Foundation Genetic mutations and disease

Question 1

Cystic fibrosis is a __________

Answer 1

1. Simple Mendelian genetic disease
   Autosomal recessive
2. Single gene disease
   Known gene - CFTR
3. Known protein
   Epithelial chloride channel
4. Known mechanism of disease
   Salt and water movement

Question 2

CFTR mutation affects the gene ________

Answer 2

CF occurs due to mutation of a single gene – CFTR on chromosome 7q

Estimated 1500 different mutations to CFTR that can cause CF

ΔF508 mutation is a deletion of 3 DNA bases
Results in deletion of one amino acid from the protein (phenylalanine = F)

Produces an abnormal CFTR protein that does not fold properly

Question 3

CFTR in healthy cells

Answer 3

In healthy cells:
CFTR is a chloride channel which in healthy airways excretes chloride.
CFTR also inhibits ENAC
Water follows NaCl movement
—————————–
- CFTR can transport in either direction depending on the cell

In the lungs Cl- would move out of the cell

In sweat glands the Cl- would move into the cell

Question 4

In ΔF508 CF:

Answer 4

The CFTR protein does not reach the membrane

The chloride can not move out to the apical surface

Sodium moves into the cell and water follows causing the mucus to thicken

Question 5

Genetic diseases can be grouped into 3 main categories:

Answer 5

1. Monogenic - e.g. CF
2. Multifactorial, complex - e.g. cancer
3. Chromosome disorders - e.g. Down syndrome

Mendelian genetic diseases – monogenic with known pattern of inheritance
Easier to determine the mechanism of disease

Monogenic diseases are relatively rare compared to more common, ‘complex’, multifactorial diseases such as heart disease, diabetes and cancer

Multifactorial genetic diseases are caused by a combination of variations in a number of genes acting with environmental factors – much more common

Question 6

Beta thalassaemia

Answer 6

β-Thalassaemia occurs due to mutation of a single gene – HBB on chromosome 11

• Autosomal recessive inheritance (same as CF)
• point mutation
• rare cases the mutation is a deletion which results in no beta haemoglobin

There are 3 severities of β-Thalassaemia and this is referred to by 3 different alleles:
β0 – No beta haemoglobin produced
β+ - Reduction of amount of beta haemoglobin produced
β++ - Slight reduction of amount of beta haemoglobin produced.

The HBB gene codes for the haemoglobin beta chain protein

• less production of haemoglobin
• Red blood cells are not produced properly leading to anaemia, iron overload and skeletal abnormalities

Question 7

Haemophilia A

Answer 7

Monogenic - factor 8 gene on chromosome X
X-linked recessive inheritance. rare in females.

F8 gene product is coagulation factor VIII which is involved in blood clotting
Mutations in F8 lead to either reduced or abnormal protein being produced

The missing or abnormal protein can not effectively participate in blood clotting
Leads to symptoms of spontaneous prolonged bleeding, excessive bruising following injury

Question 8

Huntingtons disease

Answer 8

HTT gene on chromosome 4 which codes for the Huntington protein
- Autosomal dominant inheritance

The mutation is an insertion of repeats of CAG DNA bases within the gene
- This causes production of an abnormally long Huntington protein
- In Huntington’s disease the abnormally long Huntington protein is cut into smaller toxic fragments that aggregate and accumulate in neurons
This causes dysfunction and death of neurons leading to the neuronal symptoms of Huntington’s disease and the progressive loss of cognition

Question 9

Phenylketonuria

Answer 9

PAH gene mutation on chromosome 12
Autosomal recessive inheritance (same as CF)

The PAH gene encodes the protein pheynylalanine hydroxylase

Pheynylalanine hydroxylase is an enzyme that converts the amino acid phenylalanine to the amino acid tyrosine

In PKU phenylalanine builds up in the blood and is toxic to the brain. When left untreated it can cause damage to the brain
It is treated by excluding phenylalanine from the diet

Question 10

Sickle cell disease

Answer 10

HBB gene mutation on chromosome 11 (same gene as β-Thalassaemia)
Autosomal recessive inheritance

point mutation

produce haemoglobin S from this gene rather than the normal haemoglobin A protein

• in low O2, HbS causes RBC’s to distort into a sickle shape
• The sickle cells break down more quickly causing anaemia and can get stuck in blood vessels causing pulmonary hypertension and organ damage