Genetics of Cystic Fibrosis Flashcards
Defne Cystic fibrosis
Multi-organ genetic disorder of the CFTR gene
Autosomal recessive
- Developed world: lung disease main cause of morbidity and mortatlity*
- Less-developed: Intestinal main cause of mortality (aless availbility of pancreatic enzymes)*
Describe the function of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein
Lets Cl- ions flow into the lumen.
Inhibits eNaC (so ↓Na movement from lumen so that H2O follows Cl-)
Describe the consequences of a faulty CFTR
Less Cl- movement into the lumen
ENaC is active, so Na moves into the cell from lumen
H2O follows Na
Mucus dries up and becomes thick (Low volume hypothesis)
Cilia are not standing up straight
↓Mucociliary clearance
Name two hypotheses to explain the pathology of CF
- Low Volume Hypothesis
- Bicarbonate hypothesis
- High salt hypothesis - old and disproven*
- Aletered macrophage and neutrophil activity - jury still out (leads to impaired bacterial killing and clearance)*
Explain the bicarbonate hypothesis in the pathology of CF
CFTR allows HCO3- movement into the lumen to raise the pH of the mucus - created optimum pH environment
Mutated CFTR leads to ↓HCO3- into the lumen, therefore ↓pH (more acidic) and denaturing anti-bacterial proteins
There is dysregulation of the Airway Surface Liquid (ASL) Compartment
Explain the Low Volume Hypothesis in the pathology of CF
Mutated CFTR leads to no Cl- movement into lumen and dysregulation of ENaC (activates ENaC).
Na moves in from lumen into cell and H2O follows
Mucus dries up and there is inadequate airway surface liquid for the cilia to beat
Apart from potential low volume hypothesis, what else could be making the mucus thicker?
Infections are cleared by neutrophils mainly in CF.
Neutrophil death releases genomic DNA which makes mucus thick and sticky,
DNAse degrades the genetic material but it is expensive
Describe the risk of CF mutation in caucasians
Currently >1800 mutations identified for CF
1 in 25 (30)
Name some types of mutations
Missense
Frameshift
Splicing
Nonsense
In frame insertino/deletion
Large insertion/deletion
Promotor
Sequence Variation
Explain a missense mutation
Changing of a nucleotide in a sequence causing an amino acid change
Explain a frameshift mutation
An insertion or deletion causes a shift in the reading frame so that the codons are read in different triplets, coding for different amino acids
Explain a splicing mutation
The insertion, deletion of exons/introns to form a completely different amino acid sequence
Explain a nonsense mutation
The incorporation of a STOP codon
Sickel cell anaemia give a heterozygous advantage against malaria. What does CF give a heterozygous advantage to?
Cholera (potentiatlly)
Due to the involvement of Cl- channels in the pathogenesis of the watery diarrhoea
What is the most common mutation for CF and explain what the notation means
ΔF508
Deletion of three nucleotides at position 508, leading to a frameshift mutation (phenylalanine)
NBD1 and NBD2 involved in hydrolysis of ATP -> needed to transport ions across channel