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Miklos Sahintoth - One of the best experts on this subject based on the ideXlab platform.
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misfolding cationic trypsinogen variant p l104p causes Hereditary Pancreatitis
Gut, 2017Co-Authors: Balazs Nemeth, Miklos Sahintoth, Arpad V Patai, Péter HegyiAbstract:We read the recent publication of Schnur et al 1 with great interest, in which the authors proposed that a subset of human cationic trypsinogen ( PRSS1 ) variants caused chronic Pancreatitis by inducing misfolding and endoplasmic reticulum (ER) stress rather than increased intrapancreatic trypsin activity. PRSS1 variants that promote premature trypsinogen activation are the strongest known risk factors for chronic Pancreatitis; often associated with autosomal-dominant Hereditary Pancreatitis. ER-stress causing PRSS1 variants, on the other hand, have been mostly found in sporadic disease with no family history suggesting these variants might confer lower risk. To refute this notion, here we report a Hereditary Pancreatitis family of Hungarian origin carrying the heterozygous c.311T>C (p.L104P) PRSS1 variant which was recently demonstrated to induce misfolding and ER stress.2 The index patient, his mother and first cousin developed recurrent acute or chronic Pancreatitis in this family (figure 1 …
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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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robust autoactivation chymotrypsin c independence and diminished secretion define a subset of Hereditary Pancreatitis associated cationic trypsinogen mutants
FEBS Journal, 2013Co-Authors: Andrea Geisz, Péter Hegyi, Miklos SahintothAbstract:Mutations in human cationic trypsinogen cause Hereditary Pancreatitis by altering its proteolytic regulation of activation and degradation by chymotrypsin C (CTRC). CTRC stimulates trypsinogen autoactivation by processing the activation peptide to a shorter form, but also promotes degradation by cleaving the calcium-binding loop in trypsinogen. Mutations render trypsinogen resistant to CTRC-mediated degradation and/or increase processing of the activation peptide by CTRC. Here we demonstrate that the activation peptide mutations D19A, D22G, K23R and K23_I24insIDK robustly increased the rate of trypsinogen autoactivation, both in the presence and absence of CTRC. Degradation of the mutants by CTRC was unchanged, and processing of the activation peptide was increased fourfold in the D19A mutant only. Surprisingly, however, this increased processing had only a minimal effect on autoactivation. The tetra-aspartate motif in the trypsinogen activation peptide binds calcium (KD of ~ 1.6 mm), which stimulates autoactivation. Unexpectedly, calcium binding was not compromised by any of the activation peptide mutations. Despite normal binding, autoactivation of mutants D22G and K23_I24insIDK was not stimulated by calcium. Finally, the activation peptide mutants exhibited reduced secretion from transfected cells, and secreted trypsinogen levels were inversely proportional with autoactivation rates. We conclude that D19A, D22G, K23R and K23_I24insIDK form a mechanistically distinct subset of Hereditary Pancreatitis-associated mutations that exert their effect primarily through direct stimulation of autoactivation, independently of CTRC. The potentially severe clinical impact of the markedly increased autoactivation is offset by diminished secretion, resulting in a clinical phenotype that is indistinguishable from typical Hereditary Pancreatitis.
