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PubMedDate not supplied

A closely linked genetic marker for cystic fibrosis.

Cystic fibrosis is a recessive genetic disorder, characterized clinically by chronic obstructive lung disease, pancreatic insufficiency and elevated sweat electrolytes; affected individuals rarely live past their early twenties. Cystic fibrosis is also one of the most common genetic diseases in the northern European population. The frequency of carriers of mutant alleles in some populations is estimated to be as high as 1 in 20, carrying a concomitant burden of about one affected child in 1,500 births. Because little is known of the essential biochemical defect caused by the mutant gene, a genetic linkage approach based on arbitrary genetic markers and family studies is indicated to determine the chromosomal location of the cystic fibrosis (CF) gene. We have now obtained evidence for tight linkage between the CF locus and a DNA sequence polymorphism at the met oncogene locus. This evidence, combined with the physical localization data for the met locus presented in the accompanying paper, places the CF locus in the middle third of the long arm of chromosome 7, probably between bands q21 and q31.

Chromosome Mapping↗

PubMed2004

Hepatobiliary complications of cystic fibrosis.

Cystic fibrosis (CF) is the most common potentially lethal genetic disease in the Caucasian population. The disease results from mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl(-) channel in the apical membrane of most secretory epithelia. In the liver, CFTR is located in biliary epithelial cells or cholangiocytes and gallbladder epithelia, where it appears to play a role in normal bile formation. However, how a defective CFTR protein leads to associated liver and biliary disease in a subset of patients with CF is unknown. Improvements in life expectancy have led to an increasing recognition of hepatobiliary complications from CF. Whereas the biliary tract disease is usually clinically evident, the liver involvement may progress silently, only manifesting as end-stage liver disease and portal hypertension. Unlike the pancreatic involvement in CF, a genotype-phenotype correlation is not apparent in the expression of liver disease, suggesting the presence of as yet unidentifiable "genetic modifiers" influencing disease expression. This review focuses on the pathogenesis, clinical manifestations, screening, diagnosis, and treatment of CF hepatobiliary disease.

Biliary Tract Diseases↗

PubMed1997

Pulmonary surfactant in cystic fibrosis.

Cystic fibrosis (CF) leads to a chronic inflammation of the airways with significant air flow limitations developing early in the course of the disease. As a well-functioning pulmonary surfactant is necessary to keep the alveoli and the small conducting airways open during expiration, we hypothesized that the biochemical and biophysical properties of surfactant may be impaired in CF. Bronchoalveolar lavage fluid obtained during a clinically stable period was analysed from 20 CF patients (5.9-20 yrs) and 17 healthy children and adults. CF patients had significantly elevated total and polymorphonuclear neutrophil cell counts, whereas the concentrations of total protein and phospholipids did not differ from controls. The percentage of surface active phospholipids, phosphatidylcholine and phosphatidylglycerol, and the concentration of surfactant protein A were significantly reduced in CF patients. Surfactant protein B was unchanged. Although the relative proportion of large aggregates was higher in CF, their surface active properties were inferior, as assessed in the pulsating bubble surfactometer. Because the capacity of CF lavage fractions to inhibit surfactant function was the same as that of controls, impaired minimal surface tension was more likely to be due to the biochemical alterations detected, than to inhibition of a well-functioning surfactant. The impaired pulmonary surfactant system in clinically stable patients with cystic fibrosis is in agreement with the view that surfactant dysfunction may contribute to lung disease in cystic fibrosis.

Adolescent↗

PubMed2005

Identification of molecular determinants that modulate trafficking of DeltaF508 CFTR, the mutant ABC transporter associated with cystic fibrosis.

