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David C. Whitcomb - One of the best experts on this subject based on the ideXlab platform.
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Genetic Risk Factors for Pancreatic Disorders
Gastroenterology, 2013Co-Authors: David C. WhitcombAbstract:A combination of genetic, environmental, and metabolic factors contribute to the development and recurrence of acute and chronic pancreatitis; information on all of these is required to manage patients effectively. For example, variants that affect regulation of the protease, serine (PRSS)1-PRSS2, and claudin (CLDN)2 loci, rather than their coding sequences, interact with other genetic and environmental factors to affect disease development. New strategies are needed to use these data and determine their contribution to pathogenesis, because these variants differ from previously studied, rare variants in exons (coding regions) of genes such as PRSS1, SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin (CTR)C, and calcium-sensing receptor (CASR). Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms.
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Genetics of acute and chronic pancreatitis.
Current opinion in gastroenterology, 2013Co-Authors: Rawad Mounzer, David C. WhitcombAbstract:PURPOSE OF REVIEW Acute pancreatitis, recurrent acute pancreatitis (RAP) and chronic pancreatitis are interrelated and progressive inflammatory disorders of the pancreas with highly variable and complex susceptibility, severity and outcomes. The role of genetics in acute pancreatitis, RAP and progression to chronic pancreatitis within a new framework is needed. RECENT FINDINGS The first genome-wide association study in the pancreas has been published with genome-wide significance linked with noncoding variants at the PRSS1-PRSS2 locus on chromosome seven and the CLDN2 locus on the X chromosome. A new personalized medicine paradigm is being considered to facilitate organization of genetic and other susceptibility risk compared with the risk of disease progression or resolution and risk of complications. SUMMARY A new framework for organizing multiple, complex data sets is emerging. The role of genetics in the context of other variables is important in understanding susceptibility to RAP and in the modification of disease severity and progression to chronic pancreatitis. Questions of when to order testing, what to order and how to use the data in real time remains an area for future research and development.
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Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis
Nature Genetics, 2012Co-Authors: David C. Whitcomb, Jessica Larusch, Alyssa M Krasinskas, Lambertus Klei, Jill P Smith, Randall E Brand, John P Neoptolemos, Markus M Lerch, Matt Tector, Bimaljit S SandhuAbstract:Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1 , CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1 - PRSS2 ( P < 1 × 10^−12) and X-linked CLDN2 ( P < 1 × 10^−21) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07). David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption.
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common genetic variants in the cldn2 and prss1 PRSS2 loci alter risk for alcohol related and sporadic pancreatitis
Nature Genetics, 2012Co-Authors: David C. Whitcomb, Jessica Larusch, Alyssa M Krasinskas, Lambertus Klei, Jill P Smith, Randall E Brand, John P Neoptolemos, Markus M Lerch, Matt Tector, Bimaljit S SandhuAbstract:David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption.
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Duplication of a 303 kb Locus Containing PRSS1 and PRSS2 is Associated With Hereditary Pancreatitis in a Spanish Kindred