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mutations of the trypsinogen activation peptide in Hereditary Pancreatitis
Pancreatology, 2013Co-Authors: Andrea Geisz, Péter Hegyi, Zoltan Rakonczay, Laszlo Czako, Miklos SahintothAbstract:s / Pancreatology 13 (2013) S2–S98 S56 Results: In CG animals during 12-48 h level of GTH in intestinal tissue was 40-55% lower (p<0,05) normal values, malone dialdehyde increased twice (p<0,05), BT was observed in 100% cases. GTH infusion (1 group) increased its concentration on 18-23% in comparison with CG, but it remained 1,5 time (p<0,05) lesser than in healthy animals, BT occurred in 65-85% after 24 h. In 2 group level of GTH and malon dialdehyde were not significantly differ from preoperative values, BT was diagnosed in 35-55% cases. Conclusion: Local delivery of GTH to intestinal mucosa by CNp can improve gut barrier function during SAP. PII-8 Abstract id: 70. Pathogenetic mechanisms acute Pancreatitis I. Trubitsyna, T. Tarasova, L. Vinokurova, A. Smirnova. Central Research Institute of Gastroenterology, Russia Introduction: in the process of acute Pancreatitis were essential membranodestruktivnye phenomena that lead to structural and functional changes in cells and tissues. Membranodestruktivnye processes are due to the intensification of lipid peroxidation, increased production of free radicals and lipid peroxidation products of low molecular weight, and hypoxia Aims: Reserch the changes of cytokines of inflamation and cytotoxyn Materials & methods: experimental research put on 25 white rats anesthetized peccant acute Pancreatitis by application of acetic acid on the pancreas. Biochemical methods serotonin, IFM – proinflammatory cytokines IL-1b, TNFa, INFg. Results: 24 h increased the levels of serotonin in the blood serum of the pancreas and duodenal mucosa. In the dynamics of acute Pancreatitis was observed intensification of lipid peroxidation, increased activity of phospholipase A2. Local and systemic increase in the content of 5-HT resulted in violation of the microvasculature of the pancreas. Reduction in the amount of blood flowing, increases venous engorgement. 5-HT violates the stability of biomembranes. There is an autoimmune component, which complicates the recovery of damaged tissue. Conclusion: Thus, the high content of serotonin, impaired blood flow and stability of biological membranes, increased proinflammatory cytokines either alone or together especially the combination of these factors is a pathogenetic factor in the development of acute Pancreatitis. PII-10 Abstract id: 282. Mutations of the trypsinogen activation peptide in Hereditary Pancreatitis Andrea Geisz , Peter Hegyi , Zoltan Rakonczay , L aszl o Czak o , Mikl os Sahin-T oth . 1 First Department of Medicine, University of Szeged, Szeged, Hungary, Hungary Department of Molecular and Cell Biology, Boston University Medical Center, Boston, MA, USA Introduction: Mutations in human cationic trypsinogen cause Hereditary Pancreatitis by altering its proteolytic regulation by chymotrypsin C (CTRC). CTRC stimulates trypsinogen autoactivation by processing the activation peptide to a shorter form but also promotes degradation by cleaving the calcium binding loop in trypsinogen. Mutations render trypsinogen resistant to CTRC-mediated degradation and/or increase processing of the activation peptide by CTRC. Aims: The present study was aimed at clarifying the role of CTRC in the mechanism of action of activation peptide mutations D19A, D22G, K23R and K23_I24insIDK. Materials & methods: Human pancreatic enzymes were produced recombinantly and purified to homogeneity. Trypsinogen activation was followed by enzymatic assays and SDS-PAGE. Trypsinogen secretion was measured from transfected HEK 293T cells. Results: Activation peptide mutations robustly increased trypsinogen autoactivation, both in the presence and absence of CTRC. Degradation of activation peptide mutants by CTRC was unchanged and processing of the activation peptide was increased only in the D19A mutant by 4-fold. Surprisingly, however, increased processing had essentially no effect on autoactivation. Finally, the activation peptide mutants exhibited reduced secretion from transfected cells, and secreted trypsinogen levels were inversely proportional with autoactivation rates. Conclusion: Activation peptide mutations form a mechanistically distinct subset of Hereditary Pancreatitis associated mutations, which exert their effect primarily through direct stimulation of autoactivation, independently of CTRC. The potentially severe clinical impact of the markedly increased autoactivation is offset by diminished secretion, resulting in a clinical phenotype indistinguishable from typical Hereditary Pancreatitis. Supported by NIH, OTKA and NF€ U/T AMOP. PII-11 Abstract id: 25. Effects of exocrine pancreatic insufficiency (EPI) and pancreatic enzyme substitution on bone mineral content of growing pigs âV“ used as a model for children Anne M€ ossler , Annette Liesegang , Teresa Schwarzmaier , Peter Gregory , Josef Kamphues . 