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Diseases caused by mutations

Sickle cell anaemia is a disease characterised by sickle-shaped red blood cells.

It is caused by abnormal haemoglobin proteins that are the result of a single base substitution in the haemoglobin gene.

This single base substitution is a missense mutation.

The 6th amino acid in the haemoglobin protein, normally glutamic acid, is replaced with valine in sickle cell anaemia. This change alters the overall structure of the protein.

Sickle cell anaemia reduces the ability of red blood cells to pick up oxygen and causes the cells to stick together, causing pain and reducing blood flow.

It is a life limiting disease and includes respiratory and vascular complications.

A sickle cell is seen among more normally shaped red blood cells.
A sickle cell is seen among more normally shaped red blood cells.

Sickle cell anaemia is a recessive disorder: only people who carry two copies of the mutant allele (i.e. homozygous) have the symptoms.

People who are heterozygous (carry one mutant allele) for the sickle cell anaemia gene have some protection against malaria, yet do not have the full symptoms of sickle cell anaemia.

There is very high prevalence of sickle cell anaemia in populations from regions where malaria was historically common because the mutant allele confers an evolutionary advantage in these regions. Malaria has now spread to other areas such as South America, but the allele is not present in these populations.

Only 0.005% of babies are born with sickle cell anaemia in the UK. However, in countries such as Nigeria where malaria is endemic, this number can be as high as 2%.

The historic distribution of malaria is shown on the left, and the distribution of the sickle cell trait is shown on the right.
The historic distribution of malaria is shown on the left, and the distribution of the sickle cell trait is shown on the right.

Cystic fibrosis is a life limiting disease caused by a mutant trans-membrane protein.

The protein usually transports chloride ions into the mucus that lines the cells.

These chloride ions are linked to water molecules. When the chloride ions are transported through the membrane, some of the water molecules become bound to the mucus, making the mucus more fluid.

The mutant transporter does not function correctly, so mucus becomes sticky and builds up. This prevents cells from functioning properly.

A build-up of bacteria in the mucus leaves the patient susceptible to infections.

The mutant protein is most commonly caused by a three base deletion that prevents the synthesis of the amino acid phenylalanine (Phe). There are over 1000 other rare mutations that in total make up 30% of cystic fibrosis cases.

Cystic fibrosis affects the lungs, liver, pancreas and the intestines. The damage to these organs is often so severe that many sufferers need organ transplants.

As with sickle cell anaemia, cystic fibrosis is a recessive genetic disorder.

Around 1 in 30 people are heterozygous carriers, i.e. they carry just a single copy of the mutant allele and do not exhibit symptoms.

A person with cystic fibrosis must have both copies of the mutant allele.

Cystic fibrosis carriers may have some resistance to cholera, but this has not been confirmed.

Cystic fibrosis is most common among European populations.