Gastroenterology, 2011Co-Authors: Antonio Lozano-leon, David C. Whitcomb, Pablo Raña, Raquel Cruz, Laura Nieto, Francisco Barros, M. Michael Barmada, Kim Stello, Enrique Dominguez-munozAbstract:Background:Etiologies of recurrent pancreatitis include anatomical anomalies, hereditary, metabolic and autoimmune disorders. A significant number of patients remain with a diagnosis of idiopathic pancreatitis. The advent of genetic analysis and electrophysiologic testing may further assist in the diagnostic process. Evidence has shown that specific genetic mutations in the cationic trypsinogen gene PRSS1 and the SPINK1 gene for pancreatic secretory trypsin inhibitor cause pancreatitis; furthermore cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations have been associated with pancreatitis. Aims :To present the work-up of patients with recurrent pancreatitis referred for genetic analysis and electrophysiological testing. Methods : Patients with recurrent, acute pancreatitis with no known etilology were referred to the Electrophysiology Laboratory, Division of Pediatric GI at Hadassah University Hospital for PRSS1 and SPINK1 gene mutations as well as evaluation of CFTR function by Nasal Potential Difference (NPD) testing. Results: A total of 42 patients with recurrent pancreatitis were evaluated; the mean age was 21 years ±14.9 years (range 2-54 yrs). A third (33%) of the patients was of Ashkenazi ancestry, 41% of mainly Sephardic ancestry, 24% of Arab ancestry and the remaining 2% of other ethnic background. There was a family history in 8 patients. The patients had a mean of 4 episodes (range 1-25). 6 (14%) patients showed PRSS1 genemutation (p.R112H and p.K23R) including 2 sets of siblings of Georgian Jewish ancestry with p.K23R. No SPINK1 mutation was found in the 26 patients submitted for testing. 3 patients out of 21 submitted for CFTR gene testing showed mutations (5T, F508del/p.L997F and D1152H/5T). 26 (61%) patients underwent sweat testing, with 13 patients with results >40 mmol/L. 35 (83%) patients had Nasal Potential Difference testing, 4 (11.5%) with abnormal results: 3 had sweat chloride>60mmol/L with no CFTR mutations found but one patient with D1152H/5T had a sweat test of 30 mmol/L. None of the 6 patients with PRSS1 gene mutation showed any concomitant CFTR dysfunction (by NPD or sweat testing) or gene mutation.Conclusion:This is the first study on recurrent pancreatitis in Israel examining both the presence of susceptibility gene mutations for pancreatitis and CFTR dysfunction. A prospective study with a larger number of patients may further clarify the impact of genetic mutations and CFTR dysfunction on the clinical presentation and outcome of recurrent pancreatitis.
Claude Férec - One of the best experts on this subject based on the ideXlab platform.
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Role of the Common PRSS1-PRSS2 Haplotype in Alcoholic and Non-Alcoholic Chronic Pancreatitis: Meta- and Re-Analyses
Genes, 2020Co-Authors: Anthony F Herzig, Emmanuelle Masson, Claude Férec, David Neil Cooper, Emmanuelle Génin, Jian-min ChenAbstract:The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. A meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled odds ratio (OR) 1.67, 95% confidence interval (CI) 1.56-1.78; p < 0.00001) and NACP (pooled OR 1.28, 95% CI 1.17-1.40; p < 0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with alcohol consumption.
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role of the common prss1 PRSS2 haplotype in alcoholic and non alcoholic chronic pancreatitis meta and re analyses
medRxiv, 2020Co-Authors: Anthony F Herzig, Emmanuelle Masson, Claude Férec, David Neil Cooper, Emmanuelle Génin, Jian-min ChenAbstract:The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. Meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled OR 1.67, 95% CI 1.56-1.78; P<0.00001) and NACP (pooled OR 1.28, 95% CI 1.17-1.40; P<0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with ACP.
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Role of the common PRSS1-PRSS2 haplotype in alcoholic and non-alcoholic chronic pancreatitis: meta- and re-analyses
2020Co-Authors: Anthony F Herzig, Emmanuelle Masson, Claude Férec, David Neil Cooper, Emmanuelle Génin, Jian-min ChenAbstract:The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. Meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled OR 1.67, 95% CI 1.56-1.78; P
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The CTRB1-CTRB2 risk allele for chronic pancreatitis discovered in European populations does not contribute to disease risk variation in the Chinese population due to near allele fixation.