1 University of Veterinary Medicine, Hannover, Institute of Animal Nutrition, Germany University of Zurich, Institute of Animal Nutrition, Switzerland Abbott Laboratories GmbH (Germany), Germany Introduction: The pancreatic duct ligated (PL) minipig is an established model for studying effects of exocrine pancreatic insufficiency (EPI) in adults, but studies in juveniles are rare. Aims: This study aimed to test the effects of EPI on bone density in growing pigs. Materials & methods: In 8 pigs aged 8 weeks EPI was induced surgically (PL), another 4 pigs served as controls (C). Beginning from 3 weeks post OP 4 PL-pigs received Kreon (w6300 Ph.Eur.E lipase/g dietary fatÂ,(PLþE)) while 4 PL-pigs received no enzyme substitution therapy (PL0). Diet contained (per kg DM) 85 g crude fat; 10.5 g Ca, 5.68 g P and 1875 IU vitamin D. Every 2nd week all animals received parenteral vitamin supply. 11 weeks post OP all animals were slaughtered and left tibia was taken and analysed by peripheral quantitative computer tomography for total bone mineral content (BMC) and cortex mineral content (CMC). Results: BMC and CMC were significantly reduced in PL-0-pigs compared to C-pigs while in PLþE intermediate values not differing from C at large were observed at distal end of tibia: (mg/cm): C: 482 40.2a PL:295 25.6b, PLþE: 399 70.8ab] Conclusion: Even all animals received a complete diet and were supplemented parenterally with high dosed vitamins there was an impaired bone mineralization in PL-0 âV“ despite lack of clinical symptoms. Enzyme supplementation improved (but didnâV t normalize) bone mineralization presumably due to an improved total tract digestibility of fat (%: Control: 80.9; PL-0: 7.55; PLþE: 52.0) âV“ supposed to cause an increase of the absorption of vitamin D and calcium. PII-12 Abstract id: 310. Tributaryliths as a reason of peripheral ductal hypertension in chronic Pancreatitis Aliaksandr Varabei , Anatoli Shuleika , Yury Arlouski , Egi Vizhinis , Natali Lagodich . 1 Prof., Belarus MD, Belarus
David C. Whitcomb - One of the best experts on this subject based on the ideXlab platform.
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gene expression profiling of the pancreas in patients undergoing total pancreatectomy with islet autotransplant suggests unique features of alcoholic idiopathic and Hereditary Pancreatitis
Pancreas, 2020Co-Authors: Brandon M Blobner, Melena D Bellin, Gregory J Beilman, Celeste Shelton, Hyung Jung Park, David C. WhitcombAbstract:Objectives To determine if RNA collected from pancreatic tissue, without the use of RNAlater, is useful for RNA sequencing (RNA-seq) despite degradation, and if so, then, via RNA-seq analysis, how does gene expression vary between Pancreatitis etiologies. Methods Data were assessed in 2 dimensions, based on RNA-seq signal shape assessed by RSeQC v.2.6.4 and RNA expression after accounting for different degrees of degradation. Results Six measures of RNA characteristics (median RNA fragment size, reads per million kilobases saturation, transcript integrity number, distribution of hexamers, percentage of nucleotides that are guanine or cytosine, and duplicated reads) were significantly different between Hereditary Pancreatitis and idiopathic Pancreatitis. Differential expression analysis revealed that 150 genes were differentially expressed between Hereditary and idiopathic etiologies, 197 genes were differentially expressed between alcoholic and idiopathic etiologies, and 200 genes were differentially expressed between alcoholic and Hereditary etiologies. We then determined that many enriched pathways between Hereditary and idiopathic etiologies are related to the matrisome, and many of the enriched pathways between alcoholic and idiopathic etiology or Hereditary etiology are related to ion transport. Conclusions We found distinct RNA-seq signals between different Pancreatitis etiologies in both of the dimensions in critical pathways for pancreas biology.
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impact of Hereditary Pancreatitis on patients and their families
Journal of Genetic Counseling, 2020Co-Authors: Celeste Shelton, Dhiraj Yadav, Robin E Grubs, Chandraprakash Umapathy, David C. WhitcombAbstract:Hereditary Pancreatitis (HP), a highly penetrant (~80%) autosomal dominant disease associated with PRSS1 variants, causes acute Pancreatitis in childhood and chronic Pancreatitis by early adulthood. Other clinical features include pain, diabetes, and risk of pancreatic cancer. HP kindreds were prospectively recruited from 1995 to 2015. At enrollment, study participants completed medical and family history questionnaires, and provided samples for genotyping. Participants were recontacted between 2015 and 2017 and asked to complete a survey on concerns and experiences related to HP, PRSS1 testing, and genetic counseling. Data were analyzed with descriptive and thematic methods. Thirty-nine affected participants with HP and 21 unaffected family members completed the survey. Among unaffected family members, 'worry' and 'helplessness' were frequently described as the most difficult problem in their family because of HP, particularly with regard to pain. Three participants described the impact of drug addiction on their family. 'School or work limitations' was the leading financial concern, with 65.5% (36/55) rating it as 'moderately' or 'extremely important.' Unexpectedly, only 62% (21/34) of affected PRSS1 carriers believed the chance for a parent to pass HP to his or her children was 50%, whereas 18% (6/34) believed the chance was 100%. The impact of HP on individuals and families varied, which may reflect the highly unpredictable nature of HP severity and outcomes. Based on current and previously reported findings, an overview of important issues for genetic counselors to consider for counseling HP families is included.
