Most variant hemoglobins result from single nucleotide variants in one of the globin genes. More than 500 abnormal hemoglobins have been described, and approximately half of these are clinically significant. The hemoglobin structural alterations can be separated into the following three classes, depending on the clinical phenotype (Table 1):

• Alterations that cause hemolytic anemia, most commonly because they make the hemoglobin tetramer unstable.

• Alterations with modified oxygen transport, due to increased or decreased oxygen affinity or to the formation of methemoglobin—a form of globin incapable of reversible oxygenation.

• Alterations due to variants in the coding region that cause thalassemia because they reduce the abundance of a globin polypeptide. Most of these variants impair the rate of synthesis of the mRNA or otherwise affect the level of the encoded protein.

Table1. Major Classes of Hemoglobin Structural Alterations

Hemolytic Anemias

Hemoglobins With Novel Physical Properties: Sickle Cell Disease. Sickle cell hemoglobin is of great clinical importance in many parts of the world, affecting mil lions. The causal variant is a single nucleotide substitution that changes the codon of the sixth amino acid of β- globin from glutamic acid to valine (GAG → GTG: p.Glu6Val) (see Table 1). Homozygosity for this variant is the cause of sickle cell disease. The disease has a characteristic geographic distribution: occurring most frequently in equatorial Africa and less commonly in the Mediterranean area, India, Spanish- speaking regions in the Western Hemisphere, or in countries to which people from these regions have migrated. Approximately 1 in 400 Black persons in the united States is born with sickle cell disease.

Clinical Features. Sickle cell disease is a severe autosomal recessive hemolytic condition characterized by a tendency of the red blood cells to become grossly abnormal in shape (i.e., take on a sickle shape) under conditions of low oxygen tension (see Fig. 1). Heterozygotes—who are said to have sickle cell trait, are, generally, clinically unaffected, but their red cells can sickle when subjected to very low oxygen pressure. Occasions when this occurs are uncommon, although heterozygotes appear to be at risk for splenic infarction, especially at high altitude (e.g., in airplanes with reduced cabin pressure) or when exerting themselves to extreme levels in athletic competition. The heterozygous state is present in ~8% of Black individuals in the united States, but in areas where the sickle cell allele (βS) frequency is high (e.g., West Central Africa), up to 25% of the new born population is heterozygous for the allele.

Fig1. Scanning electron micrographs of red cells from a patient with sickle cell disease. (A) Oxygenated cells are round and full. (B) The classic sickle cell shape is produced only when the cells are in the deoxygenated state. (From Kaul DK, Fabry ME, Windisch P, et al: Erythrocytes in sickle cell anemia are heterogeneous in their rheological and hemodynamic characteristics, J Clin Invest 72:22, 1983.)

The Molecular Pathology of Hb S. In the 1950s, Vernon Ingram discovered that the abnormality in sickle cell hemoglobin was a replacement of one of the 146 amino acids in the β chain of the hemoglobin molecule. All the clinical manifestations of sickle cell hemoglobin are consequences of this single change in the β- globin gene. Ingram’s discovery was the first demonstration in any organism that a variant in a structural gene could cause an amino acid substitution in the corresponding protein. Because the substitution is in the β- globin chain, the formula for sickle cell hemoglobin is written as α2 β2 S or, more precisely, α2 Aβ2 S. A heterozygote has a mixture of the two types of hemoglobin, A and S, summarized as α2 Aβ2 A/ α2 Aβ2 S, as well as a hybrid hemoglobin tetramer, written as α2 AβAβS. Strong evidence indicates that the sickle cell variant arose in West Africa, but that it occurred independently elsewhere. The βS allele has attained high frequency in malaria endemic areas of the world because it confers protection against malaria in heterozygotes.

Sickling and Its Consequences. The molecular and cellular pathology of sickle cell disease is summarized in Fig. 12.6. Hemoglobin molecules containing the altered β- globin subunits are normal in their ability to perform their principal function of binding oxygen (provided they have not polymerized, as described next), but in deoxygenated blood they are only one- fifth as soluble as normal hemoglobin. under conditions of low oxygen tension, this relative insolubility of deoxyhemoglobin S causes the sickle hemoglobin molecules to aggregate in the form of rod- shaped polymers or fibers (see Fig. 2). These molecular rods distort the α2 β2 S erythrocytes to a sickle shape that prevents them from squeezing single file through capillaries—as do normal red cells, thereby blocking blood flow and causing local ischemia. They may also cause disruption of the red cell membrane (hemolysis) and release of free hemoglobin, which can have deleterious effects on the availability of vasodilators, such as nitric oxide, thereby exacerbating the ischemia.

