Sickle cell anaemia

Sickle cell anaemia is an autosomal recessive disorder, which leads to deformation of the shape of the red blood cells, preventing the cells from being able to travel through small blood vessels. This deprives organs and tissues of oxygen. Sufferers experience severe pain, referred to as a crisis and the condition can lead to other serious medical problems.

Genetics  

Sickle cell is a genetic disorder caused by a mutation in the amino acid sequence coding for the haemoglobin gene in red blood cells. . The haemoglobin molecule is a tetramer with two alpha subunits and two beta subunits. The mutation occurs in the beta subunit when a valine(V) replaces glutamate(E) in position 6 of the beta subunit. phenylalanine 85 and leucine 88 - which are both non-polar hydrophobic amino acids on the gene - form a socket in which the valine side chain can fuse. This is possible because valine is also hydrophobic unlike glutamate and so form sticky ends with the hydrophobic leucine and phenylalanine, thus resulting in a polymerisation of the molecule which alters the tetramer structure of haemoglobin. The mutation is known as HbS, the normal haemoglobin is referred to as HbA.

Effects of the HbS Mutation

When red blood cells with the wildtype form of the gene (HbA) are subjected to low oxygen concentration the haemoglobin in the cell remains fully functional. However, in cells with the HbS mutation the haemoglobin polymerizes in environments where oxygen concentration is low. The haemoglobin polymers are responsible for the change in red blood cell shape; the cells become long, sickle shaped and fragile. The sickle cells do not deliver oxygen to tissues with the same efficiency as normal blood cells, and they often get caught in small blood vessels leading to blockages. This causes extreme pain and leads to damage of major organs such as the brain, heart, kidneys and muscles.

Inheritance   

Sickle cell is a recessive autosomal disorder, therefore two defected genes are needed (SS) for sickle cell anaemia. If one parents were to be a carrier of the gene, (SA), each child would have a 25% chance of inheriting two sickle cell genes, 25% chance of inheriting two normal genes, and 50% chance of becoming a carrier like the parents.

Sickle-Cell Trait

When people carry both the HbB gene and the mutated HbS gene they are said to have sickle-cell trait. They are relatively unaffected by the symptoms associated with sickle cell anaemia, however they can pass the HbS mutation onto their offspring. The interesting point here is that people with sickle-cell trait are resisitant to malaria. The reason for this higher resistance is because the plasmodium falciparum parasite that is responsible for malaria grows poorly in sickled cells. This means that in a carrier a proportion of the parasite will affect the sickled cells, rather than the normal red blood cells. A high proportion of the parasite attempting to grow in Sickled cells will not survive, so there will be a lower concentration of P.falciparum to affect the normal cells and this gives the carrier a higher probability of surviving the attack. HbS is hence thought to be reccessive for SCD, but dominant for Malaria resistance.

The lethal nature of malaria and its prevalance in West Africa goes towards explaining the prevalance of the HbS allele in West African populations (1 in 100 West Africans being Sickle Cell Anaemia sufferers), due to  the presence of the HbS allele favouring the survival of its carriers .