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--- chapter_15 [2025/05/04 19:52] – mike
+++ chapter_15 [2025/05/04 19:53] (current) – [Human sickle cell disease: an introduction] mike
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-The missense mutation that changes the seventh amino acid in β-globin from glutamine to valine causes devastating consequences. β-globin subunits that contain the sickle cell mutation are called β<sub>s</sub>, and Hb proteins that contain β<sub>s</sub> are called HbS (Fig. {{ref>Fig1}}A). HbS does not directly interfere with the ability of hemoglobin to store or release oxygen, but rather this amino acid change bestows a new property on the hemoglobin molecule; in its deoxygenated state the HbS molecules aggregate together to form polymeric fibers, and the presence of these fibers grossly distorts the shape of red blood cells (RBCs) (Fig. {{ref>Fig1}}B). Instead of the classic dual-concave round shape that has tremendous flexibility to squeeze through tiny capillaries within tissues, the aggregated HbS fibers cause the RBCs to become curved (like a sickle), rigid, prone to rupture, and prone to clumping; rupture causes anemia (a lack of healthy red blood cells to carry oxygen to tissues) and clumping clogs small blood vessels, leading to tissue damage (Fig. {{ref>Fig1}}1C). It is the ααβ<sub>s</sub>β<sub>s</sub> hemoglobin molecule that is responsible for aggregating and causing sickle cell disease. The ααββ<sub>s</sub> hemoglobin tetramers expressed in people heterozygous for the sickle mutation do not aggregate to form fibers, and so do not cause disease; however, if such heterozygous people live at high altitude some sickling can occur (sometimes when an allele is only weakly dominant we can describe that as being semidominant).
+The missense mutation that changes the seventh amino acid in β-globin from glutamine to valine causes devastating consequences. β-globin subunits that contain the sickle cell mutation are called β<sub>s</sub>, and Hb proteins that contain β<sub>s</sub> are called HbS (Fig. {{ref>Fig1}}A). HbS does not directly interfere with the ability of hemoglobin to store or release oxygen, but rather this amino acid change bestows a new property on the hemoglobin molecule; in its deoxygenated state the HbS molecules aggregate together to form polymeric fibers, and the presence of these fibers grossly distorts the shape of red blood cells (RBCs) (Fig. {{ref>Fig1}}B). Instead of the classic dual-concave round shape that has tremendous flexibility to squeeze through tiny capillaries within tissues, the aggregated HbS fibers cause the RBCs to become curved (like a sickle), rigid, prone to rupture, and prone to clumping; rupture causes anemia (a lack of healthy red blood cells to carry oxygen to tissues) and clumping clogs small blood vessels, leading to tissue damage (Fig. {{ref>Fig1}}C). It is the ααβ<sub>s</sub>β<sub>s</sub> hemoglobin molecule that is responsible for aggregating and causing sickle cell disease. The ααββ<sub>s</sub> hemoglobin tetramers expressed in people heterozygous for the sickle mutation do not aggregate to form fibers, and so do not cause disease; however, if such heterozygous people live at high altitude some sickling can occur (sometimes when an allele is only weakly dominant we can describe that as being semidominant).
 Sickle cell disease is very common in many parts of the world, especially sub-Saharan Africa, and even among African Americans (1 in 365 births) and Hispanic Americans (1 in 16,300 births). The prevalence of such a devastating disease allele is actually quite surprising since one would expect it to be selected against as the human population expanded. However, people who are heterozygous for the sickle mutation in the β-globin gene are resistant to malaria. This gives a survival advantage for people who are carriers (i.e., heterozygotes) of the mutant allele if they live in an area where malaria is prevalent. These individuals are said to have the sickle cell trait, but they do not have sickle cell disease.