Cystic fibrosis is a life-shortening inherited disorder associated primarily with a three-base in frame deletion that eliminates Phe508 in the ABC transporter, cystic fibrosis transmembrane conductance regulator (CFTR). Mutant CFTR, designated deltaF508 CFTR, is misprocessed and retained intracellularly. It is unclear what causes the trafficking impairment despite extensive investigative effort and the disease's prevalence. We hypothesize that the trafficking impairment is mediated by "receptors" of the cellular trafficking machinery that at three sequential "trafficking checkpoints" govern (1) exit from the endoplasmic reticulum (ER), (2) Golgi to the ER retrieval, and (3) targeting from post-Golgi compartments to lysosomes. We propose that, because of the Phe508 deletion and polypeptide misfolding: (1) a forward-directing signal recognized by the sec24 component of the COPII complex that mediates ER exit is eliminated; (2) a basic amino acid signal recognized by the COPI machinery involved in Golgi to ER retrieval becomes activated; and (3) a tyrosine-based sorting signal that targets to the lysosomes likewise becomes activated. We employed recently reported crystal structures of CFTR nucleotide binding domain 1 and sec24 in computational docking models to identify the most plausible CFTR-sec24 recognition domain. Site-directed mutagenesis and heterologous expression were also used to identify amino acid sequences that operate in Golgi to ER and post-Golgi to lysosome targeting. The importance of considering a multiple checkpoint model for trafficking is that rationale design of pharmaceutical interventions would require abrogation of all major checkpoints to deliver deltaF508 CFTR to the cell surface.

ATP-Binding Cassette Transporters↗

PubMed2004

Guide to bone health and disease in cystic fibrosis.

Cystic fibrosis (CF) is the most common genetic disease within the Caucasian population and leads to premature respiratory failure. Approximately 60,000 individuals are currently living with CF in North America and Europe, 40% of whom are adults. The life span of these patients has increased from approximately 2 to 32 yr of age over the last three decades. Bone disease has emerged as a common complication in long-term survivors of CF. Some studies have observed that 50-75% of adults have low bone density and increased rates of fractures. Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased levels of bone-active cytokines, physical inactivity, and glucocorticoid therapy) for poor bone health. This review is a condensed and updated summary of the Guide to Bone Health and Disease in Cystic Fibrosis: A Consensus Conference, a statement that evolved from a meeting convened by the Cystic Fibrosis Foundation in May 2002 to address the pathogenesis, diagnosis, and treatment of bone disease in CF. The goal of this conference was to develop practice guidelines for optimizing bone health in patients with CF.

Bone Diseases↗

PubMed2003

[Genetics and cellular biology of cystic fibrosis].

Cystic fibrosis (CF) is the most frequent lethal genetic disease in caucasians. It behaves as an autosomal recessive disease. The CF gene encodes a protein named CFTR (for "Cystic Fibrosis Transmembrane conductance Regulator") which exerts multiple functions. One of the most important function is the regulation of sodium and chlorine transport in epithelia. Defects in this control induce dehydration of airway surface liquid, which results in recurring bronchopulmonary infections, and increases in Na and Cl concentrations in sweat, which constitutes the rationale for the sweat test. CFTR also participates in the regulation of inflammation. Over one thousand mutations in the CFTR gene have been reported, the most frequent of which is the absence of the phenylalanine residue at amino acid position 508 (delta F508).

Blood Proteins↗

PubMed1986

Physiologic implications of the autonomic aberrations in cystic fibrosis.

Cystic fibrosis patients and their parents have increased alpha-adrenergic sensitivity, increased cholinergic sensitivity, and reduced beta-adrenergic sensitivity. This combination of autonomic aberrations has been associated with increased airway reactivity in other disease populations. Although studies of airway reactivity are difficult to interpret in the cystic fibrosis patients themselves, the parents have no apparent pulmonary infection or inflammation, and one-third of these people have increased airway reactivity. Moreover, parents of children with cystic fibrosis have increased prevalence of wheezing and lung disease in childhood. Airway reactivity has been associated in other populations, with increased risk of obstructive pulmonary disease. Further studies are required to test the hypothesis that heterozygosity for CF is a risk factor for development and progression of obstructive pulmonary disease.

Adult↗

PubMed2002

[Early bronchial inflammation in cystic fibrosis].

