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--- chapter_15 [2024/09/01 20:24] – [Making transgenic mice that express mutant human β-globin] mike
+++ chapter_15 [2025/05/04 19:53] (current) – [Human sickle cell disease: an introduction] mike
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-<typo fs:x-large>Chapter 15. Transgenes in multicellular model organisms</typo>
+<-chapter_14|Chapter 14^table_of_contents|Table of Contents^chapter_16|Chapter 16->
-In the next two chapters we will examine some of the ways in which we can study gene function in higher eukaryotes, using the laboratory mouse //Mus musculus// as an example. A remarkable number of manipulations have been made to the mouse genome in order to generate an experimental mouse model system for human sickle cell disease. The mouse that was developed to explore this human disease turns out to be one of most genetically modified mice on the planet! It gives us an interesting framework in which to discuss making transgenic and knockout mice. To set the scene for genetically modifying mice to mimic human sickle cell disease we need to step back a bit and consider this devastating human disease and some of its features.
+<typo fs:x-large>Chapter 15. %%Transgenes%% in multicellular model organisms</typo>
+In the next two chapters we will examine some of the ways in which we can study gene function in higher eukaryotes, using the laboratory mouse //Mus musculus// as an example. A remarkable number of manipulations have been made to the mouse genome in order to generate an experimental mouse model system for human sickle cell disease. The mouse that was developed to explore this human disease turns out to be one of the most genetically modified mice on the planet! It gives us an interesting framework in which to discuss making transgenic and knockout mice. To set the scene for genetically modifying mice to mimic human sickle cell disease we need to step back a bit and consider this devastating human disease and some of its features.
 ===== Human sickle cell disease: an introduction =====
-Human sickle cell disease (also called sickle cell anemia) is a human blood disorder that is caused by a single missense mutation in a gene that encodes one of the subunits of the protein hemoglobin (Hb), namely β-globin. Hemoglobin is a tetrameric protein made up of two α-globin polypeptides, and two α-globin polypeptides; the tetramer can be written as ααββ (Fig. {{ref>Fig1}}A). Each of the four globin polypeptides bind to an iron-containing heme molecule (iron is what makes hemoglobin and red blood cells red) whose function is to bind oxygen in the lungs and release it in all the tissues of the animal.
+Human sickle cell disease (also called sickle cell anemia) is a human blood disorder that is caused by a single missense mutation in a gene that encodes one of the subunits of the protein hemoglobin (Hb), namely β-globin. Hemoglobin is a tetrameric protein made up of two α-globin polypeptides, and two β-globin polypeptides; the tetramer can be written as ααββ (Fig. {{ref>Fig1}}A). Each of the four globin polypeptides bind to an iron-containing heme molecule (iron is what makes hemoglobin and red blood cells red) whose function is to bind oxygen in the lungs and release it in all the tissues of the animal.
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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.