CFTR,SPINK1,CTRCandPRSS1variants in chronic pancreatitis: is the role of mutatedCFTRoverestimated?

Rosendahl, Jonas; Landt, Olfert; Bernadova, Jana; Kovacs, Peter; Teich, Niels; Bödeker, Hans; Keim, Volker; Ruffert, Claudia; Mössner, Joachim; Kage, Andreas; Stümvoll, Michael; Groneberg, David A.; Krüger, Renate; Luck, W. A. P.; Treiber, Matthias; Becker, Michael; Witt, Heiko

doi:10.1136/gutjnl-2011-300645

Cited by 171 publications

(178 citation statements)

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Section: B Physiological Functionsmentioning

confidence: 90%

“…In this way, CFTR gating tightly 'regulates' the flow of anions in and out of the cell, with the anion being transported down its prevailing electrochemical gradient by a purely facilitative diffusional process. While functional measurements seem to support this contention, a genetic association between these variants and chronic pancreatitis cannot be confirmed [25][26][27].Common polymorphic CFTR alleles do not modify pancreatitis risk. There are two adjacent polymorphic regions (poly-T and poly-TG tracts) in intron-8 which can alter inclusion of exon-9 (legacy numbering) during splicing [28][29][30].…”

mentioning

confidence: 89%

“…Whether or not the T5-TG12 complex allele confers a small risk in chronic pancreatitis remains to be determined. Curiously, small but measurable differences were reported for the distribution of the TG10 and TG11 alleles between chronic pancreatitis cases and controls, either analyzed separately or as part of conserved haplotypes [26,32]. In two studies, TG10 appeared to increase disease risk slightly while TG11 seemed to be protective.…”

Section: B Physiological Functionsmentioning

confidence: 99%

“…A T5 allele combined with a severe CFTR mutation may cause CF and increases the penetrance of the mild p.R117H mutation. Studies on smaller cohorts reported enrichment of the T5 allele in chronic pancreatitis [21,23,24,31], however, more recent analyses on larger cohorts did not find such overrepresentation [26,27]. When analyzed separately, the distribution of the TG12 allele between chronic pancreatitis cases and controls was also equal [26].…”

mentioning

confidence: 96%

“…The combined effects of multiple pathogenic mutations results in strongly amplified disease risk; best documented for the cooccurrence of SPINK1 and CFTR mutations. There is no compelling evidence for epistasis between SPINK1 and CFTR mutations; the two susceptibility genes seem to act independently in determining the pancreatitis phenotype [26]. CFTR mutations can also contribute to the increased clinical penetrance of anatomical risk factors for chronic pancreatitis such as pancreas divisum [33].…”

Section: Author Manuscriptmentioning

confidence: 99%

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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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Section: B Physiological Functionsmentioning

confidence: 90%

mentioning

confidence: 89%

Section: B Physiological Functionsmentioning

confidence: 99%

mentioning

confidence: 96%

Section: Author Manuscriptmentioning

confidence: 99%

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

Hegyi

2016

Pancreatology

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Diagnosis and Management of Chronic Pancreatitis

Singh

Yadav

Garg

2019

JAMA

345

195

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hronic pancreatitis (CP) is a chronic progressive disease with an annual incidence of 5 to 8 and prevalence of 42 to 73 cases per 100 000 adults in the United States. 1-3 Prevalence rates varying from 36 to 125 per 100 000 population have been reported from Japan, China, and India, of which India has the highest prevalence. 4,5 Chronic pancreatitis is characterized by fibrosis and inflammation of the pancreas in individuals with genetic, environmental, and other risk factors such as hypertriglyceridemia. Chronic pancreatitis is characterized by pancreatic atrophy, fibrosis, ductal strictures and distortion, calcifications, dysplasia, exocrine insufficiency and diabetes, and chronic pain. 6 This review summarizes current evidence regarding risk factors, pathophysiology, clinical features, diagnostic evaluation, treatment, and prognosis of CP. MethodsWe searched PubMed for relevant English-language articles published from January 1, 2000, to July 1, 2019. Search terms included chronic pancreatitis and each of the following:

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