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Hereditary Pancreatitis in the united states survival and rates of pancreatic cancer
The American Journal of Gastroenterology, 2018Co-Authors: Celeste Shelton, Dhiraj Yadav, Chandraprakash Umapathy, Kimberly Stello, David C. WhitcombAbstract:Hereditary Pancreatitis (HP), an autosomal dominant disease typically caused by mutations in PRSS1, has a broad range of clinical characteristics and high cumulative risk of pancreatic cancer. We describe survival and pancreatic cancer risk in the largest HP cohort in the US. HP probands and family members prospectively recruited from 1995 to 2013 completed medical and family history questionnaires, and provided blood for DNA testing. Overall survival (until 12/31/2015) was determined from the Social Security Death Index (SSDI), National Death Index (NDI), and family members. Cause of death was obtained from the NDI. 217 PRSS1 carriers (181 symptomatic) formed the study cohort. The most frequently detected mutations were p.R122H (83.9%) and p.N29I (11.5%). Thirty-seven PRSS1 carriers (30 symptomatic, 7 asymptomatic) were deceased at conclusion of the study (5 from pancreatic cancer). Median overall survival was 79.3 years (IQR 72.2–85.2). Risk of pancreatic cancer was significantly greater than age- and sex- matched SEER data (SIR 59, 95% CI 19-138), and cumulative risk was 7.2% (95% CI 0–15.4) at 70 years. We confirm prior observations on survival and pancreatic cancer SIR in PRSS1 subjects. Although risk of pancreatic cancer was significantly high in these patients, its cumulative risk was much lower than previous reports.
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whole exome sequencing identifies multiple complex etiologies in an idiopathic Hereditary Pancreatitis kindred
Journal of the Pancreas, 2012Co-Authors: Jessica Larusch, Michael M Barmada, Shiela Solomon, David C. WhitcombAbstract:Context Hereditary Pancreatitis is the early onset form of chronic Pancreatitis that is carried in an autosomal dominant pattern with variable penetrance. While 80% of Hereditary Pancreatitis has been shown to be due to a single mutation in the trypsinogen gene PRSS1 , a number of Hereditary Pancreatitis families have no identified genetic cause for illness; thus no reliable screening options or clear therapy. Objective To explore the use of massive parallel DNA sequencing technology to discover the etiology of Pancreatitis in a family with idiopathic Hereditary Pancreatitis. Design Candidate gene screening and verification within a kindred. Setting Prospective cohort study, university based. Patients or participants Kindred with idiopathic Hereditary Pancreatitis. Interventions None. Main outcome measures Identification of DNA variants predicted to increase susceptibility to Pancreatitis. Methods Whole exome sequencing of two distantly related subjects with variant-specific confirmation in the subjects and other family members. Results We identified three deleterious genetic changes in the three major Pancreatitis associated genes ( PRSS1 CNV, SPINK1 c.27delC and CFTR R117H), two of which were carried by each patient. Individual targeted assays confirmed these variations in the two whole exome sequencing patients as well as affected and non-affected pedigree members. Conclusion Whole exome sequencing was useful for rapid screening of candidate genes linked to Pancreatitis. This method opens the door for time- and cost-effective screening of multiple disease-associated genes and modifying factors that associate in different ways to generate a complex genetic disorder.
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genetic analysis of the glutathione s transferase genes mgst1 gstm3 gstt1 and gstm1 in patients with Hereditary Pancreatitis
Journal of Gastroenterology, 2004Co-Authors: Alexander Schneider, Michael M Barmada, Sandra Togel, David C. WhitcombAbstract:Background Specific mutations in the cationic trypsinogen gene (PRSS1) are disease-causing in patients with Hereditary Pancreatitis, but the genetic background still remains mysterious in about 40% of patients with the disease. It has been suggested that oxidative stress contributes to pancreatic damage. The glutathione s-transferases (GSTs) represent major detoxification enzymes that protect cells from oxidative stress.
Claude Férec - One of the best experts on this subject based on the ideXlab platform.
