Genetics of Sickle Cell Disease

Genetics of Sickle Cell Disease

Sickle cell disease is an inherited condition. Two genes for the sickle hemoglobin must be inherited from one's parents in order to have the disease. A person who receives a gene for sickle cell disease from one parent and a normal gene from the other has a condition called “sickle cell trait”. Sickle cell trait produces no symptoms or problems for most people. Sickle cell disease can neither be contracted nor passed on to another person. The severity of sickle cell disease varies widely. Some people with sickle cell disease lead lives that are nearly normal. Others are less fortunate, and can suffer from a variety of complications.

Heredity of Sickle Cell Disease

 During fertilization, a person receives one set of genes from the mother (egg) and a corresponding set of genes from the father (sperm). The genes exist on structures inside cells called chromosomes. The combined effects of many genes determine some traits (hair color and height, for instance). Other characteristics are determined by one gene pair. Sickle cell disease is a condition that is determined by a single pair of genes (one from each parent).

 The genes involved in sickle cell disease control the production of a protein in red cells called hemoglobin. Hemoglobin binds oxygen in the lungs and delivers it to the peripheral tissues, such as the liver and muscles. Most people have two normal genes for hemoglobin. Some people carry one normal gene and one gene for sickle hemoglobin. This is called "sickle cell trait". These people are normal in almost all respects. People with sickle cell trait do not develop sickle cell disease as they grow older. People with sickle cell trait rarely develop problems related to their single sickle cell gene, and then only under very unusual conditions.

A person receives the sickle cell genes or not only at the time of conception. Therefore, neither sickle cell trait nor sickle cell disease can be contracted. By the same token, people cannot lose their sickle cell genes over time. A person born with sickle cell trait (one sickle cell gene) will always have sickle cell trait. The same is true of sickle cell disease (two sickle cell genes). Sickle cell disease produces illness, while sickle cell trait usually does not. The severity of sickle cell disease can change over time. The change in severity is not due to a change in the sickle cell genes over time. Rather, number of other biological factors, most of which are not understood; change to alter the severity of sickle cell disease.

 People who inherit two genes for sickle hemoglobin (one from each parent) have sickle cell disease. With a few exceptions, a child can inherit sickle cell disease only if both parents have one gene for sickle cell hemoglobin. The most common situation in which this occurs is when each parent has one sickle cell gene. In other words, each parent has sickle cell trait.

 At each conception, the probability of getting a child with two normal gene is 1/4 or 25% in all. Also  same 1/4  chance that a child will inherit two sickle cell genes, and have sickle cell disease while there is a high 50% or 1/2 probability that the child will inherit a normal gene from one parent and a sickle gene from the other and thus be a carrier of sickle trait. 

 These probabilities exist for each child independently of what happened with prior children the couple may have had. In other words, each new child has a one-in-four chance of having sickle cell disease. A couple with sickle cell trait can have eight children, none of whom have two sickle genes. Another couple with sickle trait can have two children each with sickle cell disease. The inheritance of sickle cell genes is purely a matter of chance. These probability odds cannot be altered.

Genetic Change that results in Sickle Cell Disease

Hemoglobin consists of four protein subunits, typically, two subunits called alpha-globin and two subunits called beta-globin. The HBB gene provides instructions for making beta-globin. Various versions of beta-globin result from different mutations in the HBB gene. One particular HBB gene mutation produces an abnormal version of beta-globin known as hemoglobin S (HbS). Other mutations in the HBB gene lead to additional abnormal versions of beta-globin such as hemoglobin C (HbC) and hemoglobin E (HbE). HBB gene mutations can also result in an unusually low level of beta-globin; this abnormality is called beta thalassemia.

In people with sickle cell disease, at least one of the beta-globin subunits in hemoglobin is replaced with hemoglobin S. In sickle cell anemia, which is a common form of sickle cell disease, hemoglobin S replaces both beta-globin subunits in hemoglobin. In other types of sickle cell disease, just one beta-globin subunit in hemoglobin is replaced with hemoglobin S. The other beta-globin subunit is replaced with a different abnormal variant, such as hemoglobin C. For example, people with sickle-hemoglobin C (HbSC) disease have hemoglobin molecules with hemoglobin S and hemoglobin C instead of beta-globin. The cause of sickle cell anemia is a point mutation in the gene coding for hemoglobin. The change converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of hemoglobin in persons with sickle cell anemia is referred to as HbS.

Valine has replaced glutamic acid which is present in normal hemoglobin and has resulted in sickle cell disease.