What does the F508del mutation cause?

What does the F508del mutation cause?

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

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 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.

How common is F508del mutation?

One single mutation, F508del-CFTR, accounts for about 70% of CFTR loss-of-function mutations and is present in approximately 85% of CF patients worldwide (1).

What is F508del CFTR rescue?

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. To date no commercial drugs are available.

Why is it called F508del?

The deletion of a phenylalanine at residue 508 (F508del) is the most common cause of CFTR misfolding leading to the disease. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1’s interactions with other domains.

What does delta F508 stand for?

Background and aims: Deletion of the codon for phenylalanine at position 508 (DeltaF508) is the most frequent disease-causing mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

What is G551D mutation?

The G551D mutation in ABP2, the third most common cystic fibrosis-associated mutation, abolishes ATP-dependent gating, resulting in an open probability that is approximately 100-fold lower than that of wild-type channels.

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 …

How common is the G551D mutation?

G551D is the third overall most common CF mutation with a worldwide frequency of ∼3% (www.genet.sickkids.on.ca/cftr). This mutation is associated with a severe phenotype characterized by pulmonary dysfunction and pancreatic insufficiency (Cutting et al., 1990; Kerem et al., 1990).

Where is G551D mutation?

THERAPEUTIC TARGETING OF THE G551D MUTATION The G551D mutation is the most prevalent gating mutation. It is caused by substitution of the amino acid glycine by aspartate at position 551 in the nucleotide binding domain-1 of the CFTR gene.

How many CFTR mutations are there?

All people have two copies of the CFTR gene, and there must be mutations in both copies to cause CF. More than 1,700 mutations of the CFTR gene have been identified. Although some are common, others are rare and found in only a few people.

How does the G551D mutation affect the CFTR function?

The G551D mutation completely eliminates the ability of ATP to increase the channel activity, and the observed activity is ∼100-fold smaller than WT-CFTR. G551D-CFTR does not respond to ADP, AMP-PNP, or changes in [Mg2+].