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the natural history of Hereditary Pancreatitis a national series
Gut, 2009Co-Authors: Vinciane Rebours, Claude Férec, Philippe Ruszniewski, Mariechristine Boutronruault, Matthieu Schnee, Frederique Maire, Pascal Hammel, Le C Marechal, Olivia Hentic, P LevyAbstract:Background and aims: The prevalence and natural history of Hereditary Pancreatitis (HP) remain poorly documented. The aims of this study were to assess genetic, epidemiological, clinical and morphological characteristics of HP in an extensive national survey. Methods: A cohort comprising all HP patients was constituted by contacting all gastroenterologists and paediatricians (response rate 84%) and genetics laboratories (response rate 100%) in France (60 200 000 inhabitants). Inclusion criteria were the presence of mutation in the cationic trypsingen gene (PRSS1 gene), or chronic Pancreatitis in at least two first-degree relatives, or three second-degree relatives, in the absence of precipitating factors for Pancreatitis. Results: 78 families and 200 patients were included (181 alive, 6673 person-years, males 53%, alcoholism 5%, smoking 34%). The prevalence was 0.3/100 000 inhabitants. PRSS1 mutations were detected in 68% (R122H 78%, N29I 12%, others 10%). Penetrance was 93%. Median age at first symptom, diagnosis and date of last news, were 10 (range 1–73), 19 (1–80) and 30 (1–84) years, respectively. HP was responsible for pancreatic pain (83%), acute Pancreatitis (69%), pseudocysts (23%), cholestasis (3%), pancreatic calcifications (61%), exocrine pancreatic insufficiency (34%, median age of occurrence 29 years), diabetes mellitus (26%, median age of occurrence 38 years) and pancreatic adenocarcinoma (5%, median age 55 years). No differences in clinical and morphological data according to genetic status were observed. 19 patients died, including 10 directly from HP (8 from pancreatic adenocarcinoma). Conclusion: The prevalence of HP in France is at least 0.3/100 000. PRSS1 gene mutations are found in 2/3 with a 93% penetrance. Mutation type is not correlated with clinical/morphological expression. Pancreatic adenocarcinoma is the cause of nearly half the deaths.
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Hereditary Pancreatitis caused by a double gain-of-function trypsinogen mutation
Human Genetics, 2008Co-Authors: Emmanuelle Masson, Jian-min Chen, Cédric Le Maréchal, Richard Delcenserie, Claude FérecAbstract:Hereditary Pancreatitis, an autosomal dominant disease with ∼80% penetrance, can be caused by both ‘gain-of-function’ missense and copy number mutations in the cationic trypsinogen gene ( PRSS1 ). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/ PRSS1 gene in a French white family with Hereditary Pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3–5 from PRSS1 , apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent ‘double gain-of-function’ effect, acting simultaneously as a ‘quantitative’ copy number mutation and a ‘qualitative’ missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.
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Hereditary Pancreatitis caused by a double gain of function trypsinogen mutation
Human Genetics, 2008Co-Authors: Jian-min Chen, Cedric Le Marechal, Emmanuelle Masson, Richard Delcenserie, Claude FérecAbstract:Hereditary Pancreatitis, an autosomal dominant disease with approximately 80% penetrance, can be caused by both 'gain-of-function' missense and copy number mutations in the cationic trypsinogen gene (PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/PRSS1 gene in a French white family with Hereditary Pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3-5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent 'double gain-of-function' effect, acting simultaneously as a 'quantitative' copy number mutation and a 'qualitative' missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.
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risk of pancreatic adenocarcinoma in patients with Hereditary Pancreatitis a national exhaustive series
The American Journal of Gastroenterology, 2008Co-Authors: Vinciane Rebours, Claude Férec, Philippe Ruszniewski, Mariechristine Boutronruault, Matthieu Schnee, Frederique Maire, Pascal Hammel, Philippe LévyAbstract:Risk of Pancreatic Adenocarcinoma in Patients With Hereditary Pancreatitis: A National Exhaustive Series
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Hereditary Pancreatitis caused by triplication of the trypsinogen locus
Nature Genetics, 2006Co-Authors: Cedric Le Marechal, Jian-min Chen, Emmanuelle Masson, Philippe Lévy, Philippe Ruszniewski, Frederic Morel, Claude FérecAbstract:Hereditary Pancreatitis has been reported to be caused by 'gain-of-function' missense mutations in the cationic trypsinogen gene (PRSS1). Here we report the triplication of a ∼605-kb segment containing the PRSS1 gene on chromosome 7 in five families with Hereditary Pancreatitis. This triplication, which seems to result in a gain of trypsin through a gene dosage effect, represents a previously unknown molecular mechanism causing Hereditary Pancreatitis.
