Comparing two defects in red blood cells

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Use a table to briefly outline the different types of protein defects that can be associated with the red blood cell and briefly describe how these can affect the structure and function of the red blood cell. Choose two of these defects and compare and contrast them in detail.

The different varieties of cells that are part of the human blood rely heavily on erythrocytes. The erythrocytes play an important role in supplying the cells with much needed oxygen and getting rid of toxic gases such as carbon dioxide. [1] The erythrocytes are said to be distinctive in there structure and they are also unique in their properties which allow them to fulfil their essential functions. Erythrocytes are the main cells that are found in the blood, the structure of these cells are biconcave shaped discs and which have a crater like centre; this is found on both sides of the biconcave disc. This crater like centres allow there to be increased cell membrane surface area, this structure allows the cells to be more flexible when squeezing through small passages, the cells are able to go back to their original shape once they have changed. The contents of erythrocytes do not contain the usual organelles such as mitochondria, nucleus, Golgi body or any other organelles, however within these cells there is a structure called haemoglobins, these structures are composed of proteins and iron. These haemoglobins are responsible for transporting and picking up oxygen molecules and allow them to diffuse across membranes. [2] Different type of protein defects that are associated with red blood cells, these defects can have various different effects on the red blood cells which include the structure and function of the cell. These defects can be life threatening which may not have any solution or can be mediated using drugs which can be cured. [3]

The table below shows the different types of red blood cell protein defects that are out there and also shows a summarised version of the effects it has on the structure and function on these red blood cells.

Red Blood Cell protein defects

Effects on structure and function of Red Blood Cells

Hereditary spherocytosis

Causes sphere shaped red blood cells, prevent the movement of the red blood cells to changed shape properly and to transport oxygen around the body


Causes mutated haemoglobin production also does not allow Haemoglobin A2 from being produced. Prevent s oxygen to be picked up properly

Sickle cell anaemia

Causes sickle shaped RBC to be produced which are not able to pick and transport oxygen effectively

Hereditary Elliptocytosis

RBC elliptical shaped which will prevent oxygen to be picked up easily and will prevent transport of oxygen around the body to be limited leading to fatigue

Glucose-6-Phosphate Dehydrogenase Deficiency

X linked hereditary disease which prevents production of red blood cells leading to less oxygen to be transported around the body. Glucose-6-Phosphate Dehydrogenase play a very important in red blood cell synthesis

Pyruvate Kinase Deficiency

affects the survival of red blood cells and causes them to deform into echinocytes on peripheral blood smears

Autoimmune haemolytic anaemia

Individual immune system by mistake attacks the individuals RBC’s this is an autoimmune haemolytic anaemia this loss of blood prevents the efficient amount of oxygen to be transported around the body

Alloimmune haemolytic anaemia

In this mutation antibodies are synthesised against the individual red blood cells this can be due to mixing of blood between a pregnant women and her baby

One of the most common red blood cell membrane disorders is hereditary spherocytosis; this disorder is one of the most common found in Caucasians. [4] The usual characteristics of hereditary spherocytosis is the osmotically fragile red blood cells that are found and destroyed in the spleen, this leads to the loss of surface area in erythrocytes. This disorder also can cause the loss of ability of certain cells to change shape which is necessary for red blood cells function of transporting O2 to the rest of the body. [4]

However another similar red blood cell membrane disorder is thalassemia, this disorder is found in high numbers where malaria is prevalent and when there is a humid condition. Unlike hereditary spherocytosis, thalassemia is found in all races especially in Arabs, Asians and people who originate from the Mediterranean. [5] Abnormalities that are found in the membrane of the red blood cell proteins have been found to be the reason for the arsing of the above disorders which I will be looking into more detail below, some of these mutations are very similar and occur at the same point on the protein.

In hereditary spherocytosis the main mutations that have been identified are:

protein 4.2 defects,

spectrin deficiency alone,

combined spectrin and ankyrin deficiency,

band 3 deficiency,

And also KLF1 defect. [6]

Individuals with deficiency of protein 4.2 have shown to have hereditary haemolytic anaemia. The protein 4.2 is a cytoskeleton protein that binds to ATP and which also plays a part in the binding of protein 3 with ankyrin. This protein plays a major role in red blood cell shape and its properties.

