Sickle cell disease

Abstract

A mutation in the β-hemoglobin gene that codes for a variant hemoglobin, sickle hemoglobin (HbS), in which the glutamate at position 6 of the protein is exchanged for valine (HBB glu6val), is the genetic basis of sickle cell disease (SCD). SCD is found in about 1 in 300 African Americans at birth, but its incidence can be much higher in parts of Africa, the Middle East, and India, regions where the HbS mutation first arose. When deoxygenated, HbS polymerizes resulting in erythrocyte (RBC) deformation (known as “sickling”) and cellular damage, provoking the clinical and laboratory features characteristic of SCD. These include vasoocclusion, hemolytic anemia, widespread acute and chronic organ damage, and reduced lifespan [1]. Patients with SCD can be homozygous for theHbS mutation, compound heterozygotes for the HbS mutation, and another variant that “interacts” with HbS, compound heterozygotes for HbS and a β-thalassemia mutation. Simple heterozygotes are said to have sickle cell trait and, with rare exceptions, are well [2]. HbS homozygotes show the most severe symptoms and a great deal of phenotypic heterogeneity, likely as a result of many interacting genes or proteins. Chief among the genetic abnormalities that modulate the phenotype of SCD is α-thalassemia, which reduces RBC density and HbS concentration, reducing hemolysis, and mutations in various regulators of fetal hemoglobin (HbF) gene expression. HbF can thwart the polymerization of HbS [3, 4]. Many other genes are likely to modulate the phenotype of SCD.