John P. Neoptolemos - One of the best experts on this subject based on the ideXlab platform.
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Hereditary Pancreatitis and secondary screening for early pancreatic cancer
Roczniki Akademii Medycznej w Bialymstoku (1995), 2005Co-Authors: Louis Vitone, Nathan Howes, William Greenhalf, John P. NeoptolemosAbstract:Hereditary Pancreatitis is an autosomal dominant disease with incomplete penetrance (80%), accounting for approximately 1% of all cases of Pancreatitis. It is characterized by the onset of recurrent attacks of acute Pancreatitis in childhood and frequent progression to chronic Pancreatitis. Whitcomb et al. identified the cationic trypsinogen gene (PRSS1) on chromosome 7q35 as the site of the mutation that causes Hereditary Pancreatitis. The European registry of Hereditary Pancreatitis and familial pancreatic cancer (EUROPAC) aims to identify and make provisions for those affected by Hereditary Pancreatitis and familial pancreatic cancer. The most common mutations in Hereditary Pancreatitis are R122H, N29I and A16V but many families have been described with clinically defined Hereditary Pancreatitis where there is no PRSS1 mutation. It is known that the cumulative lifetime risk (to age 70 years) of pancreatic cancer is 40% in individuals with Hereditary Pancreatitis. This subset of individuals form an ideal group for the development of a screening programme aimed at detecting pancreatic cancer at an early stage in an attempt to improve the presently poor long-term survival. Current screening strategies involve multimodality imaging (computed tomography, endoluminal ultrasound) and endoscopic retrograde cholangiopancreatography for pancreatic juice collection followed by molecular analysis of the DNA extracted from the juice. The potential benefit of screening (curative resection) must be balanced against the associated morbidity and mortality of surgery. Philosophically, the individual's best interest must be sought in light of the latest advances in medicine and science following discussions with a multidisciplinary team in specialist pancreatic centres.
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cationic trypsinogen mutations and Pancreatitis
Gastroenterology Clinics of North America, 2004Co-Authors: Nathan Howes, William Greenhalf, Deborah D Stocken, John P. NeoptolemosAbstract:The discovery of PRSS1 mutations in Hereditary Pancreatitis and analysis of how the genotype affects the presentation and progression of Hereditary Pancreatitis has led to a better understanding of the pathophysiology of the disease. Patients with Hereditary Pancreatitis present with symptoms at an early age and have a significant lifetime risk for the development of endocrine and exocrine insufficiency, albeit at a later stage than patients with either idiopathic or alcoholic chronic Pancreatitis. There are distinct phenotypic differences between Hereditary Pancreatitis and with other types of Pancreatitis. As many as 80% of patients with symptomatic Hereditary Pancreatitis have an underlying causative PRSS1 mutation; there are, however, few significant phenotypic differences between these PRSS1 mutations. The R122H mutation is the most common PRSS1 mutation observed, and patients with the R122H mutation present earlier. This, however, does not necessarily translate into a more aggressive disease with respect to complications of chronic Pancreatitis. Indeed, the age of presentation of symptoms may be a poor surrogate for predicting outcome, as inherited disorders of trypsinogen may cause subclinical attacks of Pancreatitis, which ultimately lead to pancreatic destruction and dysfunction. All patients, irrespective of whether they carry a PRSS1 mutation, are at significant risk of developing pancreatic ductal adenocarcinoma. The risk appears to be insignificant below the age of 40 years, but it increases incrementally thereafter. Significantly, the risk of pancreatic cancer is not related to PRSS1 mutation type and does not appear to be related to the mode of inheritance. The role of SPINK1 mutations in modifying the expression of PRSS1 mutations is unclear but appears to be of clinical importance. It is unlikely that they act as causative mutations per se, at least in the Western form of the disease. Additionally, they do not appear to have an impact on the penetrance of PRSS1 gene mutations in Hereditary Pancreatitis.