Cystic fibrosis (CF) is the most common genetic autosomal recessive disease in caucasian north-american and european populations. The CF gene codes for a transmembrane glycoprotein called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), a chloride channel which regulates the luminal secretion of chloride and the active ion and water transport in the airway epithelial cells. Mutations of the CF gene lead to a dysregulation of chloride and sodium channel associated to airway mucus dehydration, neutrophil-dominated airway inflammation and chronic infection responsible for the morbidity and mortality of CF patients. Although a high number of studies has been devoted to the CFTR pleiotropic functions, the chronology of the physiopathological events leading to the airway inflammation linked to mutations of the CF gene is still an open question. The issue of whether airway inflammation takes place before infection or is a consequence of infection during CF pathogenesis is still controversial. It has been recently reported that in broncho-alveolar lavages collected in CF infants, there is an increased level of interleukin IL-8 and abnormal low level of IL-10. The decreased IL-10 production has been confirmed in peripheral blood monocytes as well as in airway cell lines. Under basal conditions, the increased expression of the pro-inflammatory IL-8 cytokine has also been recently observed in the airway liquid secreted by CF naïve humanized airway xenografts and in the supernatant culture of CF human airway epithelial cells. These results suggest that CFTR dysfunction may result in a constitutive pro-inflammatory vs anti-inflammatory imbalance in CF disease. Recent data from the literature suggest that the failure of chloride transport, the maturation defect and mistraffricking of mutated CFTR, lead to its accumulation in the endoplasmic reticulum and activation of NF-kappa B, responsible for the imbalance in the CF airway cell cytokine production.

Animals↗

PubMed1993

The molecular biology of cystic fibrosis.

Cystic fibrosis afflicts many children and, as the life expectancy for patients with this disease steadily increases, many adults as well. The identification and characterization of the gene responsible for this disorder provide a basis for understanding the pathophysiology of cystic fibrosis. Basic science advances are rapidly being integrated into the diagnostic and therapeutic regimens used by physicians in the care of patients with this disease.

Chromosomes, Human, Pair 7↗

PubMed2001

[From gene to disease; from defective chloride ion transport to cystic fibrosis].

Cystic fibrosis is an autosomal recessive disorder affecting the lungs, pancreas, intestines, sweat ducts and liver, due to an abnormal salt transport across the apical border of epithelial cells. Mutations in the CF underlying gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene, result in most cell types in an misprocessing so that little of the protein reaches the membranes. In case of clinical suspicion and/or doubtful sweat test results, mutation analysis can support the diagnosis of CF. Also carrier detection is offered.

Adult↗

PubMed1997

A placebo-controlled study of liposome-mediated gene transfer to the nasal epithelium of patients with cystic fibrosis.

Cystic fibrosis (CF) is a common, serious, inherited disease. The major cause of mortality in CF is lung disease, due to the failure of airway epithelial cells to express a functional product of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. A potential treatment for CF lung disease is the expression of CFTR in the airways following gene transfer. We have undertaken a double-blinded, placebo-controlled, clinical study of the transfer of the CFTR cDNA to the nasal epithelium of 12 CF patients. Cationic liposomes complexed with plasmid containing the human CFTR cDNA were administered to eight patients, whilst four patients received placebo. Biopsies of the nasal epithelium taken 7 days after dosing were normal. No significant changes in clinical parameters were observed. Functional expression of CFTR assessed by in vivo nasal potential difference measurements showed transient correction of the CF chloride transport abnormality in two patients (15 days after dosing in one patient). Fluorescence microscopy demonstrated CFTR function ex vivo. In cells from nasal brushings. In total, evidence of functional CFTR gene transfer was obtained in six out of the eight treated patients. These results provide proof of concept for liposome-mediated CF gene transfer.

Adolescent↗

PubMed1999

Cationic lipid:pDNA complexes for the treatment of cystic fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease that results in damage to organs containing secretory epithelial cells, such as the lung, intestines, pancreas and liver. CF results from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which functions as a chloride channel in the apical membrane of secretory epithelial cells. In the lung, the loss of CFTR activity results in abnormal epithelial ion transport, including defective cyclic AMP-mediated chloride (Cl-) efflux and the hyper absorption of sodium ions. These defects in ion transport affect the osmotic flow of water across the epithelium and result in thickened airway secretions which are not properly cleared from the lung. Patients with CF suffer from chronic pathogenic infection of the lungs which in turn results in the formation of purulent mucus, chronic inflammation and fibrosis, which eventually cause a loss of lung function. One approach to treat CF is to replace the defective copy of the gene encoding for CFTR with a correct copy employing one of a number of possible gene therapy vectors. This review summarizes the most recent progress towards gene therapy for CF employing cationic lipid:pDNA complexes. The results of recent clinical trials conducted in the nasal epithelium of CF patients are presented, followed by a description of preclinical studies conducted in order to support trials of aerosolized lipid:pDNA complexes into the lungs of CF patients. A brief overview of the results of these aerosol trials is presented, followed by a discussion of the lessons learned from these studies. More specifically, the issues of efficacy and toxicity of cationic lipid:pDNA complexes in the setting of the CF lung are discussed and recent findings which are relevant to these limiting issues are introduced. Finally, studies which point to the possibility of improved formulations capable of overcoming some of the barriers identified for the current generation of cationic lipid:pDNA complexes are introduced.

