Protein Defects That Can Be Associated With The Red Blood Cell Biology Essay

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Red blood cells are the mostly found cell in blood. Their main function is to transport oxygen around the whole body. Tissues and body organs are all depend on the RBC's to supply them with oxygen. If the circulation is blocked the tissue dies. Red blood cells are also known as "erythrocyte" which means "red hollow" from Greek. Red blood cells attains its red colour from hemoglobin that constitute around 97% of the RBC's dry weight, and about 35% of the whole weight, with water.

Hemoglobin is a metalloprotein that is iron-rich and has many chemical apertures for oxygen storage. This feature allows hemoglobin to carry a large amount of O2 for distribution. Red blood cells become oxygenated in the lungs, and back to the heart where the flow starts to the extremities. According to Moore et al (2010) "Red blood cells lack a nucleus, mitochondria and they are much thinner in the middle forming a biconcave shape. Therefore they have the ability to travel through the smallest capillaries". Without this nature of flexibility, they have a high chance of getting stuck and cause obstructions in the circulation.

The red blood cell varies in size and colour. They are around 7um in diameter. Deoxygenated blood has bluish color, while oxygenated blood looks red. The second important function to transporting oxygen and less known is the capability of red blood cells to carry carbon dioxide that is formed due to metabolism in every cell in the human body.

The structure and components of the red blood cell membrane are responsible for the physiological functions and mechanical properties of the cell. A defect in any of these components may cause a dysfunction of RBC leading to serious disease. The red cell membrane consists of double lipid bilayer, various proteins and an internal membrane skeleton which provides the RBC with its biconcave shape. The skeleton is formed by a multi-protein complex including alpha and beta spectrin, ankyrin, protein 4.1 and actin.

Fig 1: The red blood cell membrane structure. [1]

The above diagram shows the red cell membrane illustrating the interaction between phospholipids and the proteins. Horizontally, alpha and beta spectrin of the cytoskeleton interact forming tetramers which then becomes linked to the cytoplasmic domin of band 3 by ankyrin (ventricle interaction). The 4.1 protein enhance the interaction between band 3 and ankyrin. The ends parts of the tetramers are then interact to actin, tropomodulin, tropomyosin and adducin.


Normal red blood cells are deformable concave disks. The external environment of the cell, the metabolic activity of the cell, the nature of hemoglobin, the membrane skeleton and the age of the cell determine the shape of the cell. Cavendish (2008:13) stated that "The red blood cells last about 120 days, until they are eventually removed by the spleen". If the RBCs tend to get destroyed very quickly than usual by disease, then the bone marrow will produce to compensate the lost cells to take the place of new red cells. But if RBCs are deformed by any reason the person can suffer from various diseases. Some defects in red cell membrane proteins have been observed as follows; (1) spectrin deficiency alone, (2) combined spectrin and ankyrin deficiency, (3) band 3 deficiency, and (4) protein 4.2 defects.(5)protein 4.1 deficiency.

Table 1: Protein deficiency associated with red blood cells and genetic information

Protein Defect


Genetic Information

Spectrin deficiency

Hereditary elliptocytosis

-Hereditary elliptocytosis (HE) is a congenital hemolytic disorder in which erythrocytes get elongated into a cigar or oval shape.

-Chromosome location 1q22-q23.

-Mutations that obstruct the formation of spectrin tetramers result in hereditary elliptocytosis.

-Symptoms are hemolytic anemia, gall stones and fatigue.

Ankyrin deficiency

Hereditary Spherocytosis

-Hereditary spherocytosis is a congenital haemolytic anemia caused by a defect in several proteins including ankyrin.

-Chromosome location: 8p11·2

-Symptoms are Severe anaemia, jaundice, splenomegaly and cholelithiasis.

Band 3 deficiency

Sickle cell disease

-Sickle cell disease possesses red blood cells that consist of abnormal hemoglobins (oxygen poorly), forming a crescent shape cells.

-Chromosme location: 11p15.5.

-Sickle cells are destroyed rapidlyin the effected individual causing anemia, jaundice and the formation of gallstones plus to other clinical features.

Protein 4.1 deficiency

Hemolytic anemia


-In the cause of hemolytic anemia, the RBC's are destroyed and excreted from the bloodstream before their usual lifetime.

-Chromosome Location: 1p36 - 2p34.

