Evidence that Systemic Gentamicin Suppresses  Premature Stop Mutations in Patients with Cystic Fibrosis

Clancy, John; Bebök, Zsuzsa; Ruiz, Fadel; King, Chris; Jones, Julie R.; Walker, Lynn; Greer, Heather; Hong, Jeong S.; Wing, L.; Macaluso, Maurizio; Lyrene, Raymond K.; Sorscher, Eric J.; Bedwell, David M.

doi:10.1164/ajrccm.163.7.2004001

Cited by 233 publications

(154 citation statements)

References 34 publications

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“…The authors observed a dose-dependent increase in fulllength CFTR produced by cells transfected with CFTR mRNAs containing stop codons and these were shown to function as cAMP-activated ion channels. Systematic treatment of CF patients with gentamicin resulted in small increases in CFTR Cl − conductance in vivo (Clancy et al 2001).…”

Section: Class I Mutations Affecting Biosynthesismentioning

confidence: 98%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

296

215

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SummaryCystic fibrosis is a common autosomal recessive disorder that primarily affects the epithelial cells in the intestine, respiratory system, pancreas, gall bladder and sweat glands. Over one thousand mutations have currently been identified in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that are associated with CF disease. There have been many studies on the correlation of the CFTR genotype and CF disease phenotype; however, this relationship is still not well understood. A connection between CFTR genotype and disease manifested in the pancreas has been well described, but pulmonary disease appears to be highly variable even between individuals with the same genotype. This review describes the current classification of CFTR mutation classes and resulting CF disease phenotypes. Complex disease alleles and modifier genes are discussed along with alternative disorders, such as disseminated bronchiectasis and pancreatitis, which are also thought to result from CFTR mutations.

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Section: Class I Mutations Affecting Biosynthesismentioning

confidence: 98%

The Phenotypic Consequences of CFTR Mutations

Rowntree¹,

Harris²

2003

Annals of Human Genetics

296

215

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“…These results thus strongly suggest that only a subset of DMD and CMD patients carrying stop mutations would potentially benefit of a gentamicin treatment aiming at suppressing premature termination codons. They may also explain the failure or relative difficulty to obtain significant improvement of symptoms in clinical trials already reported, [34][35][36] since the patients included in these trials were not chosen on the criteria of the response of their mutation. Similarly, Gentamicin and muscular dystrophies L Bidou et al our efforts to correct the albino phenotype associated with the platinum (Typ cÀp ) coat color mutation by local or systemic treatment with gentamicin at several stages during embryogenesis, in pups and in adults failed (data not shown).…”

Section: Different Rules Govern Basal and Induced Readthroughmentioning

confidence: 99%

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

et al. 2004

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The suppression levels induced by gentamicin on premature stop codons, caused by primary nonsense mutations found in muscular dystrophy patients, were assessed using a very sensitive dual reporter gene assay. Results show that: (i) the effect of gentamicin on readthrough is similar in cultured cells and in vivo in murine skeletal muscle; (ii) a wide variability of readthrough efficiency is obtained, depending on the mutation tested; (iii) due to the complexity of readthrough regulation, efficiency cannot be predicted by the nucleotide context of the stop codon; (iv) only a minority of premature stop codons found in patients show a significant level of readthrough, and would thus be amenable to this pharmacological treatment, given our present understanding of the problem. These results probably provide an explanation for the relative failure of clinical trials reported to date using gentamicin to treat diseases due to premature stop codons, and emphasize that preliminary assays in cell culture provide valuable information concerning the potential efficiency of pharmacological treatments.

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“…Either nasal or intravenous administration of gentamicin improved NPD [86][87][88][89]. In all of these studies, there was a variability of response with some patients not responding to gentamicin.…”

Section: Mutation Class Specificmentioning

confidence: 95%

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

Hegyi

2016

Pancreatology

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Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Mutations in the CFTR gene diminish the ion channel function and lead to impaired epithelial fluid transport in multiple organs such as the lung and the pancreas resulting in cystic fibrosis. Heterozygous carriers of CFTR mutations do not develop cystic fibrosis but exhibit increased risk for pancreatitis and associated pancreatic damage characterized by elevated mucus levels, fibrosis and cyst formation. Importantly, recent studies demonstrated that pancreatitis causing insults, such as alcohol, smoking or bile acids strongly inhibit CFTR function. Furthermore, human studies showed reduced levels of CFTR expression and function in all forms of pancreatitis. These findings indicate that impairment of CFTR is critical in the development of pancreatitis; therefore, correcting CFTR function could be the first specific therapy in pancreatitis. In this review, we summarize recent advances in the field and discuss new possibilities for the treatment of pancreatitis.Corresponding author: Prof. Dr. Peter Hegyi, Doctor of the Hungarian Academy of Sciences, First Department of Medicine, University of Szeged, Koranyi fsr. 8-10, SZEGED, H6720, Hungary, TEL: +3662545200, FAX: +3662545185, MOBILE: +36703751031, hegyi.peter@med.u-szeged.hu. Conflict of interest statement: the authors have no conflict of interest to declare HHS Public Access I. Basics of CFTR a. Biosynthesis and degradationThe cystic fibrosis transmembrane conductance regulator (CFTR) protein is a cyclic AMP (cAMP)-regulated chloride (Cl − )/bicarbonate (HCO 3 − ) channel, expressed in the apical plasma membrane (PM) of secretory epithelia in the airways, pancreas, intestine, reproductive organs and exocrine glands [1]. CFTR consists of two homologous halves, each containing a hexa-helical membrane spanning domain (MSD1 and MSD2) and a nucleotide binding domain (NBD1 and NBD2) (Figure 1). The two halves are connected by the R domain [2]. The NBDs contain conserved ATP-binding sequences: Walker A and B motifs, classifying CFTR as a member of the ATP-binding cassette (ABC) transporter family. Structural, biochemical and functional evidence suggest that the two NBD domains interact and the ATP-binding site of one NBD is complemented by the ABC signature motif of the other [2].While NBD1 folds largely co-translationally, the native fold of NBD2 as well as CFTR are attained post-translationally [3]. Assembly of MSD1, NBD1, R domain and MSD2 is necessary and sufficient to form the minimal folding unit of CFTR [4]. These and other observations support the cooperative domain folding model and ensure the dynamic conformational coupling between the cytosolic NBDs and the pore-forming MSDs in the native molecule and provide a structural explanation for the cooperative domain unfolding, caused by cystic fibrosis (CF) mutations [4].Despite interactions with several cytosolic and endoplasmic reticulum (ER) chapero...

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Evidence that Systemic Gentamicin Suppresses Premature Stop Mutations in Patients with Cystic Fibrosis

Cited by 233 publications

References 34 publications

The Phenotypic Consequences of CFTR Mutations

The Phenotypic Consequences of CFTR Mutations

Premature stop codons involved in muscular dystrophies show a broad spectrum of readthrough efficiencies in response to gentamicin treatment

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

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