Gut, 2017Co-Authors: Xin-ying Tang, Emmanuelle Masson, Jian-min Chen, Claude Férec, Wen-bin Zou, Zhuan LiaoAbstract:We read with great interest the article by Rosendahl et al 1 reporting the identification of CTRB1-CTRB2 (chymotrypsin B1 and chymotrypsin B2) as a new chronic pancreatitis (CP) risk locus by means of genome-wide association study, with the lead single nucleotide polymorphism (SNP) rs8055167 having an OR of 1.35. Moreover, they found that a previously reported 16.6 kb inversion in the CTRB1-CTRB2 locus2 was in linkage disequilibrium with the CP-associated SNPs and optimally tagged by rs8048956. Furthermore, they provided in silico and in vivo evidence showing that the inversion variant changes the expression ratio of the CTRB1 and CTRB2 isoforms, the major risk allele being associated with increased CTRB1 and decreased CTRB2 mRNA expression as compared with the minor allele. Finally, they provided in vitro evidence that CTRB1 was less efficient in degrading anionic trypsinogen (PRSS2) than CTRB2 (note that rapid degradation of PRSS2 conferred by a PRSS2 missense variant protects against CP).3 Taking together, Rosendahl and colleagues concluded that …
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Pathogenetics of Chronic Pancreatitis
Chronic Pancreatitis, 2017Co-Authors: Zhuan Liao, Claude Férec, David Neil Cooper, Jian-min ChenAbstract:Chronic pancreatitis is a condition that is associated with the progressive inflammation of the pancreas which over time gives rise to irreversible morphological changes accompanied by impairment of both exocrine and endocrine functions (Majumder and Chari 2016). Over the last 20 years, molecular genetics has played an increasingly important role in elucidating the aetiology of chronic pancreatitis. The dawn of the new era in the genetic analysis of autosomal dominant hereditary pancreatitis (OMIM #167800) was heralded by the mapping of a disease locus to the long arm of chromosome 7 (Le Bodic et al. 1996; Pandya et al. 1996; Whitcomb et al. 1996b) and the subsequent identification of a gain-of-function missense mutation (i.e., p.Arg122His) in the cationic trypsinogen gene (PRSS1; OMIM #276000) (Whitcomb et al. 1996a). Thereafter, a steady stream of chronic pancreatitis susceptibility (or protective) variants in different genes has been reported. The analysis of variants in four specific genes, all highly expressed in human pancreatic acinar cells [PRSS1, PRSS2 (encoding anionic trypsinogen; OMIM #601564), SPINK1 (encoding pancreatic secretory trypsin inhibitor; OMIM #167790) and CTRC (encoding chymotrypsin C, which specifically degrades all human trypsinogen/trypsin isoforms (OMIM #601405) (Szmola and Sahin-Toth 2007))] has firmly established the importance of a homeostatic balance between the activation and inactivation of trypsinogen within the pancreas, thereby defining a trypsin-dependent pathway in the pathogenesis of chronic pancreatitis. Whereas gain-of-function missense mutations and copy number variants in PRSS1 (Le Marechal et al. 2006; Whitcomb et al. 1996a) and loss-of-function variants in SPINK1 (Witt et al. 2000) and CTRC (Masson et al. 2008b; Rosendahl et al. 2008) predispose to chronic pancreatitis, loss-of-function variants in PRSS1 (Boulling et al. 2015; Chen et al. 2003; Derikx et al. 2015; Whitcomb et al. 2012) and PRSS2 (Witt et al. 2006) protect against the disease.
Miklos Sahintoth - One of the best experts on this subject based on the ideXlab platform.
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tighter control by chymotrypsin c ctrc explains lack of association between human anionic trypsinogen and hereditary pancreatitis
Journal of Biological Chemistry, 2016Co-Authors: Zsanett Jancso, Miklos SahintothAbstract:The human pancreas expresses two major trypsinogen isoforms, cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2). Mutations in PRSS1 cause hereditary pancreatitis by altering cleavage of regulatory nick sites by chymotrypsin C (CTRC) resulting in reduced trypsinogen degradation and increased autoactivation. Despite 90% identity with PRSS1 and a strong propensity for autoactivation, mutations in PRSS2 are not found in hereditary pancreatitis suggesting that activation of this isoform is more tightly regulated. Here, we demonstrated that CTRC promoted degradation and thereby markedly suppressed autoactivation of human anionic trypsinogen more effectively than previously observed with cationic trypsinogen. Increased sensitivity of anionic trypsinogen to CTRC-mediated degradation was due to an additional cleavage site at Leu-148 in the autolysis loop and the lack of the conserved Cys-139-Cys-206 disulfide bond. Significant stabilization of anionic trypsinogen against degradation was achieved by simultaneous mutations of CTRC cleavage sites Leu-81 and Leu-148, autolytic cleavage site Arg-122, and restoration of the missing disulfide bridge. This stands in stark contrast to cationic trypsinogen where single mutations of either Leu-81 or Arg-122 resulted in almost complete resistance to CTRC-mediated degradation. Finally, processing of the trypsinogen activation peptide at Phe-18 by CTRC inhibited autoactivation of anionic trypsinogen, although cationic trypsinogen was strongly stimulated. Taken together, the observations indicate that human anionic trypsinogen is controlled by CTRC in a manner that individual natural mutations are unlikely to increase stability enough to promote intra-pancreatic activation. This unique biochemical property of anionic trypsinogen explains the lack of association of PRSS2 mutations with hereditary pancreatitis.
