes’ iron atoms. Moreover, the hydrophobic structures: the T or deoxy conformer that has cleft into which the heme is inserted must be low oxygen affinity and the R or oxy conformer able to protect the Fe2þ heme iron from oxida- that has high oxygen affinity. Further fine- 3For more detailed information, see Dailey and Meissner (2013). Editors: David Weatherall, Alan N. Schechter, and David G. Nathan Additional Perspectives on Hemoglobin and Its Diseases available at www.perspectivesinmedicine.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a011684 Cite this article as Cold Spring Harb Perspect Med 2013;3:a011684 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press B.G. Forget and H.F. Bunn tuning of hemoglobin function comes from its mutations of globin genes that impair synthesis allosteric behavior triggered by the binding of give rise to thalassemia and anemia of varying two small effector molecules 2,3-BPG, and pro- degree. In addition, well-defined clinical and tons to specific sites on the T structure distant hematologic phenotypes are associated with from the heme groups.4 To endow the blood mutations that alter the structure of globin sub- with high oxygen carrying capacity hemoglo- units, discussed in more detail in Thom et al. bin must be stuffed into flexible circulating (2013). Impairment of hemoglobin solubility RBCs. A remarkably high degree of solubility can be caused either by the formation of intra- is required for hemoglobin to achieve an intra- cellular polymers (sickle cell disease) or by the cellular concentration of 34 g/dl or 5 mM development of amorphous precipitates (con- (tetramer). genital Heinz body hemolytic anemia). Abnor- To reach such a high corpuscular hemoglo- malities of oxygen binding can lead either to bin concentration it is essential that a-globin as erythrocytosis (high O2 affinity mutants) or to well as b-globin (or g-globin) mRNA be ex- cyanosis (low O2 affinity mutants). Some glo- pressed at very high levels during erythroid dif- bin mutants have structural alterations within ferentiation. Moreover, a- and non-a-globin the heme pocket that result in oxidation of synthesis must be closely matched. As explained the heme iron and pseudocyanosis because of in Nienhuis and Nathan (2012), subunit imbal- methemoglobinemia. anceis centraltothe pathophysiologyof thethal- assemias. Freea-globin subunits areparticularly toxic to erythroid cells. This threat is alleviated GENERAL CLASSIFICATION OF by the presence of a-hemoglobin stabilizing HEMOGLOBIN DISORDERS protein (AHSP), a chaperone that is expressed Hemoglobin disorders can be broadly classified at high levels in erythroid cells and binds specif- into two general categories (as listed in Table 1): ically and tightly to heme-intact a-globin sub- units (Kihm et al. 2002; Feng et al. 2004; Mollan 1. Those in which there is a quantitative defect et al. 2010, 2012). The AHSP protects the cell in the production of one of the globin sub- from potentially toxic oxidized (Fe3þ) heme un- units, either total absence or marked reduc- til it is reduced to functional Fe2þ heme by cy- tion. These are called the thalassemia syn- tochrome b5 reductase. On encountering a free dromes. heme-intact b-globin subunit, the a-globin 2. Those in which there is a structural defect in dissociates from AHSP to form the extremely one of the globin subunits. stable ab dimer. As discussed later in this www.perspectivesinmedicine.org work, this process is facilitated by electrostatic The majority of human hemoglobin mu- attraction between positively charged a-globin tants were discovered as an incidental finding, subunits and negatively charged b-globin sub- unassociated with any hematologic or clinical units. phenotype. However, a numberof a- and b-glo- In view of the multiple molecular con- bin mutants are associated with distinct clinical straints that are required for high-level produc- phenotypes. These fall into five broad catego- tion of fully functional and highly soluble he- ries: the sickle syndromes (SS, SC, Sb0-thalasse- moglobin, it is no surprise that Murphy’s law mia, and Sbþ-thalassemia); unstable mutants is in full force: whatever can go wrong will. causing congenital Heinz body hemolytic ane- As discussed briefly here, and in much more mia; mutants with high oxygen affinity result- detail in Thein (2013), Higgs (2013), Nienhuis ing in erythrocytosis; low oxygen affinity mu- and Nathan (2012), and Musallam et al. (2012), tants and the M hemoglobins causing cyanosis; and mutants associated with a thalassemia phe- notype. Most of these disorders are inherited 4For more detailed information on hemoglobin function, genetic defects, but there are some defects that see Schechter (2013). are acquired or occur de novo. 2 Cite this article as Cold Spring Harb Perspect Med 2013;3:a011684 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Classification of Hemoglobin Disorders Table 1. Classification of hemoglobin disorders I. QUANTITATIVE DISORDERS OF GLOBIN II. QUALITATIVE DISORDERS OF GLOBIN CHAIN SYNTHESIS/ACCUMULATION STRUCTURE: STRUCTURALVARIANTSOF The thalassemia syndromes HEMOGLOBIN A. b-Thalassemia A. Sickle cell disorders Clinical classification: SA, sickle cell trait b-Thalassemia minor or trait SS, sickle cell anemia/disease b-Thalassemia major SC, HbSC disease b-Thalassemia intermedia S/b thal, sickle b-thalassemia disease Biochemical/genetic classification: S with other Hb variants: D, O-Arab, other b0-Thalassemia SF, Hb S/HPFH þ b -Thalassemia B. Hemoglobins with decreased stability d-Thalassemia (unstable hemoglobin variants) g-Thalassemia Mutants causing congenital Heinz body hemolytic Lepore fusion gene anemia db-Thalassemia Acquired instability—oxidant hemolysis: Drug- 1gdb-Thalassemia induced, G6PD deficiency HPFH C. Hemoglobins with altered oxygen affinity “Dominant” b-thalassemia (structural variants with High/increased oxygen affinity states: b-thalassemia phenotype) Fetal red cells b-Thalassemia with other variants: Decreased RBC 2,3-BPG HbS/b-thalassemia Carboxyhemoglobinemia, HbCO HbE/b-thalassemia Structural variants Other Low/decreased oxygen affinity states: B. a-Thalassemia Increased RBC 2,3-BPG Deletions of a-globin genes: Structural variants One gene: aþ-thalassemia Two genes in cis: a0-thalassemia D. Methemoglobinemia Two genes in trans: homozygous aþ-thalassemia Congenital methemoglobinemia: (phenotype of a0-thalassemia) Structural variants Three genes: HbH disease Cytochrome b5 reductase deficiency Four genes: Hydrops fetalis with Hb Bart’s Acquired (toxic) methemoglobinemia Nondeletion mutants: E. Posttranslational modifications Hb Constant Spring Nonenzymatic glycosylation www.perspectivesinmedicine.org Other Amino-terminal acetylation C. De novo and acquired a-thalassemia Amino-terminal carbamylation a-Thalassemia with mental retardation syndrome (ATR): Deamidation Due to large deletions on chromosome 16 involving the a-globin genes Due to mutations of the ATRX transcription factor gene on chromosome X a-Thalassemia associated with myelodysplastic syndromes (ATMDS): Due to mutations of the ATRX gene THE THALASSEMIA SYNDROMES subunits