2- Monogenic Disease

Question 1

What are the 2 types of point mutation

Answer 1

missense – where one amino acid is replaced by another;

nonsense – where the amino acid is replaced by a stop codon

Question 2

Give an autosomal dominant example

Answer 2

Huntington’s
Mean age of onset is 35 44 years, causes motor, cognitive and psychiatric dysfunction.
Caused by inheritance of a mutated HTT gene on chromosome 4 that encodes for huntingtin.
This mutated gene encodes toxic forms of huntingtin that form clumps in thebrain. There is cell death in the basal ganglia in the brain.

Huntington’s disease is caused by an unstable triplet repeat, the number of repeats expand with each generation so there is an increase in severity and earlier onset in subsequent generations

Question 3

Give an autosomal recessive example

Answer 3

CF
Thick mucus in lungs causes breathing problems and repeated infections
Blockages in pancreas affect digestive enzymes

In the UK, 1 in 22 people are CF carriers
Caused by inheritance of a mutated form of the CFTR gene on chromosome 7 that encodes for the CF transmembrane conductance regulator
CF patients inherit two copies of the mutated form of this gene, which causes the absence of any working CFTR protein. This affects chloride ion channel function in ‘wet’ epithelial cells, causing disruption of salt/water regulation causes lack of water in mucus, causing thick mucus.
There are over 1000 mutations identified, with the most common being in ΔF508

Question 4

Give an x linked example

Answer 4

Haemophilia
There are two types:
haemophilia A and haemophilia B. Can be successfully treated with injections of clotting
factor
Haemophilia A is caused by the inheritance of a mutated form of the F8 gene on the X chromosome that encodes a protein called coagulation factor VIII.
Haemophilia B is caused by mutations in the F9 gene, also on the X chromosome, which codes
for a protein called coagulation factor IX, same symptoms as haemophilia A but is much rarer

Question 5

What is genetic heterogeneity?

Answer 5

Same gene, different mutations, different diseases
– e.g. cystic fibrosis and CAVD are both caused by mutations in the CFTR gene
Same disease, different genes
– e.g. Haemophilia A (mutations in F8 gene) and Haemophilia B (mutations in F9 gene)
Same disease, different genes, different inheritance patterns
– e.g. different forms of epidermolysis bullosa can be autosomal dominant or autosomal recessive

Question 6

What is incomplete penetrance?

Answer 6

Symptoms not present in a person with disease causing mutation

Question 7

Define variable expressively

Answer 7

Severity of disease varies between individuals with same disease cause in mutation.

Question 8

Define phenocopy

Answer 8

Same phenotypic disease but with different underlying cause which is not genetic

Question 9

Define epistasis

Answer 9

interaction between disease gene mutations and other modifier genes can affect the
phenotype

Question 10

What are the 3 mechanisms of genetic disease?

Answer 10

Dominant conditions: usually caused by genes that result in a toxic protein (e.g. huntingtin) i.e. the effects of the mutated protein mask the normal copy. Therefore, one needs to counter the effects of the toxic protein or neutralise it, or switch off the mutant gene
Recessive conditions: caused by the absence of a working gene (e.g. CF, haemophilia), i.e. the effects of the mutated gene are only seen when the normal copy is absent. Therefore, one needs to restore activity of the missing protein by replacing genes, protein, or the affected tissues
Co dominant conditions – the effects are both apparent in people e.g. sickle cell trait

Question 11

What are differences between Duchenne Muscular Dystrophy and Becker Muscular Dystrophy?

Answer 11

BMD is a more benign allelic disease. Age of onset is about 12 years, and there is a much longer survival than Duchenne’s.

Question 12

Where is the gene responsible for CF

Answer 12

chromosome 7q31