Fig2. The pathogenesis of sickle cell disease. (Redrawn from Ingram V: Sickle cell disease: molecular and cellular pathogenesis. In Bunn HF, Forget BG, editors: Hemoglobin: Molecular, genetic, and clinical aspects, Philadelphia, 1986, WB Saunders.)

Modifier Genes Determine the Clinical Severity of Sickle Cell Disease. It has long been known that a strong modifier of the clinical severity of sickle cell disease is the patient’s level of Hb F (α2 γ2 ), higher levels being associated with less morbidity and lower mortality. The physiologic basis of the ameliorating effect of Hb F is clear: Hb F is a perfectly adequate oxygen carrier in postnatal life and inhibits the polymerization of deoxyhemoglobin S.

until recently, however, it was not certain whether the variation in Hb F expression was heritable. Genome- wide association studies (GWAS) have demonstrated that single nucleotide variants (SNPs) at three polymorphic loci (SNPs)— the γ- globin gene and two genes that encode transcription factors, BCl11A and MYB— account for 40 to 50% of the variation in the levels of Hb F in individuals with sickle cell dis ease. Moreover, the Hb F– associated SNPs are associated with the painful clinical episodes thought to be due to capillary occlusion caused by sickled red cells (see Fig.2). Individuals with heterozygous loss-of function variants in BCL11A (gene) have a rare neuro genetic disorder but also hereditary persistence of fetal hemoglobin.

The genetically driven variations in the level of Hb F are also associated with variation in the clinical severity of β- thalassemia (discussed later) because the reduced abundance of β- globin (and thus of Hb A [α2 β2 ]) in that disease is partly alleviated by higher levels of γ- globin and, thus, of Hb F (α2 γ2 ). The discovery of these genetic modifiers of Hb F abundance not only explains much of the variation in the clinical severity of sickle cell dis ease and β- thalassemia, but highlights a general principle introduced in Chapter 9: modifier genes can play a major role in determining the clinical and physiologic severity of a single- gene disorder.

BCL11A, a Silencer of γ- Globin Gene Expression in Adult Erythroid Cells. The identification of genetic modifiers of Hb F levels, particularly BCl11A, has opened great therapeutic potential. The product of the BCL11A gene is a transcription factor that normally silences γ- globin expression, thus shutting down Hb F production postnatally. Accordingly, drugs that suppress BCl11A activity postnatally, thereby increasing the expression of Hb F, might be of great benefit to those with sickle cell disease and β- thalassemia. In addition, preliminary clinical trial data suggest that post-transcriptional genetic silencing of BCL11A may be an effective treatment for sickle cell disease.

Trisomy 13, MicroRNAs, and MYB—Another Silencer of γ- Globin Gene Expression. The indication from GWAS that MYB is an important regulator of γ- globin expression has received further support from an unexpected direction: studies investigating the basis for the persistent increased postnatal expression of Hb F that is observed in individuals with trisomy 13. Two miRNAs, miR- 15a and miR- 16- 1, directly target the 3′ untranslated region (UTR) of the MYB mRNA, thereby reducing MYB expression. The genes for these two miRNAs are located on chromosome 13; their extra dosage in trisomy 13 is predicted to reduce MYB expression to below normal levels, thereby partly relaxing the postnatal suppression of γ- globin gene expression normally mediated by the MYB protein. This leads to increased expression of Hb F (Fig. 3).

Fig3. A model demonstrating how elevations of microRNAs 15a and 16- 1 in trisomy 13 can result in elevated fetal hemoglobin expression. The basal level of these microRNAs moderates expression of targets such as the MYB gene during erythropoiesis. In the case of trisomy 13, elevated levels of these microRNAs result in additional down- regulation of MYB expression, which in turn results in a delayed switch from fetal to adult hemoglobin and persistent expression of fetal hemoglobin. (Redrawn from Orkin SH: Disorders of hemoglobin synthesis: The thalassemias. In Stamatoyannopoulos G, Nienhuis AW, leder P, et al, editors: The molecular basis of blood diseases, Philadelphia, 1987, WB Saunders, pp. 106– 126.)

