78 Sickle Cell Mutation

Key Idea: A point mutation to the HBB gene causes the production of an abnormal haemoglobin molecule. Two copies of the mutation must be inherited for a person to have sickle cell disease. Sickle cell disease is an inherited blood disorder caused by a gene mutation (Hbs), which produces a faulty β-chain haemoglobin protein. People with one copy of the gene are carriers of the sickle cell trait, but do not have the disease. Carriers (heterozygotes) usually only display symptoms when subjected to low oxygen concentrations. Under these conditions, the red blood cells take on a sickle shape. People with two copies of the Hbs mutation suffer from sickle cell disease. The disease causes many complications and results in a shortened life expectancy.

Normal red blood cells

Normal haemoglobin produces normal red blood cells Mutant haemoglobin produces sickle-shaped red blood cells

Sickle cells

Each red blood cell (RBC) contains about 270 million haemoglobin molecules. In their normal state, the red blood cells have a flattened disc shape which allows them to squeeze through capillaries to offload their oxygen to tissues.

The HBB Gene

The gene coding for the β-chain of haemoglobin is on chromosome 11.

p

HBB gene

First base A functional haemoglobin molecule is made up of two α-chains and two β-chains.

β-chain haemoglobin

Substituted base: A

q

DNA

Code corresponding to the 1st amino acid

This sequence is the beginning of the DNA template strand for a normal β-chain of haemoglobin (excluding start sequence TAC). The sickle cell mutation involves the substitution of one base for another in the HBB gene, causing one amino acid to be altered. This new amino acid is hydrophobic rather than hydrophilic, which makes the Hb collapse in on itself when deprived of oxygen.

1. What effect does the Hbs mutation have on haemoglobin?

2. (a) Describe the effect of inheriting two copies of the Hbs mutation:

The mutated form of haemoglobin has reduced solubility and precipitates when deprived of oxygen. This deforms the red blood cells giving them a rigid sickle shape, which prevents their movement through capillaries.

Sickle cell disease

People with two copies of the Hbs mutation are homozygous and have sickle cell disease. They have a reduced life expectancy and suffer from numerous health issues. Sickled cells are broken down, resulting in low haemoglobin levels and reduced oxygen transport, so sufferers are tired and short of breath. Sickled cells can also become stuck in blood vessels and can block oxygen transport to organs and tissues.

Sickle cell trait

People with one copy of the Hbs mutation are heterozgous for the trait. The Hbs mutation is codominant (both alleles are equally expressed) so both normal and abnormal haemoglobin is produced. People with sickle cell trait usually do not suffer any complications.

(b) Describe the effect of inheriting a single copy of the Hbs mutation:

(c) Why is it possible for a carrier to have normal and abnormal haemoglobin?