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pathogenic cellular role of the p l104p human cationic trypsinogen variant in chronic pancreatitis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2016Co-Authors: Anita Balazs, Péter Hegyi, Miklos SahintothAbstract:Mutations in the PRSS1 gene encoding human cationic trypsinogen are associated with hereditary and sporadic chronic pancreatitis. High-penetrance PRSS1 mutations found in hereditary pancreatitis al...
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uncertainties in the classification of human cationic trypsinogen prss1 variants as hereditary pancreatitis associated mutations
Journal of Medical Genetics, 2010Co-Authors: Richard Szmola, Miklos SahintothAbstract:Background Autosomal dominant hereditary pancreatitis has been conclusively linked with cationic trypsinogen (PRSS1) mutations p.R122H and p.N29I, which can be found in ∼90% of mutation-positive cases. To date, 35 additional rare or private PRSS1 variants have been identified in subjects with hereditary or sporadic, idiopathic chronic pancreatitis. Despite the lack of sufficient genetic and functional evidence, many of these rare variants have been labelled as pancreatitis associated. This problematic trend is notably illustrated by two recent studies that classified the p.A121T PRSS1 variant as pancreatitis associated, in large part owing to its intimate proximity to arginine-122, the residue affected by the disease causing p.R122H mutation. Methods and Results Here we demonstrate that the p.A121T variant is functionally innocuous and shows no verifiable association with hereditary pancreatitis, on the basis of the available inconclusive data. Conclusion This case cautions that assignment of clinical relevance to rare PRSS1 variants should not be based on a perceived analogy with genuine disease causing PRSS1 mutations, and further studies are required to prove or rule out possible low penetrance causality of rare PRSS1 variants.
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a degradation sensitive anionic trypsinogen PRSS2 variant protects against chronic pancreatitis
Nature Genetics, 2006Co-Authors: Heiko Witt, Zoltan Kukor, Miklos Sahintoth, Jian-min Chen, Olfert Landt, Thilo Kahne, Joost P H Drenth, Edit Szepessy, Walter Halangk, Stefan DahmAbstract:Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.
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gene conversion between functional trypsinogen genes prss1 and PRSS2 associated with chronic pancreatitis in a six year old girl
Human Mutation, 2005Co-Authors: Niels Teich, Volker Keim, Joachim Mössner, Zsofia Nemoda, Henrik Kohler, Wolfram Heinritz, Miklos SahintothAbstract:Gene conversion -- the substitution of genetic material from another gene -- is recognized as the underlying cause of a growing number of genetic diseases. While in most cases conversion takes place between a normal gene and its pseudogene, here we report an occurrence of disease-associated gene conversion between two functional genes. Chronic pancreatitis in childhood is frequently associated with mutations of the cationic trypsinogen gene (serine protease 1; PRSS1). We have analyzed PRSS1 in 1106 patients with chronic pancreatitis, and identified a novel conversion event affecting exon 2 and the subsequent intron. The recombination replaced at least 289 nucleotides with the paralogous sequence from the anionic trypsinogen gene (serine protease 2; PRSS2), and resulted in the PRSS1 mutations c.86A>T and c.161A>G, causing the amino acid substitutions N29I and N54S, respectively. Analysis of the recombinant N29I-N54S double mutant cationic trypsinogen revealed increased autocatalytic activation, which was solely due to the N29I mutation. In conclusion, we have demonstrated that gene conversion between two functional paralogous trypsinogen genes can occur and cause genetically determined chronic pancreatitis.
Miklós Sahin-tóth - One of the best experts on this subject based on the ideXlab platform.