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novel cationic trypsinogen prss1 n29t and r122c mutations cause autosomal dominant Hereditary Pancreatitis
Gut, 2002Co-Authors: Roland H Pfutzer, John P. Neoptolemos, S E Applebaumshapiro, Robert Finch, E Myers, Ian O Ellis, J A Kant, David C. WhitcombAbstract:Hereditary Pancreatitis (HP) is usually caused by mutations in the cationic trypsinogen (PRSS1) gene, especially R122H or N29I. We sequenced the PRSS1 gene in the proband of families without these common mutations. Novel R122C and N29T mutations were detected in independent families that segregated with the disease in an autosomal dominant fashion. The R122C mutation eliminates the arginine autolysis site as with R122H mutations. The N29T mutation may also enhance intrapancreatic trypsin activity as has been demonstrated in vitro. Identification of these new mutations requires special attention as commonly used detection methods may fail.
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a new polymorphism for the ri22h mutation in Hereditary Pancreatitis
Gut, 2001Co-Authors: Nathan Howes, William Greenhalf, David C. Whitcomb, I O Ellis, Roger Mountford, S Rutherford, M Odonnell, C W Imrie, Brendan Drumm, John P. NeoptolemosAbstract:Background and aims—Hereditary Pancreatitis (HP) is a rare form of recurrent acute and chronic Pancreatitis. Mutations in the cationic trypsinogen (protease serine 1, PRSS1) gene have been identified as causing HP. The R122H (previously known as R117H) mutation is the commonest and can be detected by a single and rapid polymerase chain reaction/restriction fragment length polymorphism (PCR/ RFLP) based technique using the AflIII enzyme.This test however may give a false negative result in the presence of a neutral polymorphism within the enzyme recognition site.The frequency of this event was examined by sequencing studies in patients with HP and in healthy controls. Methods—Of 60 families identified by the UK and Ireland consortium of EUROPAC (European Registry for Hereditary Pancreatitis and Familial Pancreatic Cancer), 51 were screened for R122H, N29I, and A16V mutations using standard techniques, and by sequencing of all five exons of cationic trypsinogen. Results—Twelve families had the N29I mutation, one family had A16V and, on standard testing, 15 families had the R122H mutation. An additional family with the R122H mutation was found on direct sequencing. The false negative result was due to a neutral polymorphism C→T at the third base of the codon, not aVecting the amino acid coded for, destroying the AflIII restriction site. This polymorphism was not observed in 50 DNA specimens (100 chromosomes) from controls nor from 50 individuals from PRSS1 mutation negative HP families. A novel mutation specific PCR was developed to avoid this pitfall. Conclusions—One of the 16 families with HP and an R122H mutation contained a polymorphism aVecting the AflIII restriction site. Adoption of an alternative R122H assay is important for genetic studies in individuals with apparent HP. (Gut 2001;48:247‐250)
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Screening for early pancreatic ductal adenocarcinoma in Hereditary Pancreatitis.
Medical Clinics of North America, 2000Co-Authors: Nathan Howes, William Greenhalf, John P. NeoptolemosAbstract:Patients with Hereditary Pancreatitis have a 40% lifetime risk of developing pancreatic ductal adenocarcinoma. Existing methods of diagnosing pancreatic cancer such as tumor markers, endoscopy, and radiological imaging lack the sensitivity and specificity for early diagnosis, particularly in a background of chronic Pancreatitis. Molecular based strategies offer new avenues of screening for pancreatic ductal adenocarcinoma in these high-risk patients, which may allow the development of highly sensitive and specific diagnostic tests for the early detection of cancer.
Jian-min Chen - One of the best experts on this subject based on the ideXlab platform.
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clinical features and endoscopic treatment of chinese patients with Hereditary Pancreatitis
Pancreas, 2015Co-Authors: Xiaotian Sun, Jian-min Chen, Tian Xia, Linli Shi, Chang Sun, Wei Wang, Zhuan LiaoAbstract:OBJECTIVES Hereditary Pancreatitis (HP) has been rarely investigated in China. We aimed to describe clinical features and mutation frequency of Chinese patients with HP and to evaluate outcomes of endoscopic treatments. METHODS Inpatients diagnosed with HP from January 1995 to March 2013 were included. Demographic and clinical data including first onset age, age at diagnosis, sex, main symptoms, radiological findings, and outcomes of endoscopic treatments were collected. Mutations in serine protease inhibitor Kazal type 1 (SPINK1), PRSS1, and cystic fibrosis transmembrane conductance regulator (CFTR) were analyzed. RESULTS A total of 22 inpatients with HP (male, 12; female, 10) participated in this study. Mean (SD) age at first onset and at diagnosis were 24.5 (11.9) years and 29.1 (11.2) years, respectively. The predominant radiological feature was pancreatic calcifications. Thirty-nine endoscopic retrograde cholangiopancreatography procedures were successfully performed on 19 cases. In the final long-term follow-up, 21 patients got complete or incomplete remission after endoscopic retrograde cholangiopancreatography and/or surgery. Genetic analyses were available in 20 patients, and mutation rates of R122H, N29I, and A16V in PRSS1 were 60%, 25% and 5%, respectively. CONCLUSIONS As compared with previous studies, our patient cohort, with a relatively higher frequency of R122H mutation, showed a much lower surgery rate, and endoscopic interventions may be recommended to be the first-line treatment.
