top-rated free essay

sickle cell anaemia

By naseemyezdan Nov 04, 2014 1640 Words

Introduction - sickle cell anemia
The first suggestion that genes might provide the information for all proteins came from Linus Pauling's lab at Caltech. He and his student Harvey Itano studied hemoglobin, the protein in red blood cells that transports oxygen from the lung to metabolically active tissues, like muscle, where it is needed. In particular, they focused on the hemoglobin of people with sickle-cell disease, also known as sickle-cell anemia, a genetic disorder common in Africans, and therefore among African Americans as well. The red blood cells of sickle-cell victims tend to become deformed, assuming a distinctive "sickle" shape under the microscope, and the resulting blockages in capillaries can be horribly painful, even lethal. Later research would uncover an evolutionary rationale for the disease's prevalence among Africans: because part of the malaria parasite's life cycle is spent in red blood cells, people with sickle-cell hemoglobin suffer less severely from malaria. Itano and Pauling compared the hemoglobin proteins of sickle-cell patients with those of non-sickle-cell individuals and found that the two molecules differed in their electrical charge. Around that time, the late forties, geneticists determined that sickle-cell disease is transmitted as a classical Mendelian recessive character. Sickle-cell disease, they therefore inferred, must be caused by a mutation in the hemoglobin gene, a mutation that affects the chemical composition of the resultant hemoglobin protein. And so it was that Pauling was able to refine Garrod's notion of "inborn errors of metabolism" by recognizing some to be what he called "molecular diseases." Sickle-cell was just that, a molecular disease. 1 in 10 African Americans has the sickle cell trait. A person with the sickle cell trait is heterozygous for the genetic allele of sickle cell anemia. This means that the person is a carrier for that allele but under normal circumstances does not show the symptoms associated with the disease sickle cell anemia. Sickle cell anemia is sometimes called a recessive disorder because the symptoms are usually evident only in persons homozygous for the sickle cell allele. Although this seems true due to the normal carrier phenotype this is not the case. Carriers are different in a person with sickle cell anemia in the fact that a person with the disease lacks no normal alleles while the carrier has a good allele that keeps the sickle cell hemoglobin from polymerizing under normal conditions. Carriers under extreme de-oxygenated conditions will exhibit similar characteristics to persons homozygous for the sickle cell anemia allele. Usually the HbS hemoglobin traits are not expressed enough to cause the carriers harm, but actually give a small protection to the carrier against malaria.

Homozygous hbA hbA - prone to malaria
Heterozygous hbS hbA- “heterozygote Advantage”- resistant to malaria and do not exhibit severe anemia due to sickle. Homozygous hb S hbS- Sickle cell anemia.
Hemoglobin, the red blood pigment, is a protein whose major function is to transport oxygen throughout the body. A molecule of hemoglobin is an 2 2 tetramer; that is, it consists of two identical chains and two identical chains. Hemoglobin is contained in the erythrocytes (red blood cells;Greek:erythros, red kytos, a hollow vessel) of which it forms 33% by weight in normal individuals, a concentration that is nearly the same as it has in the crystalline state. In every cycle of their voyage through the circulatory system, the erythrocytes, which are normally flexible biconcave disks,must squeeze through capillary blood vessels smaller in diameter than they are. In individuals with the inherited disease sickle-cell anemia, many erythrocytes assume an irregular crescentlike shape under conditions of low oxygen concentration typical of the capillaries. This “sickling” increases the erythrocytes’ rigidity, which hinders their free passage through the capillaries. The sickled cells therefore impede the flow of blood in the capillaries such that,in a sickle-cell “crisis,” the blood flow in some areas may be completely blocked, thereby giving rise to extensive tissue damage and excruciating pain. Moreover, individuals with sickle-cell anemia suffer from severe hemolytic anemia (a condition characterized by red cell destruction) because the increased mechanical fragility of their erythrocytes halves the normal 120-day lifetime of these cells. The devastating effects of this disease are such that, before the latter half of the twentieth century, individuals with sickle-cell anemia rarely survived to maturity. Sickle-Cell Anemia Is a Molecular Disease

In 1945, Linus Pauling correctly hypothesized that sickle-cell anemia, which he termed a molecular disease, is a result of the presence of a mutant hemoglobin. Pauling and his co-workers subsequently demonstrated, through electrophoretic studies, that normal human hemoglobin (HbA) has an anionic charge that is around two units more negative than that of sickle-cell hemoglobin. In 1956, Vernon Ingram developed the technique of fingerprinting peptides in order to pinpoint the difference between HbA and HbS.