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Alcohol-dependent effect of PRSS1-PRSS2 haplotype in chronic pancreatitis
Gut, 2019Co-Authors: Eszter Hegyi, Anna Zsófia Tóth, Áron Vincze, Andrea Szentesi, Péter Hegyi, Miklós Sahin-tóthAbstract:We read with great interest the studies by Derikx et al ,1 Boulling et al 2 and Masson et al ,3 in which the authors report that a commonly occurring haplotype spanning the PRSS1-PRSS2 locus (encoding human cationic and anionic trypsinogen) is associated with chronic pancreatitis with an allelic OR of 0.7 in European cohorts (figure 1). Tagged by the c.-408C>T variant (rs10273639), this haplotype was first identified in a GWAS by the Whitcomb laboratory.4 The small but significant protective effect is likely due to the c.-204C>A promoter variant (rs4726576) in PRSS1 , which decreases trypsinogen expression and thereby reduces the risk of premature trypsin activation in the pancreas.2 Curiously, Derikx et al 1 found a clear association of the PRSS1-PRSS2 haplotype with alcoholic pancreatitis only, whereas no association was evident with non-alcoholic disease. Whitcomb et al also noted that the effect of the haplotype seemed to be amplified by alcohol.4 The French study did not specify disease aetiology.2 …
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Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis
American journal of physiology. Gastrointestinal and liver physiology, 2014Co-Authors: Balázs Németh, Miklós Sahin-tóthAbstract:Variations in the serine protease 1 (PRSS1) gene encoding human cationic trypsinogen have been conclusively associated with autosomal dominant hereditary pancreatitis and sporadic nonalcoholic chronic pancreatitis. Most high-penetrance PRSS1 variants increase intrapancreatic trypsin activity by stimulating trypsinogen autoactivation and/or by inhibiting chymotrypsin C-dependent trypsinogen degradation. Alternatively, some PRSS1 variants can cause trypsinogen misfolding, which results in intracellular retention and degradation with consequent endoplasmic reticulum stress. However, not all PRSS1 variants are pathogenic, and clinical relevance of rare variants is often difficult to ascertain. Here we review the PRSS1 variants published since 1996 and discuss their functional properties and role in chronic pancreatitis.
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Variations in trypsinogen expression may influence the protective effect of the p.G191R PRSS2 variant in chronic pancreatitis
Gut, 2009Co-Authors: Frank Ulrich Weiss, Miklós Sahin-tóthAbstract:The description of a family with inherited chronic relapsing pancreatitis by Comfort and Steinberg (1952) provided the first indication towards a possible genetic component in the aetiology of chronic pancreatitis (CP).1 Subsequent genetic linkage studies and candidate gene sequencing in families with hereditary CP led to the identification of autosomal dominant mutations in the cationic trypsinogen ( PRSS1 ) gene. Biochemical studies demonstrated that these mutations facilitated the activation of trypsinogen, suggesting that trypsinogen activation can trigger pancreatitis in humans, a concept previously proposed on the basis of animal experiments.2 Screening efforts for novel, CP-associated gene variants identified a number of other important genetic factors, which included loss-of-function variants in the genes for the serine protease inhibitor Kazal type 1 (SPINK1), the cystic fibrosis transmembrane conductance regulator (CFTR) and chymotrypsinogen C (CTRC). In 2006 a surprising study by Witt and co-workers demonstrated that the p.G191R mutation in the anionic typsinogen ( PRSS2 ) gene conferred protection against chronic pancreatitis.3 In this European multicentre study the p.G191R mutation was detected in 1.3% of 2466 patients with CP and in 3.4% of 6459 healthy controls, indicating that subjects carrying a heterozygous p.G191R mutation have an approximately 3-fold decreased risk of developing CP compared to carriers of the wild-type allele. At the biochemical …
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A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2).
