The Cystic Fibrosis Gene: A Molecular Genetic Perspective

Tsui, Lap‐Chee; Dorfman, Ruslan

doi:10.1101/cshperspect.a009472

Cited by 65 publications

(48 citation statements)

References 95 publications

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“…Fourteen of the 23 nonsense mutations affected a glutamine codon. Compared to the spectrum of disease-causing stop mutations in the CFTR gene of the CF host (64), this overrepresentation is highly unusual (P ϭ 1.6 ϫ 10 Ϫ4 ). We are unaware of any report in the literature of such a strong bias toward C-to-T transitions at the first position of the glutamine codon among nonsense mutations in P. aeruginosa (see Table S3 in the supplemental material).…”

Section: Resultsmentioning

confidence: 99%

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Greipel

Fischer

Klockgether

et al. 2016

Antimicrob Agents Chemother

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bThe chronic airway infections with Pseudomonas aeruginosa in people with cystic fibrosis (CF) are treated with aerosolized antibiotics, oral fluoroquinolones, and/or intravenous combination therapy with aminoglycosides and ␤-lactam antibiotics. An international strain collection of 361 P. aeruginosa isolates from 258 CF patients seen at 30 CF clinics was examined for mutations in 17 antimicrobial susceptibility and resistance loci that had been identified as hot spots of mutation by genome sequencing of serial isolates from a single CF clinic. Combinatorial amplicon sequencing of pooled PCR products identified 1,112 sequence variants that were not present in the genomes of representative strains of the 20 most common clones of the global P. aeruginosa population. A high frequency of singular coding variants was seen in spuE, mexA, gyrA, rpoB, fusA1, mexZ, mexY, oprD, ampD, parR, parS, and envZ (amgS), reflecting the pressure upon P. aeruginosa in lungs of CF patients to generate novel protein variants. The proportion of nonneutral amino acid exchanges was high. Of the 17 loci, mexA, mexZ, and pagL were most frequently affected by independent stop mutations. Private and de novo mutations seem to play a pivotal role in the response of P. aeruginosa populations to the antimicrobial load and the individual CF host. C ystic fibrosis (CF) is a severe autosomal recessive trait that is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) (1). CFTR dysfunction affects many organs, but lung disease is responsible for the vast majority of morbidity and mortality in people with CF. The basic defect in CF predisposes to viral and bacterial airway infections (2). The most prevalent airway pathogen in adolescents and adults with CF is Pseudomonas aeruginosa (3, 4). The chronic airway colonization with P. aeruginosa has been associated with a rapid decline in lung function, heightened lung inflammation, and worse prognosis (1).Antipseudomonal chemotherapy in CF comprises intravenous combination therapy with ␤-lactam antibiotics and aminoglycosides, oral fluoroquinolones, immunomodulatory treatment with azithromycin and aerosolized antibiotics such as tobramycin, aztreonam, or colistin (4-8). The high antimicrobial pressure exerted on the microorganism, which can persist and diversify in the patient's airways for decades, drives the emergence of drug resistance phenotypes (9, 10). Typical targets are elements of replication, transcription, and translation, the cell wall, and transport and its regulation (9-11).During ongoing studies on the long-term microevolution of P. aeruginosa in lungs of 12 CF patients, we have identified 17 loci to be repetitively hit by mutations. These loci are known from the literature to be associated with the emergence of drug resistance in P. aeruginosa (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Hence, we became interested to know if and to what extent the global P. aeruginosa population in lungs of patients (CF lungs) carries mutations in these ge...

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Section: Resultsmentioning

confidence: 99%

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Greipel

Fischer

Klockgether

et al. 2016

Antimicrob Agents Chemother

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“…Its incidence is one in 2,500 with a carrier frequency of one in 25. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, causing CF, was identified in 1989 [1] and located on chromosome 7q31.2, spanning a transcription unit of about 216.7 kb with 27 exons [2]. It encodes a transmembrane protein (CFTR, 1,480 amino acids) which is an ATP-binding cassette transporter functioning as a chloride (Cl - ) channel [1–6].…”

