Molecular Pathology - Gene mutations Flashcards
What are some effects of mutation on protein function?
Most common effect is loss of function of protein
Gain of function
Acquisition of novel property
Expression at wrong time /wrong place
What cause loss of function in alpha-thalassaemia?
Deletion of alpha globin gene
What causes ataxia telangiectasia?
Loss of ATM gene. The severity of this disease that results from loss of mutations can generally be correlated with the amount of function loss.
What may make a disorder due to loss of function less severe?
Retention of a small degree of residual function.
What can the gain of function mutation lead to?
Increase in abundance of protein
Increase in ability to perform one or more functions
What is the gene that is mutated in achondroplasia?
Mutation in FGF gene.
FGFR3 is a transmembrane tyrosine kinase receptor that binds fibroblasts growth factors.
What is FGFR3s normal function?
inhibits proliferation of chondrocytes
What happens when FGFR3s mutated?
Increases its activity (gain of function) leading to inappropriate inhibition of chondrocyte proliferation leading to achondroplasia (dwarfism)
Why is there no allelic heterogeneity in achondroplasia?
There is only one position where an amino acid change in FGFR3 receptors can cause achondroplasia.
What are some examples of novel property mutations?
Sickle cell anaemia
What kind of diseases are the acquisition of a novel function rare in?
Inherited diseases but common in cancer (oncogenes)
What are multigenic traits?
Where two mutations are working together
eg. digenic disorder
What is ataxia telangiectasia?
Autosomal recessive disorder
Early oncset cerenellar ataxia (<2y)
What are the progressive degenerations of ataxia telangiectasia?
Progressive cerebellar degeneration - wheel chair by teenage
Speech difficulties
Abnormal eye movements
Telangiectasia – dilated blood vessels
Immune deficiency
Large increased risk of malignant disease
- mainly lymphoid tumours in childhood.
Increased chromosome instability
Increased radiosensitivity
Median age of death ~ 18y
What is the significance of increased radiation sensitivity?
Indicates an inability to repair DNA double strand breaks
What does a western blot tell us?
Whether there is any protein present and how much.
This gives a clue about the type of mutations present.
If there is protein the Western gives no information about whether it is still functional
What is the interpretation of total absence of ATM protein?
Feature of classical Ataxia Telangiectasia (A-T)
What would be the interpretation of a reduced level of ATM protein?
Is it normal ATM
Is it mutant ATM
May expect different results
how big is the ATM gene?
100kb (100,000 bases)
How many exons are there in the gene?
66 exons
Therefore the total coding bases is just over 9000
What is a private mutation?
When a mutation in a gene is specific to that individual
What is the function of the ATM gene?
The function of the ATM protein is to protect our cells against DNA/chromosome damage and aid in their repair.