Cations↗

PubMed1996

Hepatobiliary manifestations of cystic fibrosis.

Cystic fibrosis is the most common, potentially lethal genetic defect in the Caucasian population. During recent years it has been increasingly associated with a number of hepatic and biliary abnormalities, of which chronic cholestatic liver disease is by far the most relevant. Plugging of intrahepatic bile ducts with inspissated secretions is thought to play a major role in the pathogenesis. Attempts have been made to provide uniform criteria to identify patients with early, possibly reversible, hepatic lesions, as well as to assess severity of liver disease. It has been estimated that bout 13% of cystic fibrosis patients present serum liver enzyme abnormalities, but prevalence of liver involvement is likely to be higher. Due to decreasing mortality from extrahepatic causes in cystic fibrosis and to the widespread use of laboratory tests and ultrasound examination, patients with minor degree of liver involvement will be increasingly represented in future. Oral bile acid therapy is promising, but its long-term benefits in terms of survival and prevention of major complications of liver cirrhosis remain to be established. Liver transplantation is the only potentially curative treatment for patients with advanced stage liver disease and mild pulmonary involvement.

Bile Ducts↗

PubMed1993

[Quality of life of children with cystic fibrosis].

Cystic fibrosis is a disease that conveys a large amount of anxiety. Nevertheless, it is always said that the psychosocial adaptation of the patients and their families is good. In this study, we analyzed the quality of life and the knowledge of the illness possessed by parents of 55 children with cystic fibrosis. The data obtained suggested a good level of knowledge about the disease and an acceptable assessment of their quality of life. The familiar problems reflected in the study concerned regular school attendance and the communication between parents and patients, mainly concerning the illness. This was more obvious with teenagers (12 cases: 21.8%). Finally, it can be stated that the work activity and social relationships of the families had changed notably since the time of diagnosis (70% of the 55 cases reflect this change), with no differences among the age groups. We conclude by stressing the importance of supporting these families, especially at the moment of diagnosis. The associations for cystic fibrosis are of great importance for preventing psychosocial problems amongst their membership.

Adolescent↗

PubMed2005

Developmental paradigm for early features of cystic fibrosis.

Cystic fibrosis (CF) is a progressive disease in which the lung is perceived to be normal at birth and is injured by recurrent infection. However, there is increasing evidence that the lung is functionally and structurally abnormal prior to the appearance of clinical infection. The cystic fibrosis transmembrane regulator (CFTR) is highly expressed in fetal tissues, and this review examines the role of CFTR in regulatory cascades during lung development. Early changes in the CF lung are examined from a perspective of disrupted fetal development, explaining a number of paradoxes seen with the disease.

Cystic Fibrosis↗

PubMed1995

Diminished concentrations of insulin-like growth factor I in cystic fibrosis.

Cystic fibrosis is frequently accompanied by a catabolic condition with low body mass index caused by a number of disease complications. Insulin-like growth factor-I (IGF-I) is an anabolic hormone and an important marker of nutritional status, liver function, and linear growth. Available data on IGF-I in cystic fibrosis are sparse and conflicting. From 1990-3, 235 of our 240 patients (114 males, 121 females, median age 16.2 years, ranged 0.1-44.0 years) had IGF-I measured once by radioimmunoassay. IGF-I was significantly reduced compared with a healthy Scandinavian control population: mean (-2 SD to +2 SD) IGF-I SD score was -0.97 (-3.7 to 1.7) in males and -0.67 (-3.2 to 1.9) in females. Height SD score was -0.95 (-3.3 to 1.4) in males and -0.81 (-3.2 to 1.6) in females. In patients who were still in the growth period a significant correlation of IGF-I SD score to height SD score (r = 0.28, p < 0.001) was found. The low IGF-I concentrations may reflect the catabolic state of many patients with cystic fibrosis and play a part in their abnormal growth pattern.

