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RELEVANT LEARNING OUTCOME:
(b) Explain how gene mutations can result in diseases (including sickle cell anaemia).
🔗Recall!
🔗Recall!
From protein chapter, haemoglobin are globular proteins that transport oxygen.
Haemoglobin consists of 4 subunits:
2 α chains
2 β chains
Haemoglobin is found in red blood cells
Red blood cells have a biconcave shape
👁️Introduction
👁️Introduction
Watch the video up till 2:55 to get an overview of sickle cell anaemia.
Take note of the following:
Gene which the mutation occurs
The abbreviation for normal haemoglobin and sickle haemoglobin
The structure of sickle haemoglobin before it binds oxygen, and after it binds oxygen
When not bound to oxygne, what are sickle haemoglobin capable of forming?
Which becomes sickle in shape, the red blood cell or haemoglobin?
The gene affected is the β–globin gene
Normal haemoglobin is abbrevated as HbA, while sickle haemoglobin is HbS
The video shows that when unbound to oxygen, 'a pair of hands' stretch out excessively - this depicts the 'hydrophobic patch', which will be covered later
Deoxy HbS (not bound to oxygen) is capable of polymerisation to form long insoluble fibres
The long insoluble fibres causes the red blood cell to become sickle in shape [HAEMOGLOBIN DOES NOT BECOME SICKLE SHAPE!]
💡Sickle cell Anaemia - mechanism and effect of mutation
💡Sickle cell Anaemia - mechanism and effect of mutation
Mechanism
Sickle cell anaemia is caused by a point mutation, where a single nucleotide substitution of 'T' to 'A'.
Effect
This results in a missense mutation, where there is a change in the mRNA codon from GAG to GUG.
Instead of coding for a hydrophilic glutamic acid, a hydrophobic valine is coded for instead.
Note that this mutation is recessive, as two copies of the mutant allele is required for an individual to have the disease. Thus sickle cell is a homozygous recessive disorder.
Individuals with only one mutant allele do not have the disease, but are termed as carriers.
🕹️Simulation!
🕹️Simulation!
Use the following simulation to visualise:
structure of a normal red blood cell and a sickle red blood cell (you can rotate the cell around!)
arrangement of haemoglobin molecules within each cell (change the opaque/transparent slider)
👁️Sickle cell Anaemia
👁️Sickle cell Anaemia
Watch the following video up till 2:23 and take note of the following:
Under what conditions does the polymerisation of HbS occur?
What is the impact of red blood cells becoming sickle?
The term 'anemia' is used to describe low red blood cell count, why is the disease termed as such?
When HbS is not bound to oxygen (deoxygenated)
Impact of red blood cells becoming sickle-shape:
Inefficient in transporting oxygen.
Clump and clog small capillaries, obstructing other cells from moving through the capillaries.
Deprives multiple organs of oxygen, resulting in organ failure.
Sickle red blood cells have a lower lifespan, as such patients have reduced number of red blood cells count.
💡Summary
💡Summary
The following is a summary of explaining how mutations can result in sickle cell anaemia and its impact on the individual (take note of the underlined keywords!)
Mechanism of mutation:
A point mutation involving a single nucleotide substitution of T to A on β-globin gene;
Effect of mutation:
This results in a missense mutation, as there is a change in mRNA codon, which changes the amino acid coded from hydrophilic glutamic acid to hydrophobic valine, changing the primary structure of β-globin polypeptide chain;
Impact of mutation:
Change in primary structure and types of R-groups presents alters the type of R-group interactions formed, which changes the folding of the polypeptide and the 3D conformation of β-globin;
At low oxygen concentration, mutant haemoglobin containing mutant β-globin (HbS) has a hydrophobic patch that is exposed;
Attraction between hydrophobic patch of Hbs molecules via hydrophobic interactions;
Results in polymerization of Hbs into long insoluble rod-like fibres;
This distorts the shape of red-blood cells into a sickle-shape.
How sickle-shaped RBC results in disease/anaemia:
Sickle-shaped RBCs are inefficient in transporting oxygen gas;
Inflexibility of sickle-shaped RBCs will clump and clog small capillaries, depriving organs of oxygen, causing organ failure;
They have shorter life span and undergoes haemolysis (breakdown of RBCs) readily, resulting in anaemia (low red-blood cell count);
🖊️Conceptual Check!
🖊️Conceptual Check!
Compare between wild type (normal) and sickle-cell anaemia by completing the following table.
🖊️Check your answers here
🖊️Check your answers here
🖊️Learning Goals
🖊️Learning Goals
Check your understanding by attempting Qn 10 - 13 of the DNA Mutations Learning Goals.
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