What type of mutation causes sickle cell anemia

Sickle cell disease (SCD) is a genetic disorder caused by a mutation in the HBB gene. This gene provides instructions for the body to produce a part of hemoglobin. Hemoglobin is a protein that carries oxygen throughout the body.

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What is the HBB gene?
How is the HBB gene mutated in sickle cell disease?
Figure 1: Hemoglobin S (HbS) genetic and phenotypic mutations
Figure 2: Gene inheritance probability for sickle cell disease

A mutation in the HBB gene causes hemoglobin to clump together and change the shape of red blood cells. This can lead to anemia and blocked blood flow for people with SCD.

SCD can only be inherited if each parent passes down a mutated HBB gene. This means it is a recessive trait. It also means a person cannot get SCD later in life.

What is the HBB gene?

The term “gene” means a segment of DNA that contains instructions for the body to make a specific protein. HBB is the name of the gene that encodes, or gives instructions to, one of the protein pieces that make up hemoglobin. These pieces are called “globins.”1

Hemoglobin is made up of 4 globins, which each carry a molecule of oxygen. Normal hemoglobin, called hemoglobin A (HbA), is made up of 2 “alpha globins” and 2 “beta globins.” Alpha globin is made with instructions from HBA genes. Beta globin is encoded by the HBB gene.1,2

How is the HBB gene mutated in sickle cell disease?

Genes are made up of a string of pieces called “nucleotides.” The body’s cells use the specific order of nucleotides as a template to make a specific protein. Proteins are long strings of fragments called “amino acids.” Mutation of a single nucleotide on the HBB gene causes a single amino acid mutation on the beta-globin protein. This is an example of a “missense mutation.”

Sickle hemoglobin, also called hemoglobin S (HbS), is the most common form of abnormal hemoglobin. It has 2 normal alpha globins but contains 2 sickle beta globins. Sickle beta-globin has an amino acid called “valine” instead of an amino acid called “glutamic acid” at a specific location in the protein. Other forms of abnormal hemoglobin are caused by different mutations in the HBB gene.1

Figure 1: Hemoglobin S (HbS) genetic and phenotypic mutations

The mutation in beta-globin causes hemoglobin to cluster together and misshape the red blood cells. This leads to the symptoms and complications experienced by people with SCD. Blood tests can identify HBB mutations and abnormal hemoglobin.3

The body’s genome, or complete set of DNA, is stored on large molecules called chromosomes. We have 2 copies of 23 chromosomes, with 1 copy coming from each parent. This means we inherit 1 copy of every gene from each parent. However, mutations may cause each copy to have a slightly different nucleotide sequence. Different variants of the same gene are called “alleles.”

Alleles can either be dominant or recessive. Dominant alleles cause a specific trait no matter what the other allele is. Recessive alleles lead to a specific trait only when paired with the same allele.

SCD is a recessive trait because people must inherit 2 copies of the mutated HBB allele to show symptoms. The most common form of this is sickle cell anemia, which occurs when someone inherits 2 copies of the sickle HBB allele. If someone receives 1 copy of the mutated HBB allele and 1 copy of the normal HBB allele, they are a carrier and have “sickle cell trait.”However, they usually do not show symptoms of SCD.4

There are 3 ways that can lead to a child having SCD:5

If both parents have sickle cell trait
- There is a 25 percent chance the child will have SCD
- There is a 50 percent chance the child will have sickle cell trait
- There is a 25 percent chance the child will not have either condition

If 1 parent has SCD and 1 parent has sickle cell trait
- There is a 50 percent chance the child will have SCD
- There is a 50 percent chance the child will have sickle cell trait

If both parents have SCD
- The child will have SCD with 100 percent certainty

Figure 2: Gene inheritance probability for sickle cell disease

The HBB gene is located on chromosome number 11. This is not the sex chromosome, so SCD is not a sex-linked disease. This means that both men and women can get SCD.6

Written by: Matthew Zajac | Last reviewed: January 2021

Sickle cell anaemia is an inherited blood disorder in which red blood cells develop abnormally.

Sickle cell anaemia is caused by a mutation in a gene called haemoglobin beta (HBB), located on chromosome 11.
It is a recessive genetic disease, which means that both copies of the gene must contain the mutation for a person to have sickle cell anaemia.
If an individual has just one copy of the mutated gene they are said to be a carrier of the sickle cell trait.
If both parents are carriers there is a chance their child could be born with sickle cell anaemia.

