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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary pancreatitis is an unusual form of acute and chronic pancreatitis with a familial predisposition. Recently, the gene mutations causing most cases of hereditary pancreatitis have been identified in the cationic trypsinogen gene. The known mutations are trypsinogen R117H and N211. These may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms used by the pancreas to eliminate prematurely activated trypsin. Accumulation of active trypsin mutants are hypothesized to initiate a digestive enzyme activation cascade in the pancreatic acinar cells leading to autodigestion, an intense inflammatory response, and acute pancreatitis. The observation that these patients also develop typical chronic pancreatitis and may later develop pancreatic cancer provides strong evidence that these conditions are linked. Knowledge of the pathophysiological conditions leading to acute and chronic pancreatitis and the development of a transgenic mouse expressing the mutant human trypsinogen genes will provide directions and tools necessary for the effective treatment or prevention of this human disease.
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PMID:Hereditary pancreatitis: new insights, new directions. 1103 Jun 5

Recently, an Arg to His mutation at residue 117 of the cationic trypsinogen gene (Arg117His) has been shown to be associated with hereditary pancreatitis (hp). A serious complication of hp is development of pancreatic cancer. Patients suffering from hp have been reported to have a 53-fold increased risk to die from pancreatic cancer. However, the quantitative contribution of mutations in the cationic trypsinogen gene to all pancreatic cancer cases is unknown. A relevant contribution of the Arg117His-mutation to pathogenesis of pancreatic cancer might be possible, since also asymptomatic individuals have been reported to carry this mutation and individuals with only mild symptoms may be undiagnosed as hp. In the present study we analyzed genomic DNA obtained from pancreatic cancer tissue from 34 patients and corresponding normal tissue from 28 of these individuals. The third exon of the cationic trypsinogen gene was amplified by nested PCR and digested with AflIII, since the Arg117His mutation creates an AflIII-restriction site. None of the examined samples carried the Arg117His mutation, whereas the amplification product obtained from a patient with known hp was clearly positive. Sequencing of the complete third exon of the cationic trypsinogen gene in 10 of the pancreatic cancer patients resulted exclusively in the wild-type sequence. In addition DNA obtained from venous blood of 116 further patients with pancreatic cancer did not carry the Arg117His mutation. Our results show that the Arg117His mutation does not contribute to pathogenesis of a substantial fraction of all pancreatic adenocarcinomas. In contrast to most oncogenes or tumor suppressor genes the cationic trypsinogen gene (3rd exon) does not contain mutational hot spots.
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PMID:Mutation analysis of the cationic trypsinogen gene in patients with pancreatic cancer. 1106 9

Over the past decade, gene conversion has been shown increasingly to be a cause of human disease. Through this process, a functional gene is converted into a mutant by a homologous, nonfunctional one. In this article, we demonstrate that gene conversion is a likely cause of the mutations of the human cationic trypsinogen (PRSS1) gene that are associated with hereditary or sporadic pancreatitis, including the R122H (CGC>CAT: c.365-366 GC>AT), N29I (AAC>ATC: c.86A>T), and A16V (GCC>GTC: c.47C>T) missense mutations. This hypothesis is strongly supported by four lines of observation. First, human group I trypsinogen genes are tandemly repeated and share a high sequence homology between them. Secondly, a possible donor sequence for each variant is present in the PRSS1 gene's paralog(s). Thirdly, there exist uninterrupted sequence tracts ranging from 30 to 114 bp in the putatively converted regions. Finally, Chi-like and palindromic sequences are found in the vicinity of these missense mutations. This theory, if correct, will make the pancreatitis-associated PRSS1 mutations a unique example, as it shows that a functional gene may be converted by several paralogs, and that such an event may even occur between two functional genes (i.e., the N29I mutation), resulting in disease. This adds further to the diversity of genetic mechanisms underlying human disease. In addition, this genetic finding provides, for the first time, concrete evidence of the contribution made by gene conversion to the molecular evolution of the human trypsinogen family.
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PMID:Gene conversion-like missense mutations in the human cationic trypsinogen gene and insights into the molecular evolution of the human trypsinogen family. 1107 13

Three-point mutations (R117H, N211, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies.
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PMID:Trypsinogen gene mutations in patients with chronic or recurrent acute pancreatitis. 1113 65

Hereditary pancreatitis is an autosomal dominant form of chronic pancreatitis. It presents with recurrent attacks of acute pancreatitis, usually starting in early childhood. The attacks may vary from mild abdominal pain to pancreatic necrosis, splenic vein thrombosis, pseudocysts and death. Ultimately chronic pancreatitis ensues with unrelenting pain, calcifications, endocrine and exocrine dysfunction. The penetrance is estimated at 80%. With the use of genetic linkage analysis the gene for hereditary pancreatitis was placed on the long arm of chromosome 7 (7q35). Mutational analysis identified cationic trypsinogen as the disease gene. Cationic trypsinogen mutations are thought to result in resistance of this molecule to autolysis.
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PMID:[From gene to disease; hereditary pancreatitis]. 1114 96