-Symptoms: fatigue, arrhythmias (ah-RITH-me-ahs), pain, cardiomegaly and high bilirubin in plasma.

Protein 4.2 deficiency


-In splenomegal the spleen is enlarged. This can lead to cirrhosis and chronic infections.

-Hypersplenism is observed in patients with splenomegaly and also cytopenias and anemia.

-Chromosome Location q15-q21

Glycphorin C deficiency


-In hereditary ovalocytosis, the blood cells are slightly oval-shaped instead of round.

-Symptoms: in new born infants anemia and jaundice are common. While in adults, it's asymptomatic.

Diseases caused by protein defect in red blood cells

G6PD deficiency.

Glucose-6-phosphate dehydrogenase deficiency is the most common genetic disorder worldwide. This condition is caused due to the lack of the enzyme G6PD or a decrease in the production. The defect in making this enzyme may lead to impaired production of the molecules NADPH and NADP affecting the metabolic pathways in the human body. A decrease in the generation of NADPH molecules can affect the level of glutathione (GSH) leaving RBC's exposed to the toxic effects of O2, which in turn lead to the breakdown of RBC's prematurely (hemolysis). The G6PD gene is located in the X chromosome at the q28 locus (Moore et al, 2010). Mehta and colleagues stated that conditions such as electrolyte imbalance, membrane cross bonding and erythrocyte

Phagocytosis, are results of G6PD deficiency. G6PD deficiency is a widely seen hereditary disease among people of African, Southeast Asian and Mediterranean descent. According to Smith(2004:56-60)"G6PD is found among people who live ,or whose ancestors lived in regions of world where malaria is, or has been ,endemic".

People with Glucose-6-phosphate dehydrogenase deficiency may develop chronic hemolytic anemia as well as jaundice in new born. Other factors can also induce the hemolytic anemia such as infections and drugs.

Hereditary Spherocytosis

Hereditary spherocytosis is a disorder in which red blood cells lose their appearance producing spherical like shape, and becomes fragile due to the instability of the cytoskeleton in the red cell membrane resulting from several mutations in the membrane proteins that are involved in the vertical interaction such as ankryn, spectrin (α and β), band 3 and protein 4.2. These round and fragile cells have a reduced lifespan (between 6-20 days) comparing to 120 days in normal RBCs and have a difficulty to pass through certain organs (splenic microcirculation). Therefore, they remain in the spleen longer than normal red blood cells, leading to spleen damage. This membrane damage can reduce the cellular deformability as well as the membrane surface to volume ratio.

Fig 2: The effect of hereditary Spherosytosis

Diagram obtained from Perrotta et al (2008) quoted from Gallagher and colleagues.

Perrotta et al, (2008) stated that Hereditary spherocytosis is most commonly seen in people of northern European and North America with prevelance of 1:2000 and less common in African-American and the southeast.

Pyruvate kinase deficiency

Pyruvate kinase deficiency (PKD) is one of main second seen enzymatic defects of the RBCs following G6PD deficiency due to mutation on the PLKR gene that is located in chromosome 1, or due to protein instability. This disorder is clinically known as a hemolytic anemia sometimes as a result of condition. Zanella and collegues stated that PKD has a prevelance of 1:20.000 in the general white population as the gene frequency studies showed and is transmitted in an autosomal-recessive manner. With inherited hemolytic anemia, more than one gene that controls the production of RBCs becomes faulty. PK is a very important enzyme for the yield of pyruvate and ATP molecules by glycolysis which provides erythrocyte with oxidant defence and regulates the carrying of O2. A defect in the PK activity can cause a decrease in the number of these molecules which are needed for the red blood cells role and survivals. Some patients who are affected with PKD develop no symptoms. However, in some other serious cases, this disorder can cause angina, cardiopulmonary decompensation or death.

Sickle cell anemia

Sickle cell anemia is inherited an autosomal recessive disorder resulting from a defect in the hemoglobin β-gene (HBB) present in the short arm of chromosome 11(11p15.5) resulting the RBCs to die before their expected lifespan and not replaced with normal cells fast enough.

