Genotype-phenotype correlation in cystic fibrosis patients compound heterozygous for the A455E mutation

Braekeleer, Marc De; Allard, Christian; Leblanc, Jean-Pierre; Simard, Fernand; Aubin, G

doi:10.1007/s004390050616

Cited by 51 publications

(34 citation statements)

References 13 publications

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“…It is generally believed that patients with CF exist along a continuum from completely absent CFTR to a level of activity adequate for near-normal pulmonary physiology. For example, the A455E mutation results in marginally reduced function of CFTR and clinically mild pulmonary disease, a later age at diagnosis, and a substantially improved prognosis (37). Even classically severe mutations (e.g., the common DF508 allele) have been reported by some (but not all) groups to retain low-level function in humans and mice in vivo (38)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Role of Oxygen Availability in CFTR Expression and Function

Guimbellot¹,

Fortenberry²,

Siegal³

et al. 2008

Am J Respir Cell Mol Biol

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The cystic fibrosis transmembrane conductance regulator (CFTR) serves a pivotal role in normal epithelial homeostasis; its absence leads to destruction of exocrine tissues, including those of the gastrointestinal tract and lung. Acute regulation of CFTR protein in response to environmental stimuli occurs at several levels (e.g., ion channel phosphorylation, ATP hydrolysis, apical membrane recycling). However, less information is available concerning the regulatory pathways that control levels of CFTR mRNA. In the present study, we investigated regulation of CFTR mRNA during oxygen restriction, examined effects of hypoxic signaling on chloride transport across cell monolayers, and related these findings to a possible role in the pathogenesis of chronic hypoxic lung disease. CFTR mRNA, protein, and function were robustly and reversibly altered in human cells in relation to hypoxia. In mice subjected to low oxygen in vivo, CFTR mRNA expression in airways, gastrointestinal tissues, and liver was repressed. CFTR mRNA expression was also diminished in pulmonary tissues taken from hypoxemic subjects at the time of lung transplantation. Environmental factors that induce hypoxic signaling regulate CFTR mRNA and epithelial Cl 2 transport in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Role of Oxygen Availability in CFTR Expression and Function

Guimbellot¹,

Fortenberry²,

Siegal³

et al. 2008

Am J Respir Cell Mol Biol

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“…De Braekeleer et al 26 reported that 4 patients with PI experienced several episodes of pancreatitis. For all 4, the diagnosis of CF was made and the PI was well documented several years before the first episode of pancreatitis.…”

Section: Discussionmentioning

confidence: 99%

Pancreatitis Among Patients With Cystic Fibrosis: Correlation With Pancreatic Status and Genotype

Boeck¹,

Weren²,

Proesmans³

et al. 2005

Pediatrics

132

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ABSTRACT. Objective. Pancreatitis is an infrequent complication among patients with cystic fibrosis (CF). It has mainly been reported for patients with pancreatic sufficiency (PS). Previous studies involved only a small number of patients because they contained data from single centers. The aim of this study was to evaluate the incidence of pancreatitis in a large heterogeneous CF population, to determine the relationship with pancreatic function, and to assess whether pancreatitis is associated with specific CFTR mutations.Methods. Physicians caring for patients with CF were approached through the CF Thematic Network or through the European Cystic Fibrosis Foundation newsletter. They were asked to provide data on their current patient cohort through a standardized questionnaire and to report how many patients they had ever diagnosed as having pancreatitis. A detailed questionnaire was then sent, to be filled out for all of their patients for whom pancreatitis had ever occurred. We defined pancreatitis as an episode of acute abdominal pain associated with serum amylase levels elevated above the ranges established by each participating center's laboratory. General clinical data included age, genotype, age at diagnosis of CF, sweat chloride concentrations, pancreatic status, biometric findings, and respiratory status. CFTR mutations were also reported according to the functional classification of classes I to V. Patients were categorized as having PS, pancreatic insufficiency (PI), or PI after an initial period of PS. PI was defined as a 72-hour stool fat loss of >7 g/day, fat absorption of <93%, or fecal elastase levels of <200 g/g feces. Clinical data on pancreatitis included age at the first episode, amylase and lipase levels, possible triggers, and occurrence of relapses or complications.Results years).Conclusions. This study of 10 071 patients with CF from 29 different countries revealed an estimated overall occurrence of pancreatitis among patients with CF of 1.24% (95% CI: 1.02-1.46%). The incidence of pancreatitis was much higher among patients with PS. However, pancreatitis was also reported for 15 patients with PI from 11 centers in 9 different countries. A correct diagnosis of pancreatitis for the reported patients with PI was supported by amylase and lipase levels increased above 500 IU/L, similar to those for patients with PS and pancreatitis. A correct diagnosis of PI for these patients with pancreatitis was supported by the adequacy of the methods used. We chose the cutoff values used to distinguish between patients with PI and control subjects without gastrointestinal disease. For one half of the patients, the diagnosis of PI was established on the basis of low levels of stool elastase (mean: 97 g/g stool). With a cutoff value of 200 g/g stool, this noninvasive test has high sensitivity (>95%) and high specificity (>90%) to differentiate patients with PI from control subjects with normal pan- creatic function. For the other one half of the patients with PI in the cohort, the pancreatic status was ...

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“…Wellpowered studies that reveal correlations between genotype and pancreatic status and sweat chloride concentrations have not shown correlation with lung function (as measured by the 1-s forced expiratory volume). However, when a sufficiently large number of patients with identical genotypes are found in a single geographic location such as Belgium and in French Canada, a correlation with decline in lung function becomes evident for the A455E (p.Ala455Glu) mutation (Gan et al 1995;De Braekeleer et al 1997).…”

Section: Genotype/phenotype Correlationsmentioning

confidence: 99%