Molecular Pathology - Gene mutations

Question 1

What are some effects of mutation on protein function?

Answer 1

Most common effect is loss of function of protein

Gain of function

Acquisition of novel property

Expression at wrong time /wrong place

Question 2

What cause loss of function in alpha-thalassaemia?

Answer 2

Deletion of alpha globin gene

Question 3

What causes ataxia telangiectasia?

Answer 3

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.

Question 4

What may make a disorder due to loss of function less severe?

Answer 4

Retention of a small degree of residual function.

Question 5

What can the gain of function mutation lead to?

Answer 5

Increase in abundance of protein

Increase in ability to perform one or more functions

Question 6

What is the gene that is mutated in achondroplasia?

Answer 6

Mutation in FGF gene.

FGFR3 is a transmembrane tyrosine kinase receptor that binds fibroblasts growth factors.

Question 7

What is FGFR3s normal function?

Answer 7

inhibits proliferation of chondrocytes

Question 8

What happens when FGFR3s mutated?

Answer 8

Increases its activity (gain of function) leading to inappropriate inhibition of chondrocyte proliferation leading to achondroplasia (dwarfism)

Question 9

Why is there no allelic heterogeneity in achondroplasia?

Answer 9

There is only one position where an amino acid change in FGFR3 receptors can cause achondroplasia.

Question 10

What are some examples of novel property mutations?

Answer 10

Sickle cell anaemia

Question 11

What kind of diseases are the acquisition of a novel function rare in?

Answer 11

Inherited diseases but common in cancer (oncogenes)

Question 12

What are multigenic traits?

Answer 12

Where two mutations are working together

eg. digenic disorder

Question 13

What is ataxia telangiectasia?

Answer 13

Autosomal recessive disorder

Early oncset cerenellar ataxia (<2y)

Question 14

What are the progressive degenerations of ataxia telangiectasia?

Answer 14

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

Question 15

What is the significance of increased radiation sensitivity?

Answer 15

Indicates an inability to repair DNA double strand breaks

Question 16

What does a western blot tell us?

Answer 16

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

Question 17

What is the interpretation of total absence of ATM protein?

Answer 17

Feature of classical Ataxia Telangiectasia (A-T)

Question 18

What would be the interpretation of a reduced level of ATM protein?

Answer 18

Is it normal ATM
Is it mutant ATM

May expect different results

Question 19

how big is the ATM gene?

Answer 19

100kb (100,000 bases)

Question 20

How many exons are there in the gene?

Answer 20

66 exons

Therefore the total coding bases is just over 9000

Question 21

What is a private mutation?

Answer 21

When a mutation in a gene is specific to that individual

Question 22

What is the function of the ATM gene?

Answer 22

The function of the ATM protein is to protect our cells against DNA/chromosome damage and aid in their repair.