The Biochemical journal, 2009Co-Authors: Zsolt Rónai, Heiko Witt, Olga Rickards, Giovanni Destro-bisol, Andrew Bradbury, Miklós Sahin-tóthAbstract:Human pancreatic trypsinogens undergo post-translational sulfation on Tyr154, catalyzed by the Golgi-resident enzyme tyrosylprotein sulfotransferase 2. Sequence alignments suggest that sulfation of Tyr154 is facilitated by a unique sequence context characteristically found in primate trypsinogens. In search for genetic variants that might alter this sulfation motif, we identified a single nucleotide polymorphism (c.457G>C) in the human anionic trypsinogen gene (PRSS2), which changed Asp153 to His (p.D153H). The p.D153H variant is common in subjects of African origin, with a minor allele frequency of 9.2%, whereas it is absent in subjects of European descent. We demonstrate that Asp153 is the main determinant of tyrosine sulfation in anionic trypsinogen, as both the natural p.D153H variation and the p.D153N mutation result in complete loss of trypsinogen sulfation. In contrast, mutation of Asp156 and Glu157 only slightly decrease tyrosine sulfation, whereas mutation of Gly151 and Pro155 are without consequence. With respect to the biological relevance of the p.D153H variant, we found that tyrosine sulfation had no significant effect on the activation of anionic trypsinogen or the catalytic activity and inhibitor sensitivity of anionic trypsin. Taken together with previous studies, the observations suggest that the primary role of trypsinogen sulfation in humans is to stimulate autoactivation of cationic trypsinogen (PRSS1), whereas sulfation of anionic trypsinogen is unimportant for normal digestive physiology. As a result, the p.D153H polymorphism which eliminates this modification could become widespread in a healthy population.
Heiko Witt - One of the best experts on this subject based on the ideXlab platform.
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Genetics of pancreatitis: a guide for clinicians.
Digestive diseases (Basel Switzerland), 2010Co-Authors: Heiko WittAbstract:It is now generally believed that pancreatitis results from pancreatic autodigestion. An inappropriate conversion of pancreatic zymogens to active enzymes within the pancreatic parenchyma is thought to initiate the inflammatory process. A key role has been attributed to the activation of trypsinogen to trypsin, converting all proteolytic proenzymes to their active form. Several gain-of-function mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with chronic pancreatitis (CP). These mutations lead to enhanced intrapancreatic trypsinogen activation. In contrast, a variant in the anionic trypsinogen (PRSS2) gene, p.G191R, has been described that mitigates intrapancreatic trypsin activity and thereby plays a protective role. Beside trypsinogen mutations, loss-of-function variants in SPINK1, encoding a pancreatic trypsin inhibitor, are strongly associated with idiopathic CP. Approximately 15–40% of patients with so-called idiopathic CP carry p.N34S on one allele or on both alleles. Chymotrypsin C (CTRC) degrades all human trypsin isoforms with high specificity. Two CTRC alterations, p.R254W and p.K247_R254del, are significantly associated with idiopathic as well as alcohol-related CP. Functional analysis of the variants revealed impaired activity and/or reduced secretion. Thus, loss-of-function mutations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. Albeit the association between CFTR, the gene mutated in cystic fibrosis, and idiopathic CP is now well established, the pathogenic mechanisms are poorly understood. Nearly 25–30% of patients carry at least one CFTR mutation, but few patients only were compound-heterozygous. Several patients, however, are trans-heterozygous for a CFTR alteration and a PRSS1, SPINK1, or CTRC variant, respectively.
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A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2).
The Biochemical journal, 2009Co-Authors: Zsolt Rónai, Heiko Witt, Olga Rickards, Giovanni Destro-bisol, Andrew Bradbury, Miklós Sahin-tóthAbstract:Human pancreatic trypsinogens undergo post-translational sulfation on Tyr154, catalyzed by the Golgi-resident enzyme tyrosylprotein sulfotransferase 2. Sequence alignments suggest that sulfation of Tyr154 is facilitated by a unique sequence context characteristically found in primate trypsinogens. In search for genetic variants that might alter this sulfation motif, we identified a single nucleotide polymorphism (c.457G>C) in the human anionic trypsinogen gene (PRSS2), which changed Asp153 to His (p.D153H). The p.D153H variant is common in subjects of African origin, with a minor allele frequency of 9.2%, whereas it is absent in subjects of European descent. We demonstrate that Asp153 is the main determinant of tyrosine sulfation in anionic trypsinogen, as both the natural p.D153H variation and the p.D153N mutation result in complete loss of trypsinogen sulfation. In contrast, mutation of Asp156 and Glu157 only slightly decrease tyrosine sulfation, whereas mutation of Gly151 and Pro155 are without consequence. With respect to the biological relevance of the p.D153H variant, we found that tyrosine sulfation had no significant effect on the activation of anionic trypsinogen or the catalytic activity and inhibitor sensitivity of anionic trypsin. Taken together with previous studies, the observations suggest that the primary role of trypsinogen sulfation in humans is to stimulate autoactivation of cationic trypsinogen (PRSS1), whereas sulfation of anionic trypsinogen is unimportant for normal digestive physiology. As a result, the p.D153H polymorphism which eliminates this modification could become widespread in a healthy population.
