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Molecular Biology of Sickle Cell Anemia - Term Paper Example

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This term paper "Molecular Biology of Sickle Cell Anemia" focuses on an inherited recessive blood disorder which is caused by a point mutation which leads to the faulty synthesis of hemoglobin, in turn, resulting in the production of pathogenic or diseased erythrocytes. …
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Molecular Biology of Sickle Cell Anemia
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Molecular Biology of Sickle Cell Anemia Molecular Biology of Sickle Cell Anemia Outline  1- Hemoglobin structure, function and synthesis. 2- Mutation in HBB gene. 3- Hemoglobin S (HbS). 4- Sickle cell anemia. One page. 5- Architecture of the cytoskeleton in normal red blood cells and compares it to sickle cell shaped. 6- Sickle red cells impair the blood flow causing series of tragic events!  Sources: In attached files. Introduction: Sickle cell anemia is an inherited recessive blood disorder which is caused by a point mutation which leads to the faulty synthesis of hemoglobin in turn resulting in the production of pathogenic or diseased erythrocytes. This reduces the oxygen carrying capacity of the blood and causes the jamming of blood vessels. One of the characteristic symptoms of sickle cell anemia is pain. Sickle cell anemia is found mainly in people belonging to malaria endemic regions for e.g. Africa. A definitive cure for this debilitating illness is yet to be found and so the treatment given to the patients is still largely symptomatic and supportive. (Taylor et al. 1997 pp.859) (Abnormal phospholipid molecular species of erythrocytes in sickle cell anemia, Connor et al. 1997) Hemoglobin: Structure The structure of the hemoglobin molecule was deciphered by scientists, Kendrew and Perutz using X-ray crystallography in 1959. Hemoglobin is an oxygen-carrying chromoprotein. It is found in red blood cells of vertebrates. 1 red blood cell contains approximately 600 million hemoglobin molecules. It consists of 4 Heme molecules which are attached to 4 polypeptide or globin chains. Heme is a cyclic tetrapyrrole i.e. it consists of 4 molecules of pyrrole. It imparts a red color due to the methyl, vinyl and proprionate groups attached to it. Each heme group also contains one ferrous ion (prosthetic group)present in the porphyrin ring which is present in the center of the heme. The 4 globin chains that make up a hemoglobin molecule are known as αand β chains. The two αchains each contain 141 amino acids, while the two βchains contain 146 amino acids. These chains are derived mainly from chromosome 16 and 11. Hemoglobin is a globular protein and the 4 protein chains are held together in what is known as a quaternary structure. The hydrophobic parts of the chains point inwards towards the molecule, whereas the hydrophilic parts point outwards. This makes the molecule soluble in water. (Taylor et al. 1997 pp103, 859) (Interactive-Biology 2012) (The Molecular Biology of Sickle Cell Anemia, 2003)(Hemoglobin: Molecular modeling, 2011) Hemoglobin: Function The hemoglobin molecule is responsible for the transport of oxygen from the lungs to the cells of the body. Each oxygen molecule is attached to the ferrous ion in each heme group. Thus, one hemoglobin molecule is capable of carrying 8 oxygen atoms at a time. It also carries the carbon dioxide molecules back to the lungs for excretion. Carbon dioxide is carried in three forms: in solution, as carbamino-hemoglobin and as bicarbonate ions.(Taylor et al. 1997 pp.479, 481) The hemoglobin molecule shows cooperative binding kinetics, i.e. when one oxygen molecules has been attached, the binding of the rest of the oxygen molecules becomes easier. The oxygen-dissociation curve is sigmoid. It shows that at low partial pressures of oxygen, the hemoglobin molecule readily gives up oxygen, which is then used up by the tissues. Increased concentrations of carbon dioxide also cause the release of oxygen from the molecule. Under these conditions the curve shifts to the right. This is known as the Bohr Effect. (Taylor et al. 1997 pp.479-480) Hemoglobin: Synthesis Hemoglobin synthesis starts to occur in the proerythroblast stage of the RBC cycle. The molecule is produced by mitochondria and ribosomes in a series of reactions. Heme is synthesized in the mitochondria. Glycine &succinyl-CoA condense to form δ-aminolevulinic acid (ALA). This reaction occurs in the presence of ALA-synthase. ALA exits the mitochondria and in the presence of ALA-dehydrase forms porphobilinogen (pyrrole) and subsequently through a series of reactions, coproporphyrinogen. Coproporphyrinogen enters the mitochondria to form protoporphyrin IX which combines with iron in the presence of ferrochelatase to form a heme molecule. The globin molecule is synthesized by ribosomes. The heme molecules combine with the globin to form hemoglobin. (Interactive Biology, 2012) (Hemoglobin Synthesis, 2002) Mutation in the HBB gene: The HBB gene is located on the short (p) arm of chromosome 11 at position 15.5, i.e. from base pair 5,246,695 to base pair 5,248,300. The official name of this gene is “hemoglobin, beta”. Itprovides instructions for making a protein called beta-globin which is a component of hemoglobin. A mutation at any point in the synthesis of hemoglobin can result in disorders for e.g. thalassemia, methemoglobinemia and sickle cell disease.