Unstable Hemoglobins. The unstable hemoglobins are due largely to single nucleotide variants that cause denaturation of the hemoglobin tetramer in mature red blood cells. The denatured globin tetramers are insoluble and precipitate to form inclusions (Heinz bodies) that damage the red cell membrane and cause hemolysis of mature red blood cells in the vascular tree (Fig. 3, showing a Heinz body due to β- thalassemia).

Fig4. Visualization of one pathologic effect of the deficiency of β chains in β- thalassemia: the precipitation of the excess normal α chains to form a Heinz body in the red blood cell. Peripheral blood smear and Heinz body preparation. The peripheral smear (A) shows “bite” cells with pitted- out semicircular areas of the red blood cell membrane as a result of removal of Heinz bodies by macrophages in the spleen, causing premature destruction of the red cell. The Heinz body preparation (B) shows increased Heinz bodies in the same specimen when compared to a control (C). (From Hoffman R, Furie B, McGlave P, et al: Hematology: Basic principles and practice, ed 5, 2008, Elsevier.)

The amino acid substitution in the unstable hemoglobin, Hb Hammersmith (β- chain p.Phe42Ser; see Table 1), leads to denaturation of the tetramer and consequent hemolysis. This variant is notable because the substituted phenylalanine residue is one of the two amino acids that are conserved in all globins in nature. It is, therefore, not surprising that sub stitutions of this phenylalanine produce serious alterations in hemoglobin function. In normal β- globin, the bulky phenylalanine wedges the heme into a “pocket” in the folded β- globin monomer. Its replacement by serine, a smaller residue, creates a gap that allows the heme to slip out of its pocket. In addition to its instability, Hb Hammersmith has a low oxygen affinity, which can cause cyanosis in heterozygotes carriers.

In contrast to variants that destabilize the tetramer, other variants destabilize the globin monomer and never form the tetramer, causing chain imbalance and thalassemia (see following section).

Variants With Altered Oxygen Transport

Variants that alter the ability of hemoglobin to transport oxygen, although rare, are of general interest because they illustrate how a variant can impair one function of a protein (in this case, oxygen binding and release) and yet leave the other properties of the protein relatively intact. For example, the variants that affect oxygen transport generally have little or no effect on hemoglobin stability.

Methemoglobins. Oxyhemoglobin is the form of hemoglobin that is capable of reversible oxygenation; its heme iron is in the reduced (or ferrous) state. The heme iron tends to oxidize spontaneously to the ferric form and the resulting molecule—referred to as methemoglobin, is incapable of reversible oxygenation. If significant amounts of methemoglobin accumulate in the blood, cyanosis results. Maintenance of the heme iron in the reduced state is the role of the enzyme, methemoglobin reductase. In several altered globins (either α or β), substitutions in the region of the heme pocket affect the heme- globin bond in a way that makes the iron resistant to the reductase. Although heterozygotes for these abnormal hemoglobins are cyanotic (a sign), they are asymptomatic. The homozygous state is presumably lethal. One example of a β- chain methemoglobin is Hb Hyde Park (see Table 1), in which the conserved histidine (p.His92) to which heme is covalently bound has been replaced by tyrosine (p.His92Tyr).

Hemoglobins With Altered Oxygen Affinity. Variants that alter oxygen affinity demonstrate the importance of subunit interaction for the normal function of a multimeric protein such as hemoglobin. In the Hb A tetramer, the α:β interface has been highly conserved throughout evolution. It is subject to significant movement between the chains when the hemoglobin shifts from the oxygenated (relaxed) to the deoxygenated (tense) form of the molecule. Substitutions in residues at this inter face, exemplified by the β- globin mutant Hb Kempsey (see Table 1), prevent the normal oxygen- related movement between the chains; the variant “locks” the hemoglobin into the high oxygen affinity state, reducing oxygen delivery to tissues and causing polycythemia.

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مواضيع ذات صلة

Hemoglobin E: A Structurally Altered Hemoglobin With Thalassemia Phenotypes

The β- Thalassemias

The α- Thalassemias

Transient neonatal diabetes

Permanent neonatal diabetes

Fragile X Syndrome

Polyglutamine Disorders

Monogenic Causes of Diabetes : Glucokinase MODY and pregnancy

Monogenic Causes of Diabetes : Glucokinase MODY

Monogenic Causes of Diabetes: Maturity- onset diabetes of the young

Deletion and Duplication Syndromes

Uniparental Disomy