Section: Introductionmentioning

confidence: 99%

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

2017

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Cystic Fibrosis is the most common lethal autosomal recessive disorder in the white population, affecting among other organs, the lung, the pancreas and the liver. Whereas Cystic Fibrosis is a monogenic disease, many studies reveal a very complex relationship between genotype and clinical phenotype. Indeed, the broad phenotypic spectrum observed in Cystic Fibrosis is far from being explained by obvious genotype-phenotype correlations and it is admitted that Cystic Fibrosis disease is the result of multiple factors, including effects of the environment as well as modifier genes. Our objective was to highlight new modifier genes with potential implications in the lung, pancreatic and liver outcomes of the disease. For this purpose we performed a system biology approach which combined, database mining, literature mining, gene expression study and network analysis as well as pathway enrichment analysis and protein-protein interactions. We found that IFI16, CCNE2 and IGFBP2 are potential modifiers in the altered lung function in Cystic Fibrosis. We also found that EPHX1, HLA-DQA1, HLA-DQB1, DSP and SLC33A1, GPNMB, NCF2, RASGRP1, LGALS3 and PTPN13, are potential modifiers in pancreas and liver, respectively. Associated pathways indicate that immune system is likely involved and that Ubiquitin C is probably a central node, linking Cystic Fibrosis to liver and pancreatic disease. We highlight here new modifier genes with potential implications in Cystic Fibrosis. Nevertheless, our in silico analysis requires functional analysis to give our results a physiological relevance.

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“…L'exemple le plus connu est la mucoviscidose où des mutations altèrent cette région en 5' de l'exon 9 et entraînent une modulation de la sévérité de la maladie [26]. Dans le cas de l'hémophilie B, qui est caractérisée par un déficit en facteur IX (un facteur de coagulation) entraînant des hémorragies spontanées ou prolongées, la mutation c.392-8T>G du gène F9 (codant le facteur IX) entraîne l'exclusion de l'exon 5 due à une altération du point de branchement de l'intron 4 [27].…”

Section: Exemples De Mutations Agissant En Cis Au Niveau D'une Régionunclassified

Altérations de l’épissage et maladies rares

Grange

2016

Med Sci (Paris)

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> La majorité des gènes codant des protéines chez l'homme sont soumis à l'épissage alternatif, le principal mécanisme permettant d'augmenter la diversité du transcriptome et du protéome. La régulation de l'épissage dépend de complexes ribonucléoprotéiques qui composent le splicéosome, ainsi que de protéines régulatrices qui reconnaissent des séquences au niveau des ARN pré-messagers. De plus en plus de mutations au niveau de ces séquences, mais également au niveau de composants du splicéosome ou de facteurs d'épissage, sont décrites pour être responsables du développement de maladies rares. Depuis ces dernières années, des approches de thérapie ciblée sont développées pour restaurer au moins partiellement des événements d'épissage altérés dans le cadre de ces maladies. < La Figure 1 présente les grandes étapes de la régulation de l'expression des gènes. Un gène peut être à l'origine de la synthèse de plusieurs transcrits distincts traduits en protéines différentes, qui peuvent avoir des fonctions ou des localisations cellulaires différentes. Certains transcrits ont également un rôle régulateur et sont dégradés par la voie du NMD (nonsense-mediated mRNA decay) [2]. Ces transcrits sont reconnus par le NMD parce qu'ils présentent un codon stop pré-maturé (ou PTC pour premature stop codon). L'épissage alternatif n'est pas une exception mais plutôt une règle puisque ce mécanisme concerne la très large majorité des gènes humains codants. Si on considère les gènes avec plusieurs exons, 90 % des gènes humains codants sont soumis à épissage alternatif [3,4]. Il y a en moyenne environ quatre transcrits différents par gène [3,4] et pour un tiers des gènes, l'épissage alternatif est à l'origine de la synthèse d'au moins cinq ARN messagers différents [3,4]. L'estimation de cette diversité des ARN messagers se fonde sur les connaissances actuelles, et notamment sur les bases de données de transcrits qui restent limitées : en fonction des types cellulaires et tissulaires, des stades de développement, des pathologies et des traitements appliqués (par exemple, siARN [small interfering RNA], composés chimiques, rayonnements ultra-violet, stress cytotoxique, etc.), à peine plus de la moitié seulement des transcrits seraient mis en évi-

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The Cystic Fibrosis Gene: A Molecular Genetic Perspective

Cited by 65 publications

References 95 publications

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

Molecular Epidemiology of Mutations in Antimicrobial Resistance Loci of Pseudomonas aeruginosa Isolates from Airways of Cystic Fibrosis Patients

In silico search for modifier genes associated with pancreatic and liver disease in Cystic Fibrosis

Altérations de l’épissage et maladies rares

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