Adolescent↗

PubMed2001

Pharmacological treatment of the ion transport defect in cystic fibrosis.

Cystic fibrosis (CF) is a lethal monogenetic disease characterised by impaired water and ion transport over epithelia. The lung pathology is fatal and causes death in 95% of CF patients. The genetic basis of the disease is a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. The most common mutation, DeltaF508, results in a protein that cannot properly be folded in the endoplasmic reticulum, is destroyed and hence does not reach the apical cell membrane. This paper will discuss those pharmacological approaches that are directed at correcting the defect in ion transport. At present, no clinically effective drug is available, although research has defined areas in which progress might be made. These are the following: (1) the drug 4-phenylbutyrate (4PBA) increases the expression of DeltaF508-CFTR in the cell membrane, probably by breaking the association between DeltaF508-CFTR and a chaperone; (2) a number of xanthines, in particular 8-cyclopentyl-1, 3-dipropylxanthine (CPX), are effective in activating CFTR, presumably by direct binding and also possibly by correcting the trafficking defect; (3) the isoflavone genistein can activate both wild-type and mutant CFTR, probably through direct binding to the channel; (4) purinergic agonists (ATP and UTP) can stimulate chloride secretion via a Ca(2+)-dependent chloride channel and in this way compensate for the defect in CFTR, but stable analogues will be required before this type of treatment has clinical significance; (5) treatment with inhaled amiloride may correct the excessive absorption of Na(+) ions and water by airway epithelial cells that appears connected to the defect in CFTR; although clinical tests have not been very successful so far, amiloride analogues with a longer half-life may give better results. The role of CFTR in bicarbonate secretion has not yet been established with certainty, but correction of the defect in bicarbonate secretion may be important in clinical treatment of the disease. Currently, major efforts are directed at developing a pharmacological treatment of the ion transport defect in CF, but much basic research remains to be done, in particular, with regard to the mechanism by which defective CFTR is removed in the endoplasmic reticulum by the ubiquitin-proteasome pathway, which is a central pathway in protein production and of significance for several other diseases apart from CF.

Amiloride↗

PubMed1986

Infection in patients with cystic fibrosis.

Cystic fibrosis is the most common lethal genetic disease of Caucasians. The disease affects the exocrine gland secretions throughout the body, and as a result, major pathologic changes develop in the pancreas and in the bronchi. Obstruction of the respiratory airways results in chronic infection, and in time, this leads to progressive deterioration of lung function. In the initial stages of the disease, usually during infancy, infection with Staphylococcus aureus plays an important role. Hemophilus influenzae infections are also common. As the disease progresses, infection with Pseudomonas aeruginosa develops. Exacerbation of bronchopulmonary infection is often initiated by respiratory viral or mycoplasmal infection, with superimposed S. aureus and P. aeruginosa infections contributing to the severity of the infection. Frequent courses of antibiotic therapy are usually required, and some patients may have to receive antibiotics continuously. Oral cephalosporins, ampicillin, and the combination of trimethoprim/sulfamethoxazole are commonly used for relatively mild infections. In the treatment of exacerbation of infection, intravenous penicillinase-resistant penicillins and anti-Pseudomonas antibiotics are the drugs of choice. For Pseudomonas infections, ticarcillin, carbenicillin, the ureidopenicillins, and the aminoglycosides are indicated. The combination of an anti-Pseudomonas penicillin and an aminoglycoside are most commonly used. Of the third-generation cephalosporins, ceftazidime appears to be the most efficacious. The quinolones (such as ciprofloxacin) are also active against P. aeruginosa, and preliminary studies of these drugs in patients with cystic fibrosis appear to indicate that they are as efficacious as the already available antibiotics. In many centers, Pseudomonas cepacia has emerged as a serious problem in patients with cystic fibrosis. This organism tends to develop resistance to multiple antibiotics. In some centers, infection with P. cepacia has been associated with a severe, frequently fatal, pneumonia.

Anti-Bacterial Agents↗