Type of CFTR Mutation Determines Risk of Pancreatitis in Patients With Cystic Fibrosis

Ooi, Chee Y.; Dorfman, Ruslan; Cipolli, Marco; Gonska, Tanja; Castellani, Carlo; Keenan, Katherine; Freedman, Steven D.; Zielenski, Julian; Berthiaume, Yves; Corey, Mary; Schibli, Susanne; Tullis, Elizabeth; Durie, Peter R.

doi:10.1053/j.gastro.2010.09.046

Cited by 232 publications

(222 citation statements)

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“…154 Specific CFTR mutations cannot reliably predict which children will get pancreatitis. 155 Acute pancreatitis is a potentially life-threatening disease associated with severe pain, nausea, and vomiting.…”

Section: Figure 2dmentioning

confidence: 99%

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis

et al. 2016

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Cystic fibrosis (CF) clinical care guidelines exist for the care of infants up to age 2 years and for individuals ≥6 years of age. An important gap exists for preschool children between the ages of 2 and 5 years. This period marks a time of growth and development that is critical to achieve optimal nutritional status and maintain lung health. Given that disease often progresses in a clinically silent manner, objective and sensitive tools that detect and track early disease are important in this age group. Several challenges exist that may impede the delivery of care for these children, including adherence to therapies. A multidisciplinary committee was convened by the CF Foundation to develop comprehensive evidence-based and consensus recommendations for the care of preschool children, ages 2 to 5 years, with CF. This document includes recommendations in the following areas: routine surveillance for pulmonary disease, therapeutics, and nutritional and gastrointestinal care.

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Section: Figure 2dmentioning

confidence: 99%

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis

et al. 2016

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“…12,13,15 Recently established PI prevalence (PIP) scores are being used to distinguish more accurately between the severity of different CFTR mutations within the milder range. 16,17 By contrast, MI is commonly reported in patients with CF carrying "severe" class I-III CFTR mutations. 4 Given the early presentation with minimal opportunity for environmental influence, we sought to determine whether MI is associated with the CFTR genotype using large patient cohorts.…”

Section: Introductionmentioning

confidence: 99%

“…4 Given the early presentation with minimal opportunity for environmental influence, we sought to determine whether MI is associated with the CFTR genotype using large patient cohorts. We hypothesized that, similar to the pancreatic phenotype, 16,18 the susceptibility to MI is influenced by specific CFTR genotypes, and that the prevalence of MI can be used to discriminate among severe CFTR mutations. We estimated and compared the prevalence of MI for different CFTR mutations using data sets from four countries and investigated association with other clinical markers of disease severity, including lung function (forced expiratory volume in 1 second (FEV 1 )) and body mass index (BMI).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

Dupuis

Keenan

Ooi

et al. 2016

Genetics in Medicine

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Rationale: Meconium ileus (MI) is a perinatal complication in cystic fibrosis (CF), which is only minimally influenced by environmental factors. We derived and examined MI prevalence (MIP) scores to assess CFTR phenotype-phenotype correlation for severe mutations.Method: MIP scores were established using a Canadian CF population (n = 2,492) as estimates of the proportion of patients with MI among all patients carrying the same CFTR mutation, focusing on patients with p.F508del as the second allele. Comparisons were made to the registries from the US CF Foundation (n = 43,432), Italy (Veneto/Trentino/Alto Adige regions) (n = 1,788), and Germany (n = 3,596). Results:The prevalence of MI varied among the different registries (13-21%). MI was predominantly prevalent in patients with pancreatic insufficiency carrying "severe" CFTR mutations. In this severe spectrum MIP scores further distinguished between mutation types, for example, G542X (0.31) with a high, F508del (0.22) with a moderate, and G551D (0.08) with a low MIP score. Higher MIP scores were associated with more severe clinical phenotypes, such as a lower forced expiratory volume in 1 second (P = 0.01) and body mass index z score (P = 0.04).Conclusions: MIP scores can be used to rank CFTR mutations according to their clinical severity and provide a means to expand delineation of CF phenotypes.

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“…In fact, this subgroup of PS patients appears to be highly susceptible to pancreatitis, since almost 1 in 5 was affected by this complication. In the largest study to date of CF PS patients, Ooi et al in a seminal paper determined the association between severity of CFTR genotype and the risk of pancreatitis [50]. They examined a large cohort of 277 PS patients from two CF centers of which 62 had well documented pancreatitis.…”

Section: B Clinical Characterization Of Pancreatic Function In Cfmentioning

confidence: 99%

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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Type of CFTR Mutation Determines Risk of Pancreatitis in Patients With Cystic Fibrosis

Cited by 232 publications

References 41 publications

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis

Clinical Practice Guidelines From the Cystic Fibrosis Foundation for Preschoolers With Cystic Fibrosis

Prevalence of meconium ileus marks the severity of mutations of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene

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

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