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Hereditary Pancreatitis caused by a double gain-of-function trypsinogen mutation
Human Genetics, 2008Co-Authors: Emmanuelle Masson, Jian-min Chen, Cédric Le Maréchal, Richard Delcenserie, Claude FérecAbstract:Hereditary Pancreatitis, an autosomal dominant disease with ∼80% penetrance, can be caused by both ‘gain-of-function’ missense and copy number mutations in the cationic trypsinogen gene ( PRSS1 ). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/ PRSS1 gene in a French white family with Hereditary Pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3–5 from PRSS1 , apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent ‘double gain-of-function’ effect, acting simultaneously as a ‘quantitative’ copy number mutation and a ‘qualitative’ missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.
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Hereditary Pancreatitis caused by a double gain of function trypsinogen mutation
Human Genetics, 2008Co-Authors: Jian-min Chen, Cedric Le Marechal, Emmanuelle Masson, Richard Delcenserie, Claude FérecAbstract:Hereditary Pancreatitis, an autosomal dominant disease with approximately 80% penetrance, can be caused by both 'gain-of-function' missense and copy number mutations in the cationic trypsinogen gene (PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/PRSS1 gene in a French white family with Hereditary Pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3-5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent 'double gain-of-function' effect, acting simultaneously as a 'quantitative' copy number mutation and a 'qualitative' missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype.
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signal peptide variants that impair secretion of pancreatic secretory trypsin inhibitor spink1 cause autosomal dominant Hereditary Pancreatitis
Human Mutation, 2007Co-Authors: Orsolya Kiraly, Thomas Wartmann, Jian-min Chen, Arnaud Boulling, Heiko Witt, Cedric Le Marechal, Jonas Rosendahl, Cinzia Battaggia, Miklos SahintothAbstract:Variants of the SPINK1 gene encoding pancreatic secretory trypsin inhibitor have been described in association with chronic Pancreatitis (CP). These alterations are believed to cause a loss of function by either impairing the trypsin inhibitory activity or reducing expression. Here we report two novel SPINK1 variants in exon 1 that affect the secretory signal peptide. The disease-associated c.41T>G (p.L14R) alteration was found in two European families with autosomal dominant Hereditary Pancreatitis, whereas the c.36G>C (p.L12F) variant was identified as a frequent alteration in subjects of African descent. The functional effects of both alterations and the previously reported c.41T>C (p.L14P) variant were characterized by activity assays and Western blots of wild-type and mutant SPINK1 expressed in human embryonic kidney 293T and Chinese hamster ovary cells. Alterations p.L14R and p.L14P destined the inhibitor for rapid intracellular degradation and thereby abolished SPINK1 secretion, whereas the p.L12F variant showed no detrimental effect. The results provide the first clear experimental demonstration that alterations that markedly reduce SPINK1 expression are associated with classic Hereditary Pancreatitis. Therefore, these variants should be classified as severe and regarded as disease-causing rather than disease-modifiers.
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Hereditary Pancreatitis caused by triplication of the trypsinogen locus
Nature Genetics, 2006Co-Authors: Cedric Le Marechal, Jian-min Chen, Emmanuelle Masson, Philippe Lévy, Philippe Ruszniewski, Frederic Morel, Claude FérecAbstract:Hereditary Pancreatitis has been reported to be caused by 'gain-of-function' missense mutations in the cationic trypsinogen gene (PRSS1). Here we report the triplication of a ∼605-kb segment containing the PRSS1 gene on chromosome 7 in five families with Hereditary Pancreatitis. This triplication, which seems to result in a gain of trypsin through a gene dosage effect, represents a previously unknown molecular mechanism causing Hereditary Pancreatitis.