Sickle hemoglobin anemia/disease

Sickle-cell anemia is the classic example of an inherited disease that is caused by a change in a protein s amino acid sequence. Linus Pauling proposed in 1949 that it was caused by a defect in the hemoglobin molecule he thus coined the term molecular disease. Seven years later Vernon Ingram showed that the disease was caused by a single mutation, a change in residue 6 of the P chain of hemoglobin from Glu to Val. 

FIGURE 65-1. Sickle gene inheritance scheme for both parents with sickle cell trait (SCT). A, normal hemoglobin S, sickle hemoglobin. Possibilities with each pregnancy 25% normal (AA) 50% SCT (AS) 25% sickle cell anemia (SS). (From Chan CYJ, Moore R. Sickle cell disease. In DiPiro JT, Talbert RL, Yee GC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 1856.)... 

The Nobel Prize chemist Linus Pauling related the mechanism of sickle cell anemia to a genetic defect in hemoglobin synthesis and thus defined the first molecular disease. Pauling s groundbreaking paper in 1949 was boldly titled Sickle Cell Anemia A Molecular Disease. Many claim that this discovery laid the foundation for molecular biology. What is the chemistry that is at the heart of this pioneering work ... 

The most common abnormal hemoglobin in the United States is hemoglobin S (HbS). Two genes for HbS result in sickle cell disease (SCD) or sickle cell anemia, which occurs in 0.3% of African Americans. One gene for HbS results in sickle cell trait, which occurs in 8% of African Americans. Hemoglobin C, another abnormality, occurs in 2% to 3% of African Americans. 

We begin with the symptoms of sickle cell anemia. As the name implies, victims are frequently anemic that is, they have a content of hemoglobin in blood less than the normal range, the result of lysis of red blood cells, the carriers of hemoglobin (hemolytic anemia). In addition, disease victims are susceptible to chronic infections, may have enlarged spleens, and suffer intermittent bouts of pain, which can be severe, in the bones, joints, and periosteum. The disease can be debilitating. 

Sickle-Cell Anemia Is a Molecular Disease of Hemoglobin... 

Hemoglobinopathies have traditionally been defined as a family of dis orders caused by production of a structurally abnormal hemoglobin molecule, synthesis of insufficient quantities of normal hemoglobin, or, rarely, both. Sickle-cell anemia (HbS), hemoglobin C disease (HbC), and the thalassemia syndromes are representative hemoglobinopathies that can have severe clinical consequences. The first two conditions result from production of hemoglobin with an altered amino acid sequence, whereas the thalassemias are caused by decreased produc tion of normal hemoglobin. 

Although functioning proteins have very specific amino acid sequences, slight variations can often be tolerated. In some cases, however, a slight variation can be disastrous. For example, some people have a version of hemoglobin—a protein found in red blood cells—that has one incorrect amino acid in about 300. That minor error is responsible for sickle-cell anemia, an inherited condition with painful and often lethal effects. The sickle shape characteristic of this disease is shown in Figure 13.19. 

Genetic diseases have always been with us, but it was not until 1949 that the first disease, sickle cell anemia (Box 7-B), was understood at the molecular level. A single base substitution in DNA and the resultant single amino acid substitution in hemoglobin... 

Primary structure is the amino / ) acid sequence, which controls the shape of the protein and the role the protein serves in the body. Primary Structure Primary structure is the most fundamental of the four structural levels because it is the protein s amino acid sequence that determines its overall shape and function. So crucial is primary structure to function that the change of only one amino acid out of several hundred can drastically alter biological properties. The disease sickle-cell anemia, for example, is caused by a genetic defect in blood hemoglobin whereby valine is substituted for glutamic add at only one position in a chain of 146 amino acids. 

The disease is caused by a mutation of a gene that controls hemoglobin production. A hemoglobin molecule consists of two types of amino acid chains alpha chains and beta chains. At the molecular level, the sickle-cell anemia mutation involves the replacement of one amino acid in the beta chains by another... 

A disorder related to sickle cell anemia is the HbC disease, which is also found mostly among persons of African ancestry. Its symptoms, however, are less severe than those with the HbS disorder. HbC is a hemoglobin with a /36Glu—>Lys substitution. It is believed that HbS and HbC arose as a means of combating malaria, because red cells containing HbS and HbC are more resistant to the invasion of the malarial parasite than are normal red cells. 

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