Molecular genetics and diagnosis of sickle cell anemia

Sickle Cell Anemia

There are a number of hereditary anemias, which feature disorders of the structure or synthesis of hemoglobin, deficiencies of enzymes which provide energy to red blood cells or protect the red blood cells from damage, or abnormalities in the proteins found in the cell membranes of red blood cells. Inherited diseases of hemoglobin are the most important, and these are termed hemoglobinopathies; it is into this category that sickle cell anemia falls. Sickle cell anemia has a genetic basis, and was the first genetic disease to be characterized at the molecular level (Ingram, 2004).

Molecular Genetics

The structure of normal human hemoglobin (Hb) changes during development of the embryo and fetus, and at around week 12 of pregnancy, embryonic hemoglobin will have been replaced by fetal hemoglobin (Hb F); after birth this is gradually replaced by adult hemoglobins (Hb a and Hb A2). Each type of hemoglobin is constructed from two different types of peptide chains; HbF consists of "2"2, Hb a has "2"2 and Hb A2 has "2"2. This means that any disease which affects the ? chains will be evident from birth, while those which affect ? chains present as the fetal hemoglobin is replaced with adult hemoglobin. The sickle cell mutation is one such disease which affects the ? chains.

The sickle cell mutation results in a single amino acid substitution in the ? globin chain, which will result in the production of a different type of hemoglobin - Hb S (Weatherall, 1997). This occurs at position 6 on the ? chain, where glutamic acid is substituted by valine. Sickle cell anemia is a recessive disorder (Nagel, 2005), and so those with sickle cell anemia are homozygous for the mutation, producing mainly Hb S, with small amounts of Hb F. It is possible for individuals to inherit only one affected chromosome, and so be heterozygous for the condition, although this is termed sickle cell trait, or is seen in a combined state with thalassemia, and the patient outcomes will be different than for those with sickle cell anemia. The production of Hb S. is used as the marker for diagnosis of sickle cell disease; electrophoresis is carried out on a blood sample from the patient, which would demonstrate the presence of Hb S. As opposed to Hb a or Hb A2. It is possible that the parents may need to be tested also in order to establish whether the homozygous or heterozygous condition was present (Weatherall, 1997). Prenatal diagnosis in the first trimester is now also possible for the disease, by analyzing fetal DNA obtained through chorionic villous biopsy; there is currently research towards diagnosis from cells taken from maternal circulation in order to minimize the risks to the fetus associated with fetal DNA collection (Frenette and Atweh, 2007).

Despite the production of the mutated ? chain being the product of a singe gene, sickle cell disease itself is actually multigenic, with many genes producing the effects which present in the patient; this explains the varying severity which is seen in different patients. There are many secondary consequences to the presence of the mutation, such as increased adhesion of the cells to the endothelium, the induction of red cell dehydration and irreversibly sickled cells, and these effects will all involve other genes, creating a pleiotropic effect which can aggravate the disease in a number of ways (Nagel, 2005).

Homeostasis

The individual red cell density and shape is key to its ability to perform its function in the transport of oxygen, and sickle cell anemia alters the cell's homeostasis by impeding the ability to maintain hydration and cation content. The exposure of sickle cells to acidic environments disrupts the internal environment of the cell, as it causes loss of potassium ions, resulting in dehydration of the cell. This may also alter the functions of the transport channels in the red blood cells, further reducing function (Steinberg, 2005).

Population Dynamics

The sickle cell gene is spread widely throughout Africa and other countries in which there are large numbers of African immigrants; there are also some Mediterranean countries, many Middle Eastern countries and some parts of India in which the gene is commonly found (Weatherall, 1997). This is due to the close association between sickle cell and malaria, with the sickle cell mutation offering a degree of resistance to malaria. The expansion of the mutation to the present day frequencies indicates that the heterozygous form of the disease is favored, which is compensated by the lower fitness of the heterozygote. The cells of those with sickle cell trait offer protection, as the red cells, which do not usually sickle, are forced to sickle by the low pH which is induced by the parasite and are then selectively destroyed by the spleen, clearing the parasite out of the system without destroying healthy cells (Nagel, 2005). The map in Appendix 1 demonstrates the areas in which the sickle cell gene is most commonly found.

The large proportion of the population in the U.S.A. with African roots means that the condition is also quite prominent in the U.S. It is currently believed that around two and a half million African-Americans are carriers of the gene, many without being aware. This results in around one in every five hundred African-Americans developing sickle cell anemia (Chowning, 2000).

Evolution

The sickle gene has appeared around the world at least five different times. This can be demonstrated by the differences in the gene which are found in the different areas of the world. The mutated gene is located in chromosome 11, and by studying the haplotypes present in sufferers in different areas of the world, it is possible to identify that the variations present today have arisen from a number of separate mutations, which must have arisen exclusively. There are three distinctly different chromosomes in Africa, each located exclusively in a separate geographical region. A small ethnic group in Southern Cameroon were also found to have their own personal haplotype. A separate haplotype was again found in Saudi Arabia and India, which is the haplotype which has now become distributed across the Middle East. A final haplotype linked to Benin is believed to be the one which has spread through North Africa, the Mediterranean, and the Americas.

Conclusion

Sickle cell anemia is a homozygous condition, in which a mutation occurs resulting in the production of a different type of hemoglobin (Hb S) to that usually found in adult red blood cells (Hb a). Despite the disease being the result of a single gene mutation, the interaction of this mutation with other genes results in wide variations over the severity of the disease which is witnessed in individual patients. In sickle cell anemia, the red blood cells undergo polymerization under deoxygenation, and are destroyed by the spleen, resulting in the anemia seen in the condition. While those suffering from the disease may adapt quite well to the anemia which is present, they are likely to suffer from crises, which can be severe and potentially fatal. These crises are a direct result of way in which the deformed red blood cells adhere to both each other and the insides of the blood vessel walls, blocking tissues from receiving oxygen. The disease is prevalent across some parts of Africa, the Middle East and India, which is due to the way in which the heterozygous form of the condition offers carriers a degree of protection against malaria, which is present in these areas. As a result, there is also a significant incidence of the disease in African-Americans, as a direct result of their African heritage, which means that the condition is significantly important for practitioners across the U.S. To understand.