What is G542X?

Mutation G542X represents 8% of the total number of CF mutations in Spain, making it the second most common mutation after the ΔF508 deletion, which accounts for 48% of CF chromosomes. G542X has a higher frequency in the Mediterranean coastal area (14%) and in the Canary Islands (25%).

What class of mutation is G542X?

Mutation G542X (class I), characterized by a change that results in the absence of the CFTR protein, was the second most prevalent in this sample of patients (six alleles, 7.14%), and its frequency is estimated between 2.7 and 8.5% in Brazil. This mutation is responsible for the high incidence of meconium ileus.

What does the G542X mutation do?

Mice homozygous for the G542X mutation have reduced Cftr expression and absence of CFTR function in the airway and intestine. These mice display typical cystic fibrosis manifestations such as poor growth and reduced survival due to intestinal obstruction.

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.

What is 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.

What class of mutation is G551D?

To address this, we compared the clinical phenotype of patients with a G551D mutation, a Class 3 mutation, with patients homozygous for F508del and those with the missense mutation R117H (Arginine to histidine mutation of residue 117), a Class 2 and 4 mutation, respectively.

What is a minimal function mutation?

Minimal function mutations are gene changes that leave the CFTR protein minimally functional or unable to function at all. Earlier studies showed that patients with these types of mutations are not responsive to treatment with Kalydeco (ivacaftor), tezacaftor, or the combination of the two.

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).

What are the effects of a nonsense mutation?

A nonsense mutation is the substitution of a single base pair that leads to the appearance of a stop codon where previously there was a codon specifying an amino acid. The presence of this premature stop codon results in the production of a shortened, and likely nonfunctional, protein.

What causes 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.

How does F508del cause CF?

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 is the G542X mouse model used for?

The G542X mouse model provides an invaluable resource for the identification of potential therapies of CF nonsense mutations as well as the assessment of in vivo effectiveness of these potential therapies targeting nonsense mutations. Advertisement plos.org create account

Can CRISPR/Cas9 gene editing be used to edit the nonsense mutation G542X?

In this study, we create a CF mouse model carrying the G542X nonsense mutation in Cftr using CRISPR/Cas9 gene editing. The G542X mouse model has reduced Cftr mRNA levels, demonstrates absence of CFTR function, and displays characteristic manifestations of CF mice such as reduced growth and intestinal obstruction.

Does aminoglycoside therapy restore CFTR in G542X mice?

The G542X mouse model has reduced Cftr mRNA levels, demonstrates absence of CFTR function, and displays characteristic manifestations of CF mice such as reduced growth and intestinal obstruction. Importantly, CFTR restoration is observed in G542X intestinal organoids treated with G418, an aminoglycoside with translational readthrough capabilities.