Fig: oxyhemoglobin and deoxyhemoglobin center18923000

Ingram’s fingerprints of HbA and HbS revealed that their alpha subunits are identical but that their beta subunits differ by a vari- ation in one tryptic peptide. Sequencing studies eventually indicated that this difference arises from the re- placement of the Glu beta 6 of HbA (the Glu in the sixth posi- tion of each beta chain) with Val in HbS (Glu beta 6 S Val),thus accounting for the charge difference observed by Pauling. This was the first time an inherited disease was shown to arise from a specific amino acid change in a protein. 18859506223000

Single-Base Mutation Associated with Sickle-Cell Anemia Sequence for Wild-Type Hemoglobin GTG CAC CTG ACT CCT GAG GAG AAG TCT GCC GTT ACT
Val His Leu Thr Pro Glu Glu Lys Ser Ala Val Thr
Sequence for Mutant (Sickle-Cell) Hemoglobin GTG CAC CTG ACT CCT GTG GAG AAG TCT GCC GTT ACT
Val His Leu Thr Pro Val Glu Lys Ser Ala Val Thr

Fig; movement sickle cell causes friction
Fig :S fiber
This mutation causes deoxygenated HbS to aggregate into filaments of sufficient size and stiffness to deform erythrocytes a remarkable example of the influence of primary structure on quaternary structure. The x ray structure of deoxyhemoglobin S has revealed that one mutant Val side chain in each hemoglobin S tetramer nestles into a hydrophobic pocket on the surface of a beta subunit in another hemoglobin tetramer. This intermolecular contact shows hemoglobin S tetramers to form linear polymers. Aggregates of 14 strands that wind around each other form fibers. The fibers extend throughout the length of the erythrocyte. The hydrophobic pocket on the beta subunit cannot accommodate the normally occurring glu side chain, and pocket is absent in oxyhemoglobin. Consequently neither normal hemoglobin nor oxyhemoglobin can polymerise. In fact hemoglobin S fibers dissolve essentially instantaneously on oxygenation, so none are present in arterial blood. The danger of sickling is greatest when erythrocytes pass through the capillaries, where deoxygenation occurs. The polymerization of hemoglobin S molecules is time and concentration dependent, which explains why blood flow blockage occurs only sporadically.(sickle cell crisis). The Sickle-Cell Trait Confers Resistance to Malaria

Sickle-cell anemia is inherited according to the laws of Mendelian genetics. The hemoglobin of individuals who are homozygous for sickle-cell anemia is almost entirely HbS. In contrast, individuals heterozygous for sickle-cell anemia have hemoglobin that is 40% HbS. Such persons, who are said to have the sicklecell trait, lead a normal life even though their erythrocytes have a shorter lifetime than those of normal individuals. The sickle-cell trait and disease occur mainly in persons of equatorial African descent. The regions of equatorial Africa where malaria is a major cause of death (contributing to childhood mortality rates as high as 50%), sickle-cell gene is prevalent (possessed by as much as 40% of the population in some places).This observation led Anthony Allison to the discovery that individuals heterozygous for HbS are resistant to malaria, that is, they are less likely to die of a malarial infection.

