5.1 Sickle cell anaemia
Sickle cell anaemia gets its name from the abnormal shape of the erythrocytes, which resemble that of an old farming tool, the sickle (Figure 13). This shape is due to a single nucleotide substitution (A to T) that converts a glutamic acid codon (GAG) into a valine codon (GUG) in the beta chains of Hb.
Activity 9 RNA codon wheel
Take a look at this interactive RNA codon wheel. If you click on an amino acid, the diagram will highlight the corresponding nucleotides. You can view some further information and chemical structures for each amino acid. When you’ve done this, use the diagram to answer the question underneath.
Which nucleotide substitution would still result in a functional Hb protein?
GAG → GCG
GAG → GAA
GAG → CAG
The correct answer is b.
Correct. Both GAG and GAA are codons for glutamic acid. Therefore, substitution of G by A will still produce a functional Hb protein.
Sickle Hb is denoted as HbS. Because glutamic acid is negatively charged, these amino acids would normally repel each other and help the Hb retain its shape. However, these repulsive forces are absent in the HbS because valine is uncharged.
HbS is able to bind O2 normally in the lungs and carry it to the tissues. However, as the HbS becomes deoxygenated, the valine amino acids are exposed and start to bind to each other, forming long chains of deoxyHbS. These chains distort the cell and cause it to bend out of shape. As more and more deoxyHbS molecules come in contact with each other, they can result in the formation of a chain of sickled erythrocytes, which clump together and get stuck in the capillaries (Figure 14).
Sickled erythrocytes that return to the alveoli will regain their biconcave disc shape as they once again become oxygenated. Note that erythrocytes carrying normal Hb maintain this biconcave shape regardless of their O2 saturation levels.
The repeated episodes of polymerisation and depolymerisation of HbS as it travels between the lungs and tissues damages both the haemoglobin molecules and the erythrocyte itself, making it rigid and unable to move through the small-diameter capillaries.
Amplified many times, blockage of the capillaries can produce tissue hypoxia (i.e. low levels of oxygen), resulting in tissue pain and damage. In addition, the sickled erythrocytes are more fragile and die on average after 20 days in circulation, compared with normal erythrocytes that live for 120 days. Loss of erythrocytes leads to the anaemia (low red blood cell count) of sickle cell disease.
Symptoms of sickle cell anaemia include episodes of pain (called sickle cell crises) in tissues and bones, swelling of hands and feet, frequent infections, delayed growth and problems with vision. In addition, chronic pulmonary complications are common in individuals with sickle cell disease, including asthma, pulmonary fibrosis, decreased FEV1 values and sleep apnoea (which is further explored later in the course).
Sickle cell anaemia is a recessive disorder, meaning that in order for an individual to develop the disease, they must inherit two HbS alleles.