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Divergent roles of SPINK1 and PRSS2 variants in tropical calcific pancreatitis.
Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 2008Co-Authors: Santhosh Sundaresan, Heiko Witt, Eesh Bhatia, Ashok Chacko, Amit K Dutta, René H M Te Morsche, Jan B M J Jansen, Joost P H DrenthAbstract:Tropical calcific pancreatitis (TCP) refers to a type of idiopathic pancreatitis prevalent in Asia. The trypsin inhibitor (SPINK1) N34S variant partially explains the genetic susceptibility to TCP. As anionic trypsinogen (PRSS2) G191R protects against chronic pancreatitis in Europeans, we investigated whether this variant protects from TCP in Indians. We enrolled 174 patients and 794 controls from two Indian tertiary care referral hospitals. We analyzed PRSS2 and SPINK1 variants by melting curve analysis, allele-specific discrimination assay, and sequencing. G191R was detected in 1 TCP patient (0.6%) compared to 13 controls (1.6%; OR 0.27, 95% CI 0.03-2.1; p = 0.33). SPINK1 N34S was enriched in the TCP population 67/174 (38.5%) compared to controls 10/234 (4.3%; OR 14, 95% CI 6.9-28.3; p < 0.001). G191R PRSS2 is a rare allele in the Indian population and the data suggest a nonsignificant trend towards a protective effect. N34S SPINK1 represents the major genetic risk factor in TCP. Copyright 2008 S. Karger AG, Basel and IAP.
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Genetic aspects of tropical calcific pancreatitis
Reviews in Endocrine and Metabolic Disorders, 2008Co-Authors: Heiko Witt, Eesh BhatiaAbstract:Tropical calcific pancreatitis (TCP) is a subtype of chronic pancreatitis which is unique to tropical regions. Patients present at young age with recurrent abdominal pain, nutritional deficiencies, and insulin-requiring diabetes. For a long time, the aetiology of this disorder was poorly understood. Several environmental factors, such as malnutrition or the consumption of toxic food components such as cyanogenic glycosides, were proposed as pathogenic factors. In the last decade, a major impact on the understanding of the aetiology of TCP has come from genetic studies on hereditary and idiopathic chronic pancreatitis. Genetic alterations in at least five genetic loci are clearly associated with chronic pancreatitis in the Western world. These include alterations in genes coding for trypsinogens, the most abundant digestive enzymes ( PRSS1 and PRSS2 ), the trypsin inhibitor ( SPINK1 ) and the trypsin-degrading enzyme, chymotrypsinogen C ( CTRC ). In addition, alterations in the cystic fibrosis ( CFTR ) gene are associated with idiopathic pancreatitis. TCP clinically resembles non-alcoholic chronic pancreatitis of Western countries, suggesting that similar genetic defects might also be of importance in this disease entity. Indeed, alterations in at least two genes, SPINK1 and CTRC , are strongly associated with TCP. The current review focuses on the recent developments in the understanding of the genetic basis of inherited pancreatitis, with special emphasis on TCP.
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a degradation sensitive anionic trypsinogen PRSS2 variant protects against chronic pancreatitis
Nature Genetics, 2006Co-Authors: Heiko Witt, Zoltan Kukor, Miklos Sahintoth, Jian-min Chen, Olfert Landt, Thilo Kahne, Joost P H Drenth, Edit Szepessy, Walter Halangk, Stefan DahmAbstract:Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.
