Sickle cell disease/anemia inheritance

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. 

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.)... 

RFLPs are often a reflection of individual genetic diversity and are not related to a clinical phenotype, but occasionally they can be diagnostic of an inherited disease. This technique is relatively new yet, it has been applied to the prenatal detection of sickle cell anemia, thalassemia, phenylketonuria, a,-antitrypsin deficiency, Huntington s chorea, Duchenne muscular dystrophy, hemophilia A and B, cystic fibrosis, and several other, diseases. 

Diseases of people come in many flavors. There are infectious diseases (measles, mumps, influenza, AIDS,...), nutritional deficiency diseases (scurvy, beriberi, kwashiorkor,...), degenerative diseases (Alzheimer s disease, osteoporosis,...), cancer (of the lung, breast, prostate, liver,...), and single-gene inherited diseases or molecular diseases. In the last category, an important and instructive example is provided by sickle cell anemia. Let s consider this disease and begin to develop a sense of how we can understand it on the basis of what we now know about proteins. 

In 1922,V R. Mason (Mason, 1992) published a case review in the Journal of the American Medical Association entitled Sickle Cell Anemia, and the homozygous condition has since then been referred to by the description of the shape of the red cells seen by Dr. Irons a decade earlier In his review article, Dr. Mason promulgated the misconception that this disease was exclusively seen in persons of African origin. In 1923, Sydenstricked and colleagues reviewed the cases of two children with sickle cell disease and observed the blood smears of Caucasian and African Americans and concluded, with Mason, that sickle cell anemia was a condition peculiar to people of African descent. Neel (1949) reviewed blood smears of families with sickle cell disease over a 2-year period and correctly concluded that sickle cell anemia was a disease with Mendelian inheritance. 

Southern blotting can be used to follow the inheritance of selected genes. Mutations within restriction sites change the sizes of restriction Ifagments and hence the positions of bands in Southern-blot analyses. The existence of genetic diversity in a population is termed polymorphism. The detected mutation may itself cause disease or it may be closely linked to one that does. Genetic diseases such as sickle-cell anemia, cystic fibrosis, and Huntington chorea can be detected by RFLP analyses. 

Homozygous Hemoglobin S (HbSS). In homozygous Hb S, a valine for glutamic acid substitution occurs on both p-globin chains because of the inheritance of mutated P-globin chain genes from both parents. The condition is described as sickle cell anemia or sickle cell disease because of the sickle shaped RBCs that occur when there is a sickle cell crisis and is sometimes written as p p. ... 

Initially, the focus of gene therapy was for the treatment of inherited disorders such as cystic fibrosis, sickle cell anemia, hemophilia, and adenosine deaminase deficiency. Gene therapy trials were later expanded to include patients with acquired diseases such as cancer and heart disease. 

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