Sickle cell disorders are a type of hemoglobinopathy which are characterized by the presence of sickle hemoglobin (Hb S) in red blood cells. Hb S is a structural disorder caused by valine replacing glutamic acid in the sixth position on the beta chain.* Sickle cell disorders are autosomal recessive inherited disorders. If an individual inherits a sickle gene (S) from one parent and one normal gene (A) from the other parent, the disorder is a heterozygous condition known as sickle cell trait (Hb SA). If an individual inherits "S" genes from both parents, the disorder is a homozygous condition known as sickle cell anemia (Hb SS). Sickle cell anemia can also demonstrate hereditary persistence of fetal hemoglobin (Hb S/HPFH).
The reason that the substitution of valine for glutamic acid at this particular position on the outside of the molecule is so critical is that glutamic acid is a polar, hydrophyllic amino acid and bonds freely with water. However, valine is a non-polar hydrophobic amino acid and embeds itself in a hydrophobic pocket, leading to the polymerization with other globin chains rather than bonding with water. This polymerization leads to long chains which distort the red blood cell into the "sickle" shape. This tends to happen when the hemoglobin molecule becomes deoxygenated.
A double heterozygous condition known as Hemoglobin SC disease also exists where one beta chain carries the mutation for Hb S and the other beta chain carries the mutation for Hb C. Hemoglobin C involves the substitution of a glutamic acid residue by lysine. In addition, Hb S can be present with thalassemia (also called Mediterranean anemia and is the result of a diminished rate of hemoglobin formation).
Other Hb S combinations are very rare and include Hb S/Hb E, Hb S/Hb D Los Angeles, Hb S/Hb G-Philadelphia, and Hb S/Hb O Arab.
*The normal amino acid sequence for the beta hemoglobin chain includes glutamic acid in position 6, phenylalanine in position 85, and leucine in position 88. These amino acid positions are key to the sickling process. ß6glu-val" in the nomenclature indicates this mutation in the sixth position on the beta chain which leads to hemoglobin S production.