Fig: S fibers spilling out of a ruptured erythrocyte. Malaria is one of the most lethal infectious diseases that presently afflict humanity: Of the 2.5 billion people living within malaria-endemic areas, 100 million are clinically ill with the disease at any given time and at least 1 million, mostly very young children, die from it each year. In Africa, malaria is caused by the mosquito-borne protozoan Plasmodium falciparum, which resides within an erythrocyte during much of its 48-h life cycle. Plasmodia increase the acidity of the erythrocytes they infect by 0.4 pH units and cause them to adhere to a specific protein lining capillary walls by protein knobs that develop on the erythrocyte surfaces (the spleen would otherwise remove the infected erythrocytes from the circulation, thereby killing the parasites). Death often results when so many erythrocytes are lodged in a vital organ (such as the brain in cerebral malaria) that its blood flow is significantly impeded. How does the sickle-cell trait confer malarial resistance?Normally, 2% of the erythrocytes of individualswith the sickle-cell trait are observed to sickle under the low oxygen concentration conditions found in the capillaries. However, the lowered pH of infected erythrocytes increases their proportion of sickling in the capillaries to 40%. Thus, during the early stages of a malarial infection, parasite-enhanced sickling probably causes the preferential removal of infected erythrocytes from the circulation. In the later stages of infection, when the parasitized erythrocytes are attached to the capillary walls, the sickling induced by this low oxygen environment may mechanically and/or metabolically disrupt the parasite. Consequently, bearers of the sickle-cell trait in a malarial region have an adaptive advantage: The fractional population of heterozygotes (sickle-cell trait carriers) in such areas increases until their reproductive advantage becomes balanced by the in viability of the correspondingly increasing proportion of homozygotes (those with sickle-cell disease).

Cite This Document

Related Documents

  • Sickle Cell

    ...Sickle cell disease is present usually in those of African or Mediterranean descent (Saladin 2007). About 1.3% of African Americans have sickle cell (Saladin, 2007). Sickle cell was originated in Africa where malaria was killing a vast number of people (Saladin, 2007). The sickle cell hemoglobin is not able to be digested by the parasites tha...

    Read More
  • Sickle Cell

    ...Sickle Cell Anemia is a hereditary disease that changes the smallest and most important components of the body. A gene causes the bone marrow in the body to make sickled shapes, when this happens; it causes the red blood cell to die faster. This is what causes Hemolytic Anemia. Older children and adults with sickle cell disease may experience a ...

    Read More
  • The Discussion on Sickle Cell Disease

    ...Sickle Cell Disease is an illness that affects people all across the globe. This paper will give a description of the sickness through the discussion of the causes, symptoms, and possible cures. Sickle Cell Disease (SCD) is a "group of inherited red blood cell disorders."(1) These disorders can have various afflictions, such as pain, damage and ...

    Read More
  • Genetics of Sickle Cell Anemia

    ...Genetics of Sickle Cell Anemia Objectives • To observe how a disease can act as a selective force • To describe changes in allele frequencies in a population as a result of a selective force Hypothesis The starting ratio of HbA to HbS is 3:1; in a typical population, the Homozygous Dominant Gene would become the standard, but because ...

    Read More
  • Sickle Cell Anemia

    ...Sickle Cell Anemia Sickle cell anemia is an inherited blood disease. The word anemia is defined as meaning that the blood does not have the required number of red blood cells. These cells take on a crescent shape, which is where the disease takes its name from the abnormal sickle shapes of the cells. It is commonly found in people from Africa, ...

    Read More
  • Sickle Cell Anemia

    ...Sickle Cell Anemia Pathophysiology: Sickle cell anemia is a disease passed down through families in which red blood cells form an abnormal crescent shape. The “sickling” occurs because of a mutation in the hemoglobin gene. Sickle cells are stiff and sticky. They tend to block blood flow in the blood vessels of the limbs and organs. B...

    Read More
  • Sickle Cell Disease

    ...09/08/2012 Sickle Cell Disease Blood has been considered the essence of life for centuries, and our blood is a living tissue made up of liquid and solids. There are many diseases related to blood such as anemia which is the decrease in oxygen supply to tissue and causes hypoxia, thalassemia is the mutation in one or more globin gene of hemoglo...

    Read More
  • Sickle Cell Disease

    ...Sickle-Cell Anemia is a genetic blood disorder caused by the presence of an abnormal form of hemoglobin. These hemoglobin molecules tend to aggregate after unloading oxygen forming long, rod-like structures that force the red cells to assume a sickle shape. Unlike normal red cells, which are usually smooth and malleable, the sickle red cells ...

    Read More

Discover the Best Free Essays on StudyMode

Conquer writer's block once and for all.

High Quality Essays

Our library contains thousands of carefully selected free research papers and essays.

Popular Topics

No matter the topic you're researching, chances are we have it covered.