Hemoglobin is responsible for carrying O2 inside RBCs and gives them their red color. Normal hemoglobin becomes defected due to the replacement of the amino acid glutamine in position 6 with valine, producing hemoglobin sickle (HbS). When HbS polymerize, Sickle cell anemia is developed. The function of normal hemoglobin molecule is to pick up as much O2 from lungs and become oxygenated in erythrocytes and give it away to tissues when RBCs get to the peripheral sites. However, in the case of sickle hemoglobin, the molecules form a long chain like structure as they tend to hold together. Thus, the shape of RBCs alters forming sickle like shape. The change of the structure may destruct the transportation of the cells through the capillaries causing them to cluster in one place blocking the blood vessels leading to other complications too.

Millions of people are affected by sickle cell worldwide. However people from African America are the most vulnerable to disease with prevalence of 1 in 500 births.


Thalassemia is another type of genetic blood disorder which is inherited from parents due to a mutation in α or β gene in the hemoglobin protein. Thalassemia can be divided into two different types according to the defected gene. It can be either alpha-thalassemia where α globin gene is altered or fully absent, or beta-thalassemia in which the production of β globin gene is hampered.

Thalassemia conditions can affect the number of RBCs from the bone marrow and their role. Thus people with this disorder normally show a smaller size and a decreased level of erythrocytes in their bloodstream compared to healthy person. This can cause damage to the organs and tissues in the body as they are not getting enough oxygen.

Thalassemia disorders are found most often among people of Middle Eastern, Italian, Greek, Asian, and African descent. Many cases are diagnosed in early childhood and remain as lifelong condition. Treatments for thalassemias have seen a great improvement in recent years. Complications from thalassemias are nor uncommon and their treatments are more frequent.

Comparison and contrast of Pyruvate kinase deficiency and sickle cell disease


The pyruvate kinase deficiency and sickle cell disease have a common point where both are resulting of a defect in red blood cell and causing anemia. Pyruvate deficiency occurs when the protein pyruvate kinase is deficient in the red blood cell due to the destruction of hemoglobin. Thus affecting the survival of RBCs. whereas sickle cell happens when the hemoglobin in the RBCs become mutated and take the shape of sickle "C" causing an obstruction to the function of the cells. Both Pyruvate kinase deficieny and sickle cell disorders are hereditary conditions that are passed on from parents to the child.

In pyruvate kinase deficiency the body attacks the red blood cells where the hemoglobin is destroyed, whereas in sickle disease the hemoglobin is formed defective. Both cases occur when there is mutation in the hemoglobin genes. There are also similarities in the symptoms of both diseases like fatigue and jaundice. People suffering from pyruvate deficiency also suffer from anemia like sickle cell disease. Severe anemia need blood transfusion in both cases. However, this can make the infected individual very ill and fragile. Since PKD lead to the breakdown of RBCs and sickle cell alter the shape of the red molecules as a result of hemoglobin defect, a decreased level of hemoglobin is seen.

In sickle cell disease the blood cells cluster together and shut the blood vessels as cells does not move easily along the blood vessels. They become stiff and sticky and form clumps and tend to get stuck in the blood vessels. While in pyruvate kinase deficiency the RBCs are left with very low energy due to the decreased number in generating ATP molecules. Thus, they get breaking down more quickly and not enough new cells replacing them. This comparison in the biochemical processes shows that each disorder has its clinical effect on RBCs.

These two blood disorders may lead to other serious complications. For example, a person affected with pyruvate kinase deficiency may develop cardiovascular disease; however, cases of death are low. Unlike a person with sickle cell anemia it can cause damage to organs of the body and it can turn out fatal. Bloom(1995:25)states that "The large proportion of sickle cell disease cases occur among black, both in Africa and in countries with slave-trading history". But pyruvate deficiency is seen in all races, worldwide.


The diseases occur due to red blood cell defect, have various reasons. Some are hereditary and some are acquired. But mostly, the defects in the protein of RBCs are due to hereditary factor and can tremendously affect the health of a person. Some studies have stated that these syndromes are significant genetic heterogeneity". Lots of treatments are now available for most of the disease and people can live healthily once encounter with diseases. Blood is the life of human being and any deficiency in blood can be a very dangerous for life.

Bone marrow transplantation is available for patients who are diagnosed with genetic blood disorders that do not have an HLA-matched sibling donor. The study treatment plan makes use of new transplant treatment plan that aims in lowering toxicities and complications associated with the normal treatment plans. The blood stem cells will be obtained from either not related donor or unrelated umbilical cord blood. So medical field is growing and this is definitely a positive sign for patients of red blood cell diseases.