The main mutations that cause hereditary sphereocytosis disorder are usally found on genes, ANK1, SPTB, SLC4A1, EPB42, SPTA1 and E339D which encode for ankyrin, spectrin beta-chain, the anion exchanger 1 (band 3), protein 4.2, spectrin alpha-chain and KLF1, respectively.[7][8]

Studies have shown that when there has been a mutation on gene SPTB which causes the encoding on the Beta chain of the spectrin this makes up 20% of the cases of hereditary spherocytosis and the mutation that occurs on ANK1 gene which encodes ankyrin makes up 50% of the disorders cases. The other genes that play a significant part in the number of cases of hereditary spherocytosis include SLC4A1 which encodes the band 3 protein will account for 15-25%. [7]

Recessive form of hereditary spherocytosis is associated with mutations of the alpha spectrin. However the mutations that occur on b-spectrin occur when there is an autosomal dominant form of hereditary spherocytosis. The formation of alpha spectrin is said to be in a lot higher rate than that of b-spectrin, this excess amount of alpha chains get broken down. Individuals that suffer from a-spectrin defects will produce enough amount of normal a-spectrin this will equal the amount of beta-spectrin production, however this is found only in heterozygotes. In the heterozygous state there is a lot higher chance of finding defects of beta-spectrin due to it being the limiting factor. Individuals that suffer from autosomal recessive type of hereditary spherocytosis will only obtain 40% of the average amount of spectrin; this is based on band protein 3. In autosomal dominant form of the disorder the level of normal spectrin is as high as 80%. [8][9]

The method in which the defect occurs is by mutation occurring on the codon 969, this will result in the substitution of alanine by aspartic acid, and this mutation causes the number of spectrin to decrease. This mutation will prevent the binding of ankyrin and also will not allow protein 4.1 to bind effectively either to the alpha and beta spectrin chains. [10] This will lead patients from suffering from symptom such as fatigue, jaundice or even death.

Another mutation that can occur which will lead to hereditary spherocytosis from occurring as mentioned above is if ankyrin defect occurs. Ankyrin are described as adaptor proteins that will regulated the binding of membrane proteins to the actin based membrane skeleton.

Another mutation that can occur which will lead to hereditary spherocytosis from occurring as mentioned above is if ankyrin defect occurs. Ankyrin are described as adaptor proteins that will regulated the binding of membrane proteins to the actin based membrane skeleton.

Ankyrin is the main binding site that is found on the erythrocyte membrane, this site where the mutation occurs, either the deletion of the short arm of chromosome 8 or the translocation of chromosome 8 occurs.[12] Individuals who suffer from this normally have shown to have decreased levels of ankyrin content. Studies have shown very interestingly that about 70% of people suffering with autosomal dominant hereditary spherocytosis have got deficiency in both ankyrin and spectrin. [13]

Research has shown in 2010 that mutation of E339D is the primary factor that is responsible for HS occurring. KLF1 primary role is to regulate definitive erythropoiesis by high affinity binding to CACCC elements within its erythroid specific target genes including those encoding erythrocyte membrane skeleton (EMS) proteins. [8] This study is still being trialled and has shown to have positive results on mice this is the first time there has been any link between KLF1 mutation with any human disease and also first time to be linked with hereditary spherocytosis.

In thalassemia the main mutations that have been identified are:

Alpha thalassemia

Beta thalassemia

and Delta thalassemia

Beta thalassemia is a heterozygous carrier it has one of the beta globin genes that are defective. This disorder can occur due to reduced production of B-globin or can be due to the absence of any B-globin proteins. The mutation that occurs on the gene is due usually to a nonsense mutation that can occur on the B-globin gene. [14]However in homozygote carriers the synthesis of the chains is hugely limited due to there being a mutation on both genes. [15[This irregular balance leads to anaemia from occurring, this odd balance of alpha and beta globin chains leads to the formation of small objects that cause the damaging of red cell membranes. [16]

The mutation that occurs on alpha globin causes alpha thalassemia which causes deletions of parts of the alpha globin genes. This can also cause the prevention of Haemoglobin from functioning effectively due to several reasons which include point mutations, nonsense mutations and chain termination mutations. Studies have highlighted that these mutation may cause unstable a-chain variants or they may play a major part in the intuition of mutated mRNA translation. [17][18]

Haemoglobin consist of both alpha and beta chains however within the structure there is about three % of alpha and delta chains. [19]As mentioned above mutations may occur which neither will not allow the specific gene to produce delta chains. Any mutation that occurs that does not allow the production of delta chains are known as delta0 mutation and the mutation which causes the depletion of delta chain is labelled as delta+ mutation. [20] If an individual inherits two homozygotes’ chains of the genes which prevent the production of delta chains then there is no synthesis of hemoglobin A2 this mutation usually occurs on the 69 position on the chromosome. However a person who inherits just one of these mutated genes then they will have decreased levels of hemoglobin A2. [21]

The similarities between the two different disorders are very limited as thalassemia mutations cause hemoglobin structure to be altered to prevent the proper function of the structure; however the hereditary spherocytes causes the change of the structure of the red blood cells cytoskeleton which will prevent the red blood cells from functioning properly. Both of these factors structurally affect the red blood cells differently but cause the lack of the function which more or less does the same thing. This is quite clear also from the similar symptoms that the individual may suffer from both cases of these diseases which include splenomegaly, anemia, jaundice, fatigue, headaches and much other similar type of symptoms. We can see even though there is much different type of mutations that do occur under the banner of hemolytic anemia which will cause the same thing for the individual which is to prevent the red blood cells from functioning in the correct many that it should. This can also be further confirmed by looking at the table which clearly shows the structural differences each of the mutations cause however all of the function that are loss are all the same.