Identification of the Cystic Fibrosis Gene: Genetic Analysis

Kerem, Bat Sheva; Rommens, Johanna M.; Buchanan, Janet A.; Markiewicz, Danuta; Cox, Tara K.; Chakravarti, Aravinda; Buchwald, Manuel; Tsui, Lap Chee

doi:10.1126/science.2570460

Cited by 3,570 publications

(796 citation statements)

References 40 publications

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“…Cystic fibrosis (CF) is caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) [1-3] and constitutes with 1 case per 2500 births the most common autosomal recessive disorder in the EU and the USA. Approximately 40 000 children and young adults are affected in the EU.…”

Section: Cystic Fibrosismentioning

confidence: 99%

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

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Sphingolipids and in particular ceramide have been shown to be critically involved in the response to many receptor-mediated, but also receptor-independent, mainly stress stimuli. Recent studies demonstrate that ceramide plays an important role in the pathogenesis of cystic fibrosis, a hereditary metabolic disorder caused by mutations of the Cystic Fibrosis Transmembrane Conductance Regulator. Patients with cystic fibrosis suffer from chronic pulmonary inflammation and microbial lung infections, in particular with Pseudomonas aeruginosa. Chronic pulmonary inflammation in these patients seems to be the initial pathophysiological event. Inflammation may finally result in the high infection susceptibility of these patients, fibrosis and loss of lung function. Recent studies demonstrated that ceramide accumulates in lungs of cystic fibrosis mice and causes age-dependent pulmonary inflammation as indicated by accumulation of neutrophils and macrophages in the lung and increased pulmonary concentrations of Interleukins 1 and 8, death of bronchial epithelial cells, deposition of DNA in bronchi and high susceptibility to Pseudomonas aeruginosa infections. Genetic or pharmacological inhibition of the acid sphingomyelinase blocks excessive ceramide production in lungs of cystic fibrosis mice and corrects pathological lung findings. First clinical studies confirm that inhibition of the acid sphingomyelinase with small molecules might be a novel strategy to treat patients with cystic fibrosis.

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Section: Cystic Fibrosismentioning

confidence: 99%

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

Becker

Riethmüller²,

Zhang³

et al. 2010

TORMJ

View full text Add to dashboard Cite

show abstract

“…Mutations in this gene cause cystic fibrosis, which is one of the most common inherited genetic life-shortening diseases, reducing the life expectancy to 37.5 years, across different populations. 74 Two particular mutations, ∆F 508 the most common CFTR mutation (70% and 90% of cystic fibrosis cases in U.K. and U.S., respectively) and 1653C/T a relatively rare single point mutation occurring in the same gene fragment, were targeted. We show that we can distinguish between the wild type, the single nucleotide mutation, and the most common triplet deletion in the human CFTR gene by employing SER(R)S to follow melting of the dsDNA from the SSV surface as either the temperature or the applied potential is scanned.…”

Section: Introductionmentioning

confidence: 99%

SERS-Melting: A New Method for Discriminating Mutations in DNA Sequences

et al. 2008

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Abstract:The reliable discrimination of mutations, single nucleotide polymorphisms (SNPs), and other differences in genomic sequence is an essential part of DNA diagnostics and forensics. It is commonly achieved using fluorescently labeled DNA probes and thermal gradients to distinguish between the matched and mismatched DNA. Here, we describe a novel method that uses surface enhanced (resonance) Raman spectroscopy (SER(R)S) to follow denaturation of dsDNA attached to a structured gold surface. This denaturation is driven either electrochemically or thermally on SERS active sphere segment void (SSV) gold substrates. Using this method, we can distinguish between wild type, a single point mutation (1653C/ T), and a triple deletion (∆F 508) in the CFTR gene at the 0.02 attomole level, and the method can be used to differentiate the unpurified PCR products of the wild type and ∆F 508 mutation. Our method has the potential to provide small, rapid, sensitive, reproducible platforms for detecting genetic variations and sequencing genes.

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“…Recent studies demonstrated that CF is caused by mmations in the gone coding for a transmembrahe protein denominated Cystic Fibrosis Transmembrane conductance Regulator, CFTR [2][3][4]. Transfeetion experiments [5][6][7] and the functional reconstitution into liposomes [8] demonstrated that CFTR is indeed a cAMP-dependent chloride transporter.…”

Section: Introductionmentioning

confidence: 99%

Effect of modulation of protein kinase C on the cAMP‐dependent chloride conductance in T84 cells

et al. 1992

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The regulation of chloride conductance was investi~ted in the T84 human colon carcinoma cell line by the quenching of the fluore.~.cent probe 6-methoxy-N-(3-sulfopropyl)quinollnium. The permeable cAMP analog 8.Br-eAMP (100/JM) and the calcium ionophom ionomyein (l/aM) activate a chloride conductancE. A prolonged (4 h) preineubation of cells with phorbol 12-myristate 13-acetate (100 nM) or with the diaeylgly~rol analog l-oleoyl-2-acctyl-l~lycerol (100 ,tiM): (i) down-modulates to almost zero the protein kinase C activity in the membranes; (ii) inhibits the activation of the chloride conductance mediated by 8-Br.cAMP but not by calcium; (iii) reduces the mRNA without chan#ng the ¢xpr~sion of the protein prod uct of the cystic fibrosis gone. The data suggest that PKC is essential for the activation of the cAMP-dependent chloride conductan~ in TM cells.

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Identification of the Cystic Fibrosis Gene: Genetic Analysis

Cited by 3,570 publications

References 40 publications

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

The Role of Sphingolipids and Ceramide in Pulmonary Inflammation in Cystic Fibrosis

SERS-Melting: A New Method for Discriminating Mutations in DNA Sequences

Effect of modulation of protein kinase C on the cAMP‐dependent chloride conductance in T84 cells

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