Several missense mutations, including R122H, N29I, K23R, A16V and D22G, in the cationic trypsinogen gene (PRSS1), have been associated with certain forms of hereditary pancreatitis (HP). Their occurrence in the idiopathic chronic pancreatitis (ICP) and whether novel mutations could be identified in PRSS1 remain to be further evaluated. These were addressed by the mutational screening of the entire coding sequence and the intronic/exonic boundaries of the PRSS1 gene in 221 ICP subjects, using a previously established denaturing gradient gel electrophoresis technique. Among the known PRSS1 mutations, only the R122H was detected in a single subject and the A16V in two subjects in the cohort, strengthening that HP-associated PRSS1 mutations are rare in ICP. Additional missense mutations, including P36R, E79K, G83E, K92N and V123M, were identified once separately. By analogy with the known PRSS1 mutations, predisposition to pancreatitis by some of them, particularly the V123M autolysis cleavage site mutation, is suspected. Functional analysis is expected to clarify their possible medical consequences.
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PMID:Mutational screening of the cationic trypsinogen gene in a large cohort of subjects with idiopathic chronic pancreatitis. 1126 Feb 29

Hereditary pancreatitis (HP) is clinically indistinguishable from pancreatitis with other causes. Patients with HP have an increased chance of developing pancreatitis. Mutations in the cationic trypsinogen gene appear to cause most HP, although there is evidence for mild genetic heterogeneity with defects in other genes. Trypsin stabilization and protection from autolysis appear to play a central role in the pathogenesis of pancreatitis. The role of mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) as well as the pancreatic secretory trypsin inhibitor (PSTI) in patients with pancreatitis is intriguing but as yet incompletely understood. Genetic testing may help to identify and manage patients with HP. Healthcare professionals should understand the elements necessary for obtaining informed consent for patients undergoing these tests, the limits in interpreting test results, and the psychosocial issues that may arise from genetic testing.
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PMID:Genetic testing in acute and chronic pancreatitis. 1127 78

Authors report two cases of childhood chronic pancreatitis, causing severe symptoms and common bile duct stenosis with cholestasis. Both patients had to be operated on. Chronic pancreatitis with calcification led to significant common bile duct stenosis in a 13 years old girl. After ERCP a double bypass procedure was performed (Wirsungo-jejunostomy and hepatico-jejunostomy). During 42 months follow-up the patient remained pain- and symptom-free gaining 16 kilograms. In a 9 years old girl severe stenosis of the intrapancreatic common bile duct and a small duct type chronic pancreatitis with extensive fibrosis was found. Treatment was Roux-en-Y hepatico-jejunostomy. Thirty-four months after the operation she is symptom-free with normal enzyme parameters. Authors report results of genetic investigations performed on registered chronic pancreatitis children and their families in Hungary, including the two operated cases. Two of the 5 patients were hereditary type, despite negative family history. Cationic trypsinogen gene R122H (R117H) mutation were detected in both patients. Chronic non-hereditary pancreatitis is a very rare disease in childhood but may cause severe secondary conditions requiring surgery.
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PMID:[Cholestasis caused by chronic pancreatitis in childhood. Surgical treatment and genetic analysis]. 1129 60

Hereditary, chronic pancreatitis is an autosomal dominant genetic disorder, frequently associated with two point mutations in the cationic trypsinogen gene. The mutations result in characteristic changes in the amino-acid sequence of trypsinogen: an arginine residue at position 117 is changed to histidine (Arg117-->His) or an asparagine residue at position 21 is replaced by isoleucine (Asn21-->Ile). Current opinion on the pathogenesis of hereditary pancreatitis suggests that the mutations lead to increased trypsin activity in the pancreatic tissue as a result of enhanced autoactivation of trypsinogen or decreased autocatalytic degradation (autolysis) of trypsin. To investigate the relationship between the altered properties of mutant trypsinogens and the pathomechanism of pancreatitis, wild-type and two mutant forms of recombinant human cationic trypsinogen were produced and autoactivation of trypsinogens and autolysis of trypsins were studied. The results indicate that trypsin stabilization (i.e. decreased autolysis) caused by the Arg117-->His mutation may contribute to the development of pancreatitis, however, the Asn21-->Ile mutation has no such effect. In contrast, enhanced autoactivation of mutant trypsinogens may contribute to the pathogenesis of both forms of hereditary pancreatitis. This notion is strongly supported by the clear correlation between the autoactivation rates of mutant trypsinogens and the severity of clinical symptoms.
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PMID:[Significance of trypsinogen gene mutations in the etiology of hereditary pancreatitis]. 1132 17

For decades there has been slow progress in understanding pancreatic diseases, particularly acute and chronic pancreatitis. As a result, there were no significant advances in the management of these patients. Treatment was mostly directed towards symptomatic relief and management of complications. A simple clinical observation that multiple members of a large family are affected by acute and chronic pancreatitis, some at very young age and in the absence of any alcohol use, led physician-scientists of the Midwest Multicenter Pancreatic Study Group (investigators from the University of Cincinnati, University of Kentucky, and University of Pittsburgh) to investigate the genetic basis of hereditary pancreatitis. Using information from the human genome project, the hereditary pancreatitis gene was identified as the cationic trypsinogen gene (protease serine 1, PRSS1). This discovery has led to the identification of a number of other genes and their products playing role in the pathogenesis of acute and chronic pancreatitis. In the emerging picture of pathogenesis of acute and chronic pancreatitis, trypsin appears to play a central role. This newly acquired knowledge is setting the stage for new preventive and management strategies for hereditary and sporadic acute and chronic pancreatitis.
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PMID:Lessons from hereditary pancreatitis. 1147 Dec 4


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