How does the F508del mutation change the CFTR protein?

How does the F508del mutation change the CFTR protein?

These mutations are considered to be protein processing mutations. The most common CF mutation, F508del, is primarily considered to be a processing mutation. The F508del mutation removes a single amino acid from the CFTR protein. Without this building block, the CFTR protein cannot stay in the correct 3-D shape.

What does the F508del mutation cause?

The mutation F508del is the commonest cause of the genetic disease cystic fibrosis (CF).

What is the result of the delta F508 deletion?

Abstract. The most common mutation in the gene associated with cystic fibrosis (CF) causes deletion of phenylalanine at residue 508 (delta F508) of the gene product called CFTR. This mutation results in the synthesis of a variant CFTR protein that is defective in its ability to traffic to the plasma membrane.

What is a CFTR corrector?

Correctors. The next type of CFTR modulator A small molecule which binds to CFTR and improves its ability to function properly. is called a “corrector.” Correctors help the CFTR protein to form the right 3-D shape so that it is able to move — or traffic — to the cell surface.

How does F508del cause cystic fibrosis?

A defective protein or absence of this protein is the root cause of cystic fibrosis. The F508del defect prevents the CFTR from assembling correctly within the cell or causes it to be fragile, which means that it does not transport chloride properly and quickly falls apart.

What class of mutation is delta F508?

That is, ΔF508 is a class 2 mutation in the sweat gland but a class 3 mutation in the airway and gut, so a therapy effective in one tissue might not apply to another. Disease of the airway is the major cause of mortality in CF, so understanding the effect of ΔF508 on the respiratory epithelium is of major importance.

Why is the cystic fibrosis delta F508 mutation so common in Europe?

We therefore propose that the high frequency of the CFTR gene, and in particular, the common Delta F508 allele mutation in current European and European-derived populations might be a consequence of the impact of selective pressures generated by the transmission of pathogenic agents from domesticated animals, mainly …

What is a corrector and a potentiator?

Correctors are principally targeted at F508del cellular misprocessing, whereas potentiators are intended to restore cAMP-dependent chloride channel activity to mutant CFTRs at the cell surface.

How effective are CFTR modulators?

After 24 weeks of treatment with Orkambi, patients homozygous for F508del experienced a reduction in the rate of pulmonary exacerbations (30–39%), an absolute change in body mass index (BMI, 0.13–0.41) and an increment of percentage of predicted forced expiratory volume in 1 s (FEV1 % pred) between 4.3% and 6.7% [13].

What class of mutation is F508del?

F508del is the most common mutation that results in CF; it is characterized as a class II defect. Class II defects are among those associated with more severe manifestations of CF, and they result in complete loss of chloride channel function.

How common is F508del in cystic fibrosis?

F508del is the most common of the more-than 1,400 CF mutations. Around 90% of the UK CF population carries at least one copy, and around 50% carries two.

Where is F508 located?

The most common CF-causing mutation, the deletion of phenylalanine 508 (F508), is located in the N-terminal cytoplasmic NBD1 (5–9). This single amino acid deletion results in a dramatic reduction of mature, plasma membrane resident CFTR.

What factors might influence the severity of cystic fibrosis caused by the F508del mutation?

The variability in CF severity is associated principally with genetic factors, such as modifier genes and CFTR mutation classes, as well as with environmental factors. The F508del mutation is a class II mutation (causing misprocessed/misfolded CFTR proteins), and it is associated with higher clinical severity of CF.

How does the delta F508 mutation affect lung cells?

The most common mutation – called delta F508 – causes people to lose a small bit of genetic sequence in each of the genes that makes CFTR. This leads to one crucial building block being left out. As a result, the protein doesn’t fold properly and is destroyed by the body, leaving its cells short of CFTR.

What does F508del stand for?

The deletion of Phenylalanine in position 508 of the Cystic Fibrosis Transmembrane conductance Regulator (F508del-CFTR) is the most common mutation in CF patients: the deleted protein, not properly folded, is degraded.

What function corrector molecule has in the personalized treatment of CF?

A CF corrector is defined as a chemical chaperone that increases cell-surface levels of F508del-CFTR. A series of CF correctors have been developed, and VX-809 (lumacaftor) has been cited as the most effective symptomatic CF corrector to date.

Are CFTR modulators gene therapy?

CFTR modulator agents. CFTR modulator agents are small molecules which ‘modulate’ the function of the abnormal CFTR protein. Unlike gene therapy, they do not alter the CFTR gene. However, these agents do manipulate the underlying genetic consequence of CF mutations.

When were CFTR modulators approved?

In January 2012, ivacaftor (Kalydeco, Vertex Pharmaceuticals, Boston, Massachusetts, USA) was the first CFTR modulator approved by the FDA. It is a potentiator, that is increasing activity of CFTR in the cell membrane by increasing open channel probability.

Where is the F508del mutation?

Description of F508del Mutation F508del is the most common mutation that results in CF; it is characterized as a class II defect. Class II defects are among those associated with more severe manifestations of CF, and they result in complete loss of chloride channel function.