Sickle Cell Anaemia Genetic Basis

Sickle Cell Anaemia is an autosomal recessive disorder which is passed through generations; meaning it is a hereditary disease. To inherit Sickle Cell Anaemia an individual must receive a mutated gene from both their paternal and maternal side. Those who only receive one mutated gene are said to be carriers of the disease but are not affected.

Sickle Cell Anaemia is most commonly found in Mediterranean countries which have African descent. According to (Hematology.org, 2019) Sickle Cell Anaemia affects 1 million to 3 million Americans and 8 to 10 percent of African Americans. Meaning that more than 100 million people worldwide are currently living with Sickle Cell Anaemia.

Sickle Cell Anaemia is caused by a mutation in the HBB gene also known as haemoglobin beta which is found on chromosome eleven, this codes for production of haemoglobin for red blood cells. The type of mutation that occurs is called a point mutation, this happens when a base sequence in the coding DNA has a base changed in its nucleotide sequence. The nucleotide base sequence which codes for the gene haemoglobin beta (HBB) is; GAG also known as guanine, adenine and guanine. However, the nucleotide base sequence in individuals with Sickle Cell Anaemia for haemoglobin is; GTG also known as guanine, thymine and guanine. These errors occur in the transcription stage of protein synthesis where the information from genes are taken and transcribed onto messenger RNA (mRNA) to be further transcribed at a later point in the process.

One the point mutation has taken place and the nucleotide sequence has been transcribed onto messenger RNA (mRNA), it is taken to the ribosomes in the cytoplasm of the cell where it can be translated into an amino acid. The transfer RNA (tRNA) carry the anticodon which is responsible for matching the correct complementary base sequence to the codon base sequence of nucleotides on the mRNA. Each anticodon is specific to one type of amino acid. This means that the bases on the mRNA strand is read in coding triplets, because every three bases codes for an amino acid. In saying this when the point mutation GTG; guanine, thymine and guanine was read by the tRNA it will have been given the anticodon CAC; cytosine, adenine and cytosine. This means that the amino acid produced is Valine rather than the Glutamic acid which is produced in the normal process of making haemoglobin. This mutated form of haemoglobin found in individuals with Sickle Cell Anaemia is called HbS. This change in protein sequence causes a change in structure of the haemoglobin causing the biconcave shape of the red blood cell to be disformed. This deformity is in the shape of a crescent.

The mutated amino acid Valine is positioned on the top of the protein structure meaning that once it loses oxygen there is a hydrophobic region on the Valine amino acid which can then react with large fibres of granular haemoglobin. This is what causes the distorted crescent shape of the red blood cells in Sickle Cell Anaemia. This crescent shape causes many disruptions in the function of the red blood cell as the biconcave shape is used for its large surface area to carry oxygen from the lungs to cells and carry carbon dioxide away from cells back to the lungs as a waste product. This sickle crescent shape decreases the surface area meaning less area for oxygen to diffuse out of the red blood cell into the body and less area to pick up waste carbon dioxide from the cells. This in turn can cause fatigue and weakness making daily tasks with this disease more challenging.

The crescent shape of the red blood cell is fragile meaning they often rupture and cannot serve their purpose. Also due to the extra fibres attached the red blood cells are less flexible and often get caught in the capillaries and cannot pass through causing blockages which slow down or stop the flow of red blood cells in that area. This can cause damage to organs and tissue due to a lack of oxygen which would have been carried on the red blood cell. Individuals may also suffer from swelling of the legs and arms due to blockages in the capillaries which can be painful.

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There is currently only one potential cure for Sickle Cell Anaemia; bone marrow transplant which is also known as stem cell transplant. This procedure requires the individual to find a donor of the same type of stem cells so that the transplant will be successful. Once a donor has been found stem cells can be extracted from the donor usually from the hipbone. This is then harvested into the patient with Sickle Cell Anaemia. Stem cells are undifferentiated cells meaning that they have the potential to change form and function depending on their location of origin. In successful cases the stem cells can correct the mutated gene for HBB and give fully functioning red blood cells. This treatment can be a very lengthy process in trying to find a matching donor, alongside its adverse side effects. Therefore, it is not used as a method of treatment in those under the age of sixteen years old.

There are other methods of treatment, although they are not cures, they help to reduce the severity of the symptoms for example, young children may take antibiotics to help resist against illnesses such as pneumonia which otherwise could be fatal to a young child with Sickle Cell Anaemia.

As suggested by Sickle Cell patients may also receive Hydroxyurea which is take orally daily to help to increase the number of haemoglobin in the body and reduce the need for blood transplants. However, studies have shown that this drug can increase the individual’s risk of infection and so long-term use can cause issues later in life. In saying this blood transfusions could be a more reliable source of treatment as it has less possibility of adverse health conditions, although the demand for blood could make this treatment less readily available.

Currently there is prospect of gene therapy being used to treat Sickle Cell Anaemia. Gene therapy is when individual’s defected genes are targeted and genetically engineered to produce a functioning gene by adding a functioning copy of the gene required. There are currently two strategies which both involve altering the individuals hemopoietic stem cells. As stated by these are stem cells found in the bone marrow which divide and specialise to produce different types of blood cells.

The first of the two strategies involves extracting the patients hemopoietic stem cells and replace the mutated HBB gene in these cells and replace it with the fully functioning gene for haemoglobin. One this is completed the stem cells would be harvested back into the patient using an inactive virus with hope that the steam cells would divide and differentiate with the ability to produce haemoglobin rather than the mutated version.

The second strategy involves genetically altering a different gene in the patients hemopoietic stem cells to enhance the production of foetal haemoglobin. This is produced by babies 3 months after conception until around 6 months old. This type of haemoglobin represses the production of sickling or ‘crescent shaped’ cells in patients with Sickle Cell Anaemia. However, people only produce very little amounts of these after infancy. The aim of this strategy is to increase production of foetal haemoglobin by using an enzyme to cut the section of DNA which supresses the production of foetal haemoglobin. This should then allow the cell to produce more foetal haemoglobin.