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1
المؤلفون: Daizhan Zhou, Liang-Hao Hu, Miklós Sahin-Tóth, Wen-Bin Zou, An-Jing Zhao, Andrea Geisz, Xiao-Tian Sun, Zhuan Liao, Zhen-Hua Zhao, Hao Wu, Zhao-Shen Li, David Neil Cooper, Lin He, Jian-Min Chen, Dorottya Berki, Claude Férec
المصدر: Human Mutation. 38:959-963
مصطلحات موضوعية: Male, 0301 basic medicine, medicine.medical_specialty, Carboxypeptidases A, Genotype, Idiopathic chronic pancreatitis, Population, Biology, Bioinformatics, Gastroenterology, Article, DNA sequencing, Cohort Studies, 03 medical and health sciences, symbols.namesake, Asian People, Pancreatitis, Chronic, Internal medicine, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, education, Gene, Genetics (clinical), Sanger sequencing, education.field_of_study, medicine.disease, R1, 030104 developmental biology, Mutation, Cohort, symbols, Pancreatitis, Female
الوصف: Rare functionally defective carboxypeptidase A1 (CPA1) variants have been reported to predispose to nonalcoholic chronic pancreatitis, mainly the idiopathic subtype. However, independent replication has so far been lacking, particularly in Asian cohorts where initial studies employed small sample sizes. Herein we performed targeted next-generation sequencing of the CPA1 gene in 1112 Han Chinese idiopathic chronic pancreatitis (ICP) patients – the largest ICP cohort so far analyzed in a single population – and 1580 controls. Sanger sequencing was used to validate called variants, and the CPA1 activity and secretion of all newly found variants were measured. A total of 18 rare CPA1 variants were characterized, 11 of which have not been previously described. However, no significant association was noted with ICP irrespective of whether all rare variants [20/1112 (1.8%) in patients vs. 24/1580 (1.52%) in controls; P = 0.57] or functionally impaired variants [3/1112 (0.27%) in patients vs. 2/1580 (0.13%) in controls; P = 0.68] were considered. This article is protected by copyright. All rights reserved
وصف الملف: application/pdf
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2
المؤلفون: Grzegorz Oracz, Jarosław Poznański, Jerzy Bal, Markus M. Lerch, Miklós Sahin-Tóth, Torsten Kucharzik, Sebastian Beer, Andrzej Tysarowski, Katarzyna Wertheim-Tysarowska, Frank Ulrich Weiss, Jaroslaw Kierkus, Marta Jurek, Pawel Gawlinski, Agnieszka Magdalena Rygiel, Katarzyna Niepokój, Peter Simon
المصدر: Human Mutation. 36:350-356
مصطلحات موضوعية: Male, Trypsinogen, Mutant, Gene Conversion, Biology, Article, Cell Line, Young Adult, chemistry.chemical_compound, Exon, Pancreatitis, Chronic, Genetics, medicine, Humans, Trypsin, Gene conversion, Trypsinogen activation, Pancreatitis, chronic, Child, Alleles, Genetics (clinical), Hereditary pancreatitis, medicine.disease, Molecular biology, chemistry, Female, Pseudogenes, medicine.drug
الوصف: Mutations of the human cationic trypsinogen gene (PRSS1) are frequently found in association with hereditary pancreatitis. The most frequent variants p.N29I and p.R122H are recognized as disease-causing mutations. Three pseudogene paralogs in the human trypsinogen family, including trypsinogen 6 (PRSS3P2), carry sequence variations in exon 3 which mimic the p.R122H mutation. In routine genetic testing of patients with chronic pancreatitis we identified in two unrelated individuals similar gene conversion events of 24–71 nucleotides length between exon 3 of the PRSS1 (acceptor) and PRSS3P2 (donor) genes. The converted allele resulted in three non-synonymous alterations c.343T>A (p.S115T), c.347G>C (p.R116P) and c.365_366delinsAT (p.R122H). Functional analysis of the conversion triple mutant revealed markedly increased autoactivation resulting in high and sustained trypsin activity in the presence of chymotrypsin C. This activation phenotype was identical to that of the p.R122H mutant. In addition, cellular secretion of the triple mutant from transfected HEK 293T cells was increased about two-fold and this effect was attributable to mutation p.R116P. Our observations confirm and extend the notion that recombination events between members of the trypsinogen family can generate high risk PRSS1 alleles. The pathogenic phenotype of the novel conversion is explained by a unique combination of increased trypsinogen activation and secretion.
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3
المؤلفون: Miklós Sahin-Tóth
المصدر: Human Mutation. 38:1619-1619
مصطلحات موضوعية: 0301 basic medicine, Genetics, 03 medical and health sciences, Phenotype, 030104 developmental biology, Trypsin Inhibitor, Kazal Pancreatic, Mutation, Biology, Carrier Proteins, Genetics (clinical)
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4
المؤلفون: Niels Teich, Miklós Sahin-Tóth, Henrik Köhler, Zsofia Nemoda, Wolfram Heinritz, Volker Keim, Joachim Mössner
المصدر: Human Mutation. 25:343-347
مصطلحات موضوعية: Adolescent, Trypsinogen, Pseudogene, Molecular Sequence Data, Gene Conversion, Biology, medicine.disease_cause, Article, chemistry.chemical_compound, Exon, Sequence Homology, Nucleic Acid, Genetics, medicine, Humans, PRSS2, Trypsin, Gene conversion, Pancreatitis, chronic, Child, Gene, Genetics (clinical), Mutation, Base Sequence, Models, Genetic, medicine.disease, Molecular biology, Pancreatitis, chemistry, Female
الوصف: 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.
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5
المؤلفون: Karel Caca, Volker Keim, Miklós Sahin-Tóth, Miklós Tóth, Cédric Le Maréchal, Joachim Mössner, Jian-Min Chen, Helmut Witzigmann, Niels Teich, Claude Férec, Zoltán Kukor
المصدر: Human Mutation. 23:22-31
مصطلحات موضوعية: Adult, Male, Trypsinogen, Trypsin inhibitor, DNA Mutational Analysis, Biology, digestive system, Isozyme, Catalysis, chemistry.chemical_compound, Genetics, medicine, Humans, PRSS2, Trypsin, RNA, Messenger, Pancreatic Secretory Trypsin Inhibitor, Genetics (clinical), Aged, Hereditary pancreatitis, Middle Aged, medicine.disease, Cathepsins, Molecular biology, digestive system diseases, Pedigree, Enzyme Activation, Isoenzymes, Kinetics, Pancreatitis, chemistry, Biochemistry, Trypsin Inhibitor, Kazal Pancreatic, Chronic Disease, Mutation, Intercellular Signaling Peptides and Proteins, Female, Carrier Proteins, medicine.drug
الوصف: The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis-associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild-type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. Furthermore, in contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N29I had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis.
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6دورية أكاديمية
المؤلفون: Niels Teich, Cédric Le Maréchal, Zoltán Kukor, Karel Caca, Helmut Witzigmann, Jian-Min Chen, Miklós Tóth, Joachim Mössner, Volker Keim, Claude Férec, Miklós Sahin-Tóth
المصدر: Human Mutation; Jan2004, Vol. 23 Issue 1, p22-31, 10p
مصطلحات موضوعية: TRYPSINOGEN, PANCREATITIS, TRYPSIN, PROTEOLYTIC enzymes, CATIONS
مستخلص: The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis-associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild-type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. Furthermore, in contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N29I had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis. Hum Mutat 23:2231, 2004. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
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