Genetic Diseases

Question 1

What is a copy number variant mutation?

Answer 1

When a given genetic sequence of variable length (from few nucleotides to whole chromosomes) is present and repeated a variable number of times
Change in number of repeats may be considered a mutations e.g Huntingtons disease

Question 2

What are microsatellites in genomics?

Answer 2

A type of copy number variations - small repetitive sequences that vary in length between individuals
Typically underly DNA fingerprinting.

Question 3

What is the most common type of mutation causing disease?

Answer 3

Single nucleotide variants

Question 4

What is the CFRT protein?

Answer 4

Is an anion channel that transports Cl- and HCO3-
Is an ATP-binding cassette transporter, regulated by PKA (phosphorylation)
Associated with mucus production - typically lung epithelium and pancreas

Question 5

What is the functional affect of a mutated CFTR in CF?

Answer 5

Adherent mucus plug in submucosal glands - dehydrated and thick
Destroys periciliary layers - decrease mucociliary transport
Recurrent infections
Bronchiectasis.

Question 6

What are the six different classes of mutation present in CF?

Answer 6

1 - protein synthesis (typically premature stop codons = abnormal protein)
2 - trafficking = does not reach membrane
3 - channel gating/opening = cannot by regulated
4 - channel conductance = reduced Cl- passage when open
5 - alternative splicing (reduced protein numbers)
6 - recycling and halflife

Question 7

What are the functional consequences of the CFRT mutation in CF?

Answer 7

Loss of mucociliary transport leads to chronic infections = chronic inflammation

Question 8

What are some CFTR related disorders?

Answer 8

Chronic sinusisitis
Nasal Polyps
Primary Sclerosing Cholangitis
Cervical mucus abnormality
CBAVD
Recurrent pancreatitis
Bronchiectasis

Question 9

What are some multifactorial complications of cystic fibrosis?

Answer 9

Antimicrobial allergy and polypharmacy
increased arterial stiffness
GI malignancy
Dyspepsia
Female urinary incontinence
Infection MDR microorganisms
Renal failure
MSK abnormalities
Hearing and vestibular impairement

Question 10

What is the most common mutation in CF?

Answer 10

F508del found in 70% of patients
This is a type 2 mutation (trafficking)

Question 11

What experimental causative treatments are being investigated for CF?

Answer 11

This can be targeting…..
Translational
On channel modulators
Intracellular trafficking
CFTR modulators
Geneotherapy

Question 12

What ‘potentiator drugs’ exist to treat CF on NHS?

Answer 12

Potentiators - help the CFTR channel open - ivakaftor

Question 13

What corrector drugs exist to help treat CF on the NHS?

Answer 13

Correctors - aid the protein folding so more CFTR make it to the surface (Tezakaftor and Elaxakaftor both contain ETI ‘Kaftrio’)