Cystic fibrosis
From Ganfyd
CF is the most common inherited genetic disease in white northern populations. The gene (the defect of which was characterised in 1989) may mutate de novo, but the incidence of heterozygosity, i.e. carrier status, is around 1/400.
The defect is of chloride transport, and results in viscous secretions which may have severe pancreas and gut effects in utero, and lead on to severe chest infections and lung damage over the years.
Until the second quarter of the 20th century the disease was conflated with Coeliac disease in failure to thrive. The name is a contraction of its older label, cystic fibrosis of the pancreas.
Survival steadily lengthened during the C20 due to antibiotics, digestive enzyme preparations, improved integration of care, practice, and increased expectations of success. Further increase in survival or a cure require some means of patching the genome or correcting the somatic cells' function. Progress may well address minority genetic defects rather than the most common first.
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Molecular Genetics
The cystic fibrosis transmembrane conductance regulator becomes faulty due to alteration of the CFTR gene on chromosome 7 at 7q31.2. Three isoforms produced by alternative splicing are known. The commonest form involves the faulty CFTR being made, but the cell detects the fault during the assembly stage in the endoplasmic reticulum and the protein is marked for degradation, never making it to the cell membrane. Another mutation in CFTR alters the amount of time the channel stays open, making a faster closing channel. There are several other characterised mutations.
The most common mutation (~70%) is the ΔF508 mutation, so named as loss of 3 nucleotides causes deletion (Δ) of the phenylalanine (amino acid code F) that should be at 508th amino acid in the polypeptide sequence. ΔF508 homozygotes tend to display the most severe phenotype.
Several mutations of the CFTR gene, including some of those responsible for cystic fibrosis cause congenital bilateral absence of the vas deferens.
CFTR function
It is involved in the transport of chloride ions and may regulate bicarbonate secretion. It is activated by phosphorylation.
Channel opening is controlled by:
- Intracellular ATP
- Phosphorylation by cAMP- or cGMP-dependent kinases
In the operation of the initially closed CFTR channel
- Phosphorylation occures at CFRT's R-domain by cyclic AMP (cAMP) catalylsed by protein kinase (PKA)
- ATP is bound
- Then hydrolysed to ADP+Pi
- Changing the shape of CFTR, opening the Cl- channel. Sodium (Na+) ions follow by passive diffusion.
Screening
In early 2007 CF was added to the newborn bloodspot screening programme on a national basis. Screening had been carried out since the 1980s in several areas . The UK national protocol for biochemical screening is based on a biochemical marker, immunoreactive trypsin (IRT), in conjunction with mutation screening of DNA.[1] The DNA testing stage consists of an initial screen of 4 mutations: ΔF508, G551D, G542X and 621 + 1G>T. These 4 mutations cover ~80% of mutations in the UK. If 2 mutations are detected at this stage, the risk of CF is flagged up. Presence of a single mutation triggers a second analysis stage, which include re-assay or IRT as well as screening for a further ~30 mutations (depending on the laboratory).
See also http://www.newbornscreening-bloodspot.org.uk/