(Genetics Home Reference, 2009) Sickle cell anemia is a common form of sickle cell disease. It is caused by a mutation which results in the formation of an abnormal version of hemoglobin called Hemoglobin S or HbS. In this condition, the polar amino acid i.e. glutamic acid is replaced by a non-polar one i.e. valine at position 6 in beta-globin. This happens because of a base substitution. The triplet code for glutamic acid is CTT i.e. cytosine-thymine-thymine, whereas that for valine is CAT i.e. cytosine-adenine-thymine. Thus, adenine substitutes the first thymine in glutamic acid converting it to the insoluble valine. (Taylor et al. pp.860) Hemoglobin S (HbS): HbS is the most common abnormal hemoglobin in humans. In people with sickle cell disease at least one of the beta-globin chains is replaced by HbS. In sickle cell anemia both beta-globin chains are replaced whereas in other forms of the disease, only one beta-goblin subunit is replaced by HbS, whereas the other one could be replaced by another mutated hemoglobin chain for instance HbC. (Genetics Home Reference, 2009) The presence of the non-polar valine in HbS causes the creation of a hydrophobic region on the outside of the polypeptide chain. This region can interact with another hydrophobic region on an adjacent molecule, leading to clumping or sticking together of HbS molecules to form long, rigid and fibrous molecules. This is known as polymerization and happens under low blood oxygen conditions. (HBB: The Gene Associated with Sickle Cell Anemia, 2003) Sickle Cell Anemia: In the 1950’s research done by Pauling et al. revealed the true cause of sickle cell anemia i.e. a point mutation of the HBB gene and thus it became the first inherited disease to have been understood at the molecular level. Sickle cell anemia is an autosomal recessive genetic disorder.The mutant allele (HbS) is recessive tothe normal allele (HbA). Homozygous (HbSS) recessive individuals have sickle cell disease. Heterozygotes (HbAS) are carriers. If two carriers have children, each child has a 25% chance of having the full sickle cell disease; a 25% chance of inheriting the two normal genes; a 50% chance of being an unaffected carrier. This heterozygous condition is known as sickle cell trait.(Abnormal phospholipid molecular species of erythrocytes in sickle cell anemia, 1997 Connor et al.) Sickle cell anemia has affected numerous human individuals throughout the world. Sickle cell anemia and sickle cell trait are common in people from malaria endemic regions. This is because malaria is not experienced by those who have sickled cells. Thus, the heterozygous sufferers have a selective advantage over non-carriers. It is common among people whose ancestors are from Africa; Mediterranean countries such as Greece, Turkey, and Italy; the Arabian Peninsula; India; and Spanish-speaking regions in South America, Central America, and parts of the Caribbean.In the United States, it affects around 72,000 people, most of who descend from Africans. The disease occurs in about 1 in every 500 African-American births and 1 in every 1000 to 1400 Hispanic-American births. About 2 million Americans, or 1 in 12 African Americans, carry the sickle cell trait.This makes it the most widely inherited blood disorder in United States. A blood test can be carried out to diagnose sickle cell anemia. Hemoglobin electrophoresis is done and if the results are positive for sickle cell anemia, a second blood test is done. Prenatal diagnosis can be done using gene probes for HbS or restriction enzymes on the DNA of the embryo which can be obtained by amniocentesis or chrionic villus sampling (CVS). (Taylor et al. 1997 pp.859-860) (Genetic Disease Profile: Sickle Cell Anemia, 2005) Architecture of the cytoskeleton in normal red blood cells and compares it to sickle cell shaped. The presence of the defective hemoglobin causes the otherwise smooth and biconcave red blood cells to bend into a sickle (crescent) shape. These sickled-shaped cells are unable to squeeze through small blood vessels. They form stacks inside the blood vessels, thus causing blockage and depriving organs of the required oxygen. The sickled cells have a short lifetime of 10-20 days whereas normal red blood cells have a lifetime of 120 days. Thus the sickled cells die prematurely, leading to anemia. (Genetic Disease Profile: Sickle Cell Anemia, 2005) According to research published in the Journal of Lipid Research (J. Lipid Re. 1997. 