Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies

Ramalho, Sofia; Silva, Iris; Amaral, Margarida D.; Farinha, Carlos M.

doi:10.3390/ijms23010024

Cited by 15 publications

(15 citation statements)

References 51 publications

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“…These particles were used to transduce parental CFBE41o- cells. After selection with puromycin 5 mg/mL for 15 days, the efficiency of the transduction was assessed by WB to confirm CFTR expression [ 39 , 40 ].…”

Section: Methodsmentioning

confidence: 99%

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction

Zacarias

Batista

Ramalho

et al. 2023

IJMS

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Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF. However, these drugs do not apply to all patients with CF, especially those with rare mutations—for which there is a lack of knowledge on the molecular mechanisms of the disease and the response to modulators. In this work, we evaluated the impact of several rare putative class II mutations on the expression, processing, and response of CFTR to modulators. Novel cell models consisting of bronchial epithelial cell lines expressing CFTR with 14 rare variants were created. The variants studied are localized at Transmembrane Domain 1 (TMD1) or very close to the signature motif of Nucleotide Binding Domain 1 (NBD1). Our data show that all mutations analyzed significantly decrease CFTR processing and while TMD1 mutations respond to modulators, those localized in NBD1 do not. Molecular modeling calculations confirm that the mutations in NBD1 induce greater destabilization of CFTR structure than those in TMD1. Furthermore, the structural proximity of TMD1 mutants to the reported binding site of CFTR modulators such as VX-809 and VX-661, make them more efficient in stabilizing the CFTR mutants analyzed. Overall, our data suggest a pattern for mutation location and impact in response to modulators that correlates with the global effect of the mutations on CFTR structure.

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Section: Methodsmentioning

confidence: 99%

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction

Zacarias

Batista

Ramalho

et al. 2023

IJMS

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“…Besides F508del, many mutations are thought to lead to CFTR misfolding, although the position of the mutations may cause differences in the intramolecular interactions that are disrupted and thus on the interacting proteins that are mediators in the specific retention processes, contributing to the notion that not all trafficking mutations are ‘created equal’ [ 87 ].…”

Section: Molecular Mechanisms Of Disease – How Do Cftr Mutations Caus...mentioning

confidence: 99%

Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Farinha

Callebaut

2022

Bioscience Reports

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Cystic Fibrosis, the most common autosomal recessive disorder in Caucasians, is caused by mutations in the CFTR gene, which encodes a cAMP-activated chloride and bicarbonate channel that regulates ion and water transport in secretory epithelia. Although all mutations lead to the lack or reduction in channel function, the mechanisms through which this occurs are diverse – ranging from lack of full-length mRNA, reduced mRNA levels, impaired folding and trafficking, targeting to degradation, decreased gating or conductance, reduced protein levels to decreased half-life at the plasma membrane. Here, we review the different molecular mechanisms that cause cystic fibrosis and detail how these differences identify theratypes that can inform the use of directed therapies aiming at correcting the basic defect. In summary, we travel through CFTR life cycle from the gene to function, identifying what can go wrong and what can be targeted in terms of the different types of therapeutic approaches.

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“…Over 2000 mutations currently exist [ 1 , 2 , 3 ]. The most common CFTR mutation is F508del, which is involved in 80% of cases worldwide [ 4 ]. As a result of advances in the diagnosis and management of such patients, the life expectancy of these patients has improved.…”

Section: Introductionmentioning

confidence: 99%

Advances in Cystic Fibrosis Research in Qatar: A Commentary

Hammoudeh

Janahi

2023

JPM

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Rare Trafficking CFTR Mutations Involve Distinct Cellular Retention Machineries and Require Different Rescuing Strategies

Cited by 15 publications

References 51 publications

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction

Molecular mechanisms of cystic fibrosis – how mutations lead to misfunction and guide therapy

Advances in Cystic Fibrosis Research in Qatar: A Commentary

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