BIOCHEMISTRY - L. Stryer - 1984

VOLUME 1

PART I. CONFORMATION AND DYNAMICS

CHAPTER 5. MOLECULAR DISEASES: SICKLE-CELL ANEMIA

Conclusions

The alteration of a single amino acid in a single protein, caused by a Gene mutation, can be the underlying cause of a specific disease. The most thoroughly studied molecular disease is Sickle-Cell Anemia. The abnormal Hemoglobin in patients with sickle-cell anemia, designated as hemoglobin S, consists of two normal $\alpha$-chains and two mutant $\beta$-chains. The mutation manifests itself in the replacement of glutamate by valine at the 6th position in the $\beta$-chain of hemoglobin S. This substitution of a polar side chain for a nonpolar one leads to a drastic decrease in the solubility of deoxyhemoglobin S. In contrast, the solubility of oxyhemoglobin S remains normal. Deoxygenated hemoglobin S forms a fibrous precipitate that deforms the erythrocyte, giving it a sickle shape. Sickled red Blood Cells are rapidly destroyed, ultimately resulting in the clinical picture of chronic hemolytic anemia. Sickle-cell anemia occurs exclusively in individuals homozygous for the mutant gene that determines the Synthesis of the $\beta$-chain of hemoglobin S. Heterozygous individuals synthesize both hemoglobin S and hemoglobin A. The heterozygous state, known as the sickle-cell trait, is usually asymptomatic. Approximately one in ten individuals of African descent is heterozygous for the sickle-cell gene. Such a high frequency of this mutant gene, which is deleterious in the homozygous state, is due to the fact that carrying the mutant gene confers a survival advantage—a phenomenon known as balanced polymorphism. Individuals heterozygous for the sickle-cell gene exhibit resistance to the most severe, fatal form of malaria.

The Study of hemoglobin in hematological patients, as well as the screening of healthy individuals, has revealed more than 100 mutant forms of hemoglobin. Hemoglobins that differ in electrophoretic mobility from hemoglobin A are analyzed by peptide mapping ("fingerprinting"), followed by the Determination of the Amino Acid Sequence of the specific peptide by which the studied hemoglobin differs from hemoglobin A. Several classes of hemoglobin Mutations have been identified. Class I mutations involve Amino Acid Substitutions On the surface of the molecule; these substitutions are almost invariably harmless, with hemoglobin S being a striking exception. Class II mutations are amino acid substitutions near the heme group, which typically disrupt oxygen binding. For instance, in hemoglobin M, either the proximal or distal Histidine is replaced by Tyrosine, resulting in hemoglobin M being stabilized in the ferric (met) form and rendered incapable of binding oxygen. Class III mutations involve substitutions in the interior of the molecule, which frequently lead to alterations in tertiary Structure and, consequently, to instability of the hemoglobin molecule. An example is a hemoglobin variant in which Arginine replaces Glycine at a site where glycine is strictly required due to its small size. Alterations at the subunit contact interfaces are typically accompanied by the loss of allosteric properties. Amino acid substitutions that stabilize hemoglobin in either the T or R state result in altered oxygen affinity.