The HBB gene codes for haemoglobin, a protein in red blood cells that carries oxygen around the body .
A mutation in HBB results in a change in one of the bases in the DNA sequence from an A to a T.
This then changes the amino acid in the haemoglobin protein from glutamic acid to valine.
This causes the body to produce a new form of haemoglobin called HbS, which behaves very differently to regular haemoglobin (HbA).
HbS causes the red blood cells to develop abnormally and become sickle-shaped (rather than the usual doughnut shape), harder and less flexible.
This means that they can become stuck in the blood vessels, causing blockages.

Illustration showing the difference between normal red blood cells and sickle red blood cells.
Image credit: Genome Research Limited

Symptoms

The symptoms of sickle cell anaemia vary considerably from person to person.
Pain develops when sickle-shaped red blood cells block the flow of blood to the chest, abdomen and joints.
These spells of pain are called ‘sickle cell crisis’ and can last anything from a few minutes to several months.
Symptoms can have a significant impact on quality of life and can lead to life-threatening complications such as:
- stroke: where the supply of blood to the brain becomes blocked.
- acute chest syndrome: where the lungs suddenly lose their ability to breathe in oxygen as a result of sickle cells blocking blood vessels in the lungs.
- increased risk of infection: sickle cell anaemia can damage the spleen, a key organ involved in fighting infection.
- pulmonary hypertension: where sickle-shaped red blood cells block the flow of blood from the heart to the lungs causing the blood pressure in these vessels to become dangerously high.
Sudden deterioration may be characterised by:
- high body temperature of 38˚C or above
- severe pain that cannot be controlled with paracetamol or ibuprofen
- difficulty breathing.
Methods to deal with sickle cell anaemia have improved dramatically in recent years, so serious complications rarely occur and people now live much longer than they used to.
40 years ago, few people lived past their teenage years and many died before the age of two years. The main cause of death was bacterial infection.
Now, most affected people are expected to live to about 40 or 50 years old. The main causes of death are infections and stroke.

Diagnosis

Sickle cell anaemia is diagnosed using a blood test which detects the presence of the abnormal HbS haemoglobin in the red blood cells.
In children the blood is taken by pricking a finger or heel.
In adults the blood is drawn from a vein in the arm.
The blood sample is analysed to see if the abnormal HbS haemoglobin (rather than normal HbA haemoglobin) is present.

Treatment

Most treatments aim to treat the individual symptoms of sickle cell such as anaemia.
Treatment plans require a number of different healthcare professionals working together, such as haematologists (specialists in blood disorders), clinical psychologists, social workers and physiotherapists who can help patients with pain monitoring and relief.
Regular blood transfusions can help reduce the risk of complications, such as stroke, by up to 90 per cent.
However, chelation therapy may need to be given after transfusion to remove excess iron from the patient’s body. This excess iron can lead to complications including liver cancer, diabetes and infections.
Daily antibiotics, such as penicillin, are often given to help protect against serious infections in children aged under five years.
Pain relief is provided to reduce the pain associated with sickle cell crisis.
Lifestyle advice, such as drinking plenty of fluids, is given to help reduce the risk of sickle cell crisis.
If individuals continue to experience pain, a medication called hydroxycarbamide may be offered, to be taken once a day.
- This drug works by stimulating the body to produce another type of haemoglobin, called foetal haemoglobin.
- Foetal haemoglobin is not affected by the mutation that causes sickle cell anaemia.
- Foetal haemoglobin can substitute for the adult haemoglobin to carry oxygen around the body and help reduce the risk of a sickle cell crisis occurring.
The risk of an individual developing complications can also be assessed to help prevent them occurring.
- A child’s risk of a stroke can be assessed using a test known as a Transcranial Doppler scan that measures the rate of blood flow in blood vessels in the head and neck, which supply blood to the brain.
- If the arteries are narrow, which can increase the risk of having a stroke in the future, blood travels faster and makes a high pitched noise that can be detected by the scanner.
Blood and bone marrow stem cell transplants may offer a cure for a small number of people.

Screening

In the UK, all pregnant women are asked to answer a questionnaire to assess their risk of carrying a baby with sickle cell anaemia.
Pregnant women may also be offered a blood test to find out if they are a carrier of the faulty HBB gene that causes sickle cell anaemia.
If they are found to be a carrier, the baby’s father is then offered a blood test too.
If both parents are carriers there is a chance the baby will be born with sickle cell anaemia.
All babies in the UK are tested for sickle cell anaemia after birth through the heel-prick newborn screening test.
Anyone from at risk groups having a general anaesthetic is tested for sickle cell anaemia. This is because general anaesthetic reduces the amount of oxygen in the blood, which could be dangerous for someone with the condition.

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