A prime example of a single-gene disorder is sickle cell disease. This refers to an autosomal recessive blood disorder caused by a variant of the β-globin gene called sickle hemoglobin (Hb S).
With sickle cell disease, a single nucleotide substitution (T→A) in the sixth codon of the β-globin gene results in the substitution of valine for glutamic acid (GTG→GAG). This causes Hb S to polymerize, form long chains, when deoxygenated.
When an individual inherits two copies of Hb S (Hb SS), they are considered to have sickle cell anemia. However, if an individual inherits one copy of Hb S plus another deleterious β-globin variant (e.g., Hb C or Hb β-thalassemia) they are considered to have sickle cell disease. A person is thought to be a carrier of the sickle cell trait if they have one copy of the normal β-globin gene and one copy of the sickle variant (Hb AS).
Researchers have identified four major β-globin gene haplotypes. Three of these gene haplotypes were named for the regions in Africa where the mutations first appeared: BEN (Benin), SEN (Senegal), and CAR (Central African Republic). The fourth haplotype was named Arabic-India as it was found to occur in the India and Arbic peninsula.
The severity of sickle cell disease is connected with several genetic factors. The highest degree of severity is associated with Hb SS, followed by Hb s/β0-thalassemia, and Hb SC. Hb S/β+-thalassemia is associated with a more benign course of the disease. Disease severity also is related to β-globin haplotypes, which is likely due to variations in hemoglobin level and fetal hemoglobin concentrations. The most benign form is the Senegal haplotype, followed by the Benin. The most severe form is the Central African Republic haplotype.
While sickle cell disease is considered a monogenetic disorder, its phenotypic expression is multigenic. There are two primary pathophysiologic features of sickle cell disease—chronic hemolytic anemia and vaso-occlusion.
Two of the main consequences of hypoxia, secondary to vaso-occlusive crisis, are pain and damage to organ systems. Since blood flow is slow, organs like the spleen and bone marrow are at the greatest risk. Other organs with limited arterial blood supply, including the eye, the head of the femur and the humerus, and the lung as the recipient of deoxygenated sickle cells that escape the spleen or bone marrow are also at the greatest risk.
Major clinical manifestations of sickle cell disease include painful events, splenic dysfunction, acute chest syndrome, and cerebrovascular accidents.
Clinical care efforts are focused on increasing understanding of the pathophysiology of sickle cell disease in order to facilitate a precise prognosis and individualized treatment. Further research and studies are being done to better understand which genes are associated with the hemolytic and vascular complications of sickle cell disease as well as how variants of these genes interact among themselves and with their environment.
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