scholarly journals Therapy for Cystic Fibrosis Caused by Nonsense Mutations

10.5772/61053 ◽  
2015 ◽  
Author(s):  
Roberto Gambari ◽  
Giulia Breveglieri ◽  
Francesca Salvatori ◽  
Alessia Finotti ◽  
Monica Borgatti
Keyword(s):  
Cystic Fibrosis ◽  
Nonsense Mutations

scholarly journals Prevalence and impact of oprD mutations in Pseudomonas aeruginosa strains in cystic fibrosis

2019 ◽  
Author(s):  
Laura J. Sherrard ◽  
Bryan A. Wee ◽  
Christine Duplancic ◽  
Kay A. Ramsay ◽  
Keyur A. Dave ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Lung Function ◽  
Hazard Rate ◽  
Carbapenem Resistance ◽  
Adverse Outcomes ◽  
Nonsense Mutations ◽  
Allelic Variants ◽  
Novel Variants

ABSTRACTDefective OprD porins contribute to carbapenem resistance and may be important in Pseudomonas aeruginosa adaptation to cystic fibrosis airways. It is unclear whether oprD mutations are fixed in populations of shared strains that are transmitted between patients or whether novel variants arise during infection. We investigated oprD sequences and antimicrobial resistance of two common Australian shared strains, constructed P. aeruginosa mutants with the most common oprD allelic variants and compared characteristics between patients with or without evidence of infection with strains harbouring these variants. Our data show that three independently acquired nonsense mutations arising from a 1-base pair substitution are fixed in strain sub-lineages. These nonsense mutations are likely to contribute to reduced carbapenem susceptibility in the sub-lineages without compromising in vitro fitness. Not only was lung function worse among patients infected with strains harbouring the nonsense mutations than those without, but they also had an increased hazard rate of lung transplantation/death. Our findings further highlight that understanding adaptive changes may help to distinguish patients with greater adverse outcomes despite infection with the same strain.

scholarly journals Two Patients with Cystic Fibrosis, Nonsense Mutations in Each Cystic Fibrosis Gene, and Mild Pulmonary Disease

1990 ◽  
Vol 323 (24) ◽  
pp. 1685-1689 ◽  
Author(s):  
Garry R. Cutting ◽  
Laura M. Kasch ◽  
Beryl J. Rosenstein ◽  
Lap-Chee Tsui ◽  
Haig H. Kazazian ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pulmonary Disease ◽  
Cystic Fibrosis Gene ◽  
Nonsense Mutations

New Pharmacological Approaches to Treat Patients with Cystic Fibrosis with Nonsense Mutations

2016 ◽  
Vol 194 (9) ◽  
pp. 1042-1044 ◽  
Author(s):  
Isabelle Sermet-Gaudelus ◽  
Olivier Namy
Keyword(s):  
Cystic Fibrosis ◽  
Nonsense Mutations

scholarly journals Efficient Suppression of Endogenous CFTR Nonsense Mutations Using Anticodon Engineered Transfer RNAs

2021 ◽  
Author(s):  
Wooree Ko ◽  
Joseph J. Porter ◽  
Matthew T. Sipple ◽  
Katherine M. Edwards ◽  
John D. Lueck
Keyword(s):  
Cystic Fibrosis ◽  
Mammalian Cells ◽  
Genetic Diseases ◽  
Protein Translation ◽  
Nonsense Mutations ◽  
Channel Function ◽  
Associated Diseases ◽  
Highly Active ◽  
Premature Termination Codons ◽  
Efficient Suppression

Nonsense mutations or premature termination codons (PTCs) comprise ~11% of all genetic lesions, which result in over 7,000 distinct genetic diseases. Due to their outsized impact on human health, considerable effort has been made to find therapies for nonsense-associated diseases. Suppressor tRNAs have long been identified as a possible therapeutic for nonsense-associated diseases, however their ability to inhibit nonsense-mediated mRNA decay (NMD) and support significant protein translation from endogenous transcripts has not been determined in mammalian cells. Here we investigated the ability of anticodon edited (ACE)-tRNAs to suppress cystic fibrosis (CF) causing PTCs in the cystic fibrosis transmembrane regulator (CFTR) gene in gene-edited immortalized human bronchial epithelial (16HBEge) cells. Delivery of ACE-tRNAs to 16HBEge cells harboring three common CF mutations G542X-, R1162X- and W1282X-CFTR PTCs significantly inhibited NMD and rescued endogenous mRNA expression. Furthermore, delivery of our highly active leucine encoding ACE-tRNA resulted in rescue of W1282X-CFTR channel function to levels that significantly exceed the necessary CFTR channel function for therapeutic relevance. This study establishes the ACE-tRNA approach as a potential stand-alone therapeutic for nonsense-associated diseases due to its ability to rescue both mRNA and full-length protein expression from PTC containing endogenous genes.