38: 2516-2528, Connor et al.), there were “distinct abnormalities of the phospholipid molecular species composition in the membrane lipids of sickle erythrocytes”. In addition to the flaws in the phospholipid bilayer, there are some other defects which include “altered cation homeostasis with cellular dehydration and changes in membrane proteins”. Atomic force microscopy was employed to measure the stiffness of abnormal red blood cells and sickled ones. The Young’s modulus of both was determined and compared. The results showed that the Young’s modulus of the diseased erythrocytes was approximately three times higher than in normal cells. Additionally, the sickled cells were smaller in size and had “an irregular biconcave morphology”. These observed differences can be associated with “dehydration due to HbS polymerization”. (Sickle cell trait human erythrocytes are significantly stiffer than normal, 2010) Sickle red cells impair the blood flow causing series of tragic events!  Symptoms: The blockage in the blood vessels causes the following problems: 1. Hand-foot syndrome– Swelling occurs in the hands and the feet, along with fever and pain. This is the first symptom to occur in infants. 2. Fatigue, paleness, and shortness of breath. 3. Pain – Pain is the main symptom of sickle cell anemia and can be treated with painkillers. 4. Eye problems – the retina of the eye disintegrates due to lack of nourishment. 5. Yellowing of skin and eyes – this is due to jaundice which results from the breakdown of red blood cells. 6. Slowed rate of growth and hence delayed puberty. 7. Stiffening of joints occurs. 8. Children may suffer from “sickle cell crises” occasionally, which is a sudden increase in pain. Anemia and infection can also happen. Individuals with sickle cell anemia are more vulnerable to infections. This is because spleen damage occurs due to the sickled cells and thus the spleen is unable to combat the bacteria present in the body. Also, the sickled cells become sticky and may adhere to the walls of blood vessels causing clot formation and if this occurs in the brain, it could lead to stroke. Acute chest syndrome is similar to pneumonia and is caused by an infection in the lungs, which could be a result of the trapped sickled cells in the lung capillaries. Treatment: There is no cure for sickle cell anemia, yet. Blood transfusions can be done to increase the number of normal erythrocytes and also to treat spleen enlargement. This process also helps prevent recurring strokes. Oral antibiotics such as penicillin have shown to prevent pneumococcal infection in children. In 1995, a study conducted by the National Heart, Lung, and Blood Institute revealed that the anti-cancer drug, hydroxyurea reduced the episodes of pain and the frequency of acute chest syndrome. Thus doctors are heavily reliant on painkillers and oral and intravenous fluids in order to treat the symptoms of this crippling disease. The patients are in need of good nutrition, protection from infections, bed rest in order to prevent any complications that may arise. Although, good health care has increased life expectancy substantially and people are living productive lives, thirty years later now the permanent cure for this disease is still elusive. (Genetic Disease Profile: Sickle Cell Anemia, 2005) Bibliography TAYLOR, D. J., GREEN, N. P. O., STOUT, W., & SOPER, R. (1997). Biologicalscience 1 & 2. Cambridge, Cambridge University Press. Hemoglobin Synthesis. 2012. Hemoglobin Synthesis. [ONLINE] Available at:http://sickle.bwh.harvard.edu/hbsynthesis.html. [Accessed 11 November 2012]. . 2012. . [ONLINE] Available at:http://www.explorebiology.com/documents/sickle_cell_teacher-guide.pdf. [Accessed 11 November 2012]. Sickle Cell Anemia Gene. 2012. Sickle Cell Anemia Gene. [ONLINE] Available at:http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml. [Accessed 11 November 2012]. Sickle Cell Anemia Disease Profile. 2012. Sickle Cell Anemia Disease Profile. [ONLINE] Available at:http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/sca.shtml. [Accessed 11 November 2012]. Function and Synthesis of Hemoglobin | Interactive Biology, by Leslie Samuel. 2012. Function and Synthesis of Hemoglobin | Interactive Biology, by Leslie Samuel. [ONLINE] Available at: http://www.interactive-biology.com/3955/function-and-synthesis-of-hemoglobin/. [Accessed 11 November 2012]. HBB - hemoglobin, beta - Genetics Home Reference. 2012. HBB - hemoglobin, beta - Genetics Home Reference. [ONLINE] Available at:http://ghr.nlm.nih.gov/gene/HBB#conditions. [Accessed 11 November 2012]. Elsevier. 2012. Elsevier. [ONLINE] Available at:http://www.sciencedirect.com/science/article/pii/S0021929010006329. [Accessed 11 November 2012]. The Molecular Biology of Sickle Cell Anemia. 2012. The Molecular Biology of Sickle Cell Anemia. [ONLINE] Available at:http://www.nslc.wustl.edu/sicklecell/part2/molecular.html. [Accessed 11 November 2012]. . 2012. . [ONLINE] Available at: http://www.jlr.org/content/38/12/2516.full.pdf. [Accessed 11 November 2012]. Sickle cell disease - Genetics Home Reference. 2012. Sickle cell disease - Genetics Home Reference. [ONLINE] Available at:http://ghr.nlm.nih.gov/condition/sickle-cell-disease. [Accessed 11 November 2012].  Hemoglobin - Life Sciences Foundation. 2012. Hemoglobin - Life Sciences Foundation. [ONLINE] Available at:http://lifesciencesfoundation.org/printer_events-Hemoglobin.html. [Accessed 11 November 2012]. Read More
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