Ataluren/ivacaftor combination therapy: Two N‐of‐1 trials in cystic fibrosis patients with nonsense mutations

2020 ◽  
Vol 55 (7) ◽  
pp. 1838-1842 ◽  
Author(s):  
Jacelyn E. Peabody Lever ◽  
Venkateshwar Mutyam ◽  
Heather Y. Hathorne ◽  
Ning Peng ◽  
Jyoti Sharma ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Combination Therapy ◽  
Nonsense Mutations

scholarly journals CFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic pathway

2021 ◽  
Author(s):  
Edward Sanderlin ◽  
Melissa Keenan ◽  
Martin Mense ◽  
Alexey Revenko ◽  
Brett Monia ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Exon Junction Complex ◽  
Transmembrane Conductance Regulator ◽  
Loss Of Function ◽  
Transmembrane Conductance ◽  
Nonsense Mutations ◽  
Nonsense Mediated Decay ◽  
Nonsense Codon ◽  
Translational Readthrough ◽  
Nonsense Codons

Abstract Cystic fibrosis is caused by loss of function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene resulting in severe lung disease. Nearly 10% of cystic fibrosis patients have at least one CFTR allele with a nonsense mutation that generates a nonsense codon in the mRNA. Nonsense mutations can result in significant reduction of gene expression partially due to rapid mRNA degradation through the nonsense-mediated decay (NMD) pathway. It has not been thoroughly investigated which branch of the NMD pathway governs the decay of CFTR mRNAs containing nonsense codons. Here we utilized antisense oligonucleotides targeting NMD factors to evaluate the regulation of nonsense codon-containing CFTR mRNAs by the NMD pathway. Interestingly, we found that CFTR mRNAs with G542X, R1162X, and W1282X nonsense codons require UPF2, UPF3, and exon junction complex proteins for NMD, whereas CFTR mRNAs with the Y122X nonsense codon do not. Furthermore, we demonstrated that all evaluated CFTR mRNAs harboring nonsense codons were degraded by the SMG6-mediated endonucleolytic pathway rather than the SMG5/SMG7-mediated exonucleolytic pathway. Finally, we found that stabilization of CFTR mRNAs by NMD inhibition alone improved functional W1282X protein production, and improved the efficiency of aminoglycoside translational readthrough of CFTR-Y122X, -G542X, and -R1162X mRNAs.

scholarly journals Synthetic Aminoglycosides Efficiently Suppress Cystic Fibrosis Transmembrane Conductance Regulator Nonsense Mutations and Are Enhanced by Ivacaftor

2014 ◽  
Vol 50 (4) ◽  
pp. 805-816 ◽  
Author(s):  
Xiaojiao Xue ◽  
Venkateshwar Mutyam ◽  
Liping Tang ◽  
Silpak Biswas ◽  
Ming Du ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Nonsense Mutations ◽  
Cystic Fibrosis Transmembrane

scholarly journals LasR Variant Cystic Fibrosis Isolates Reveal an Adaptable Quorum-Sensing Hierarchy in Pseudomonas aeruginosa

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
John B. Feltner ◽  
Daniel J. Wolter ◽  
Christopher E. Pope ◽  
Marie-Christine Groleau ◽  
Nicole E. Smalley ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Chronic Infections ◽  
Nonsense Mutations ◽  
Sensing System ◽  
Secreted Proteases ◽  
Lung Infections ◽  
Coding Variants ◽  
Null Mutants

ABSTRACT Chronic Pseudomonas aeruginosa infections cause significant morbidity in patients with cystic fibrosis (CF). Over years to decades, P. aeruginosa adapts genetically as it establishes chronic lung infections. Nonsynonymous mutations in lasR , the quorum-sensing (QS) master regulator, are common in CF. In laboratory strains of P. aeruginosa , LasR activates transcription of dozens of genes, including that for another QS regulator, RhlR. Despite the frequency with which lasR coding variants have been reported to occur in P. aeruginosa CF isolates, little is known about their consequences for QS. We sequenced lasR from 2,583 P. aeruginosa CF isolates. The lasR sequences of 580 isolates (22%) coded for polypeptides that differed from the conserved LasR polypeptides of well-studied laboratory strains. This collection included 173 unique lasR coding variants, 116 of which were either missense or nonsense mutations. We studied 31 of these variants. About one-sixth of the variant LasR proteins were functional, including 3 with nonsense mutations, and in some LasR-null isolates, genes that are LasR dependent in laboratory strains were nonetheless expressed. Furthermore, about half of the LasR-null isolates retained RhlR activity. Therefore, in some CF isolates the QS hierarchy is altered such that RhlR quorum sensing is independent of LasR regulation. Our analysis challenges the view that QS-silent P. aeruginosa is selected during the course of a chronic CF lung infection. Rather, some lasR sequence variants retain functionality, and many employ an alternate QS strategy involving RhlR. IMPORTANCE Chronic Pseudomonas aeruginosa infections, such as those in patients with the genetic disease cystic fibrosis, are notable in that mutants with defects in the quorum-sensing transcription factor LasR frequently arise. In laboratory strains of P. aeruginosa , quorum sensing activates transcription of dozens of genes, many of which encode virulence factors, such as secreted proteases and hydrogen cyanide synthases. In well-studied laboratory strains, LasR-null mutants have a quorum-sensing-deficient phenotype. Therefore, the presence of LasR variants in chronic infections has been interpreted to indicate that quorum-sensing-regulated products are not important for those infections. We report that some P. aeruginosa LasR variant clinical isolates are not LasR-null mutants, and others have uncoupled a second quorum-sensing system, the RhlR system, from LasR regulation. In these uncoupled isolates, RhlR independently activates at least some quorum-sensing-dependent genes. Our findings suggest that quorum sensing plays a role in chronic P. aeruginosa infections, despite the emergence of LasR coding variants.

scholarly journals 264 Natural history of patients with cystic fibrosis carrying nonsense mutations: an analysis of placebo-treated patients from the 009 study

2016 ◽  
Vol 15 ◽  
pp. S118-S119 ◽  
Author(s):  
E. Kerem ◽  
I. Sermet-Gaudelus ◽  
L. Hjelte ◽  
K. De Boeck
Keyword(s):  
Cystic Fibrosis ◽  
Natural History ◽  
Nonsense Mutations ◽  
History Of
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