Gene/Protein Disease Symptom Drug Enzyme Compound
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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 a rare autosomal dominant inherited disease with 80% penetration rate. The disease is characterized by recurrent episodes of pancreatitis often beginning in childhood, positive family history with at least two other affected members and no known precipitating factors. Most forms of hereditary pancreatitis are caused by one of two commoner mutations, R122H in exon 3 and N29I in exon 2 of the cationic trypsinogen (CT) (PRSS1) gene, located on chromosome 7. These genetic defects are speculated to cause excessive trypsin activity or to prevent inactivation of prematurely activated trypsin, resulting in pancreatitis. We performed mutation analysis of a Korean family with two members having clinically suspicious hereditary pancreatitis. We analyzed the CT gene in DNA samples extracted from peripheral blood of five family members. First of all, polymerase chain reaction and restriction enzyme digestion were performed in exon 3 of the CT gene. And then DNA products were purified and sequenced. We found out that three members of the family, the mother and two daughters, had a R122H mutation of the CT gene. We report the first family of hereditary pancreatitis associated with the CT gene mutation, an arginine to histidine amino acid substitution at residue 122, in Korea.
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PMID:[A case of R122H mutation of cationic trypsinogen gene in a pediatric patient with hereditary pancreatitis complicated by pseudocyst and hemosuccus pancreaticus]. 1572 20

Hereditary pancreatitis (HP) is an autosomal dominant inherited disease characterized by recurrent episodes of pancreatitis often beginning in childhood, a family history of at least 2 other affected members, and the absence of known etiologic factors. The discovery of mutations in cationic trypsinogen gene (PRSS1) in HP not only provided insights into the molecular mechanisms of pancreatitis, but also opened a new era in the field of chronic pancreatitis. The detection of mutations in serine protease inhibitor, Kazal type 1 (SPINK1) and CFTR in patients with hereditary or idiopathic chronic pancreatitis has placed the emphasis on the importance of genetic mutations in pancreatitis. Because the estimated cumulative risk of pancreatic cancer development in hereditary pancreatitis is nearly 40%, screening tests are important in selected cases. There are no specific medical therapies recommended in patients with HP. Registration of patients with Nationwise Registries is essential if management strategies are to be improved and genetic research to be continued.
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PMID:[Hereditary pancreatitis]. 1572 18

Considerable progress in the understanding of the pathogenesis of acute pancreatitis is based on the conclusive finding that the initiation of the disease occurs within the acinar cell. Two lines of evidence have contributed to the progress in understanding the disease process: (1) the identification of patients with a hereditary form of pancreatitis as carriers of germline-mutations in the genes for cationic trypsinogen and the pancreatic secretory trypsin inhibitor and (2) the use of various transgenic and knock-out mouse strains in experimental models of acute pancreatitis. On the other hand, these studies have delivered several unexpected results that appear to be incompatible with long-standing dogmas and paradigms of pancreatic research. Further progress in knowledge will result if the well-characterized enzymatic properties of human enzymes that are involved in the initial activation cascade can be investigated under in vivo conditions in transgenic animals or in permanent acinar cell lines. Such studies will permit the development of effective strategies for the prevention and treatment of this disease.
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PMID:Early events in acute pancreatitis. 1574 29

One of ostrich (Struthio camelus) trypsinogen genes was cloned from pancreatic cDNA. Its amino acid sequence compared to known trypsin sequences from other species shows high identity and suggests that it is a member of the phylogenetically anionic trypsinogen I subfamily. After cytoplasmic over expression in Escherichia coli and renaturation, the activation properties of ostrich trypsinogen were studied and compared to those of human trypsinogen 1 (also called as human cationic trypsinogen). Ostrich trypsinogen undergoes bovine enterokinase activation and autoactivation much faster than human trypsinogen 1 and exhibits on a synthetic substrate a somewhat higher enzymatic activity than the latter one. The most interesting property of ostrich trypsin is its relatively fast autolysis that can be explained via a mechanism different from the common mechanism for rat and human 1 trypsins. The latter proteases have a site, Arg117-Val118, where the autolysis starts and then goes on in a zipper-like fashion. This is absent from ostrich trypsin. Instead it has a couple of cleavage sites within regions 67-98, including two unusual ones, Arg76-Glu77 and Arg83-Ser84. These appear to be hydrolysed fast in a non-consecutive manner. Such an autolysis mechanism could not be inhibited by a single-site mutation which in humans is proposed to lead to pancreatitis.
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PMID:Cloning and expression of ostrich trypsinogen: an avian trypsin with a highly sensitive autolysis site. 1575 90

The understanding of pathogenesis of acute and chronic pancreatitis has benefited from the progress made in genetic investigations. The discoveries of the gain of function mutations of cationic trypsinogen gene (PRSS1) and the loss of function mutations of pancreatic secretory trypsin inhibitor (SPINK 1) or other potential defects in genes that regulate pancreatic secretory function or modulate inflammatory response to pancreatic injury has changed our current concepts on the pathogenesis of pancreatitis. Genetic factors play an important role in the susceptibility to pancreatic injury, severity and evolution of inflammatory process, leading in some cases to chronic inflammation and/or fibrosis. Acute pancreatitis is viewed as an event and chronic pancreatitis as a process, sequentially linked, reflecting a complex interaction between genetic and environmental factors.
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PMID:Genetic factors in pancreatitis. 1580 Jun 94

Alcoholic pancreatitis is an old disease that continues to present controversial issues. One of the most hotly debated issues is whether alcoholic pancreatitis is a chronic disease from the beginning or if instead it becomes chronic after repeated episodes of acute pancreatitis. Histologic studies, including very large series of patients with alcoholic pancreatitis, have clearly shown that this disease is chronic from the beginning and that, if acute necrotic pancreatitis occurs, it is associated with chronic lesions. The possibility that acute alcoholic pancreatitis can occur in the absence of chronic lesions cannot be excluded, but, if this occurs, it is rare. In addition to alcohol, genetic factors certainly play a determining role. Until now many genetic studies have been made on chronic pancreatitis; the first dealt with hereditary pancreatitis. In this disease it has been shown that mutations of the cationic trypsinogen gene and of SPINK1 are implicated in its pathogenesis. Concerning alcoholic pancreatitis, several studies have been made, but the results so far are disappointing.
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PMID:Alcoholic pancreatitis: new insights into an old disease. 1580 96

Chronic pancreatitis: Only recently mutations in several genes were found in patients with chronic pancreatitis. In those with a familial chronic pancreatitis mutations of the cationic trypsinogen were identified and the variants N29I and R122H lead to an autosomal dominant disease. In this group of patients the mutation N34S of the trypsin inhibitor SPINK1 was detected. In so-called idiopathic pancreatitis both variants of the SPINK1 and of the CFTR (cystic fibrosis transmembrane conductance regular) were identified. Alterations in both genes were also found in patients with alcoholic chronic pancreatitis. The strongest risk factor for chronic pancreatitis were trypsinogen mutations N29I and R122H mutations. However, both SPINK1 and CFTR increased the risk for chronic pancreatitis to a higher level than alcohol consumption. A genetic investigation should be performed in familial disease and younger age, but also in patients without family history and higher age a mutation could be found. Pancreas cancer: In 10% of the patients with pancreas cancer other members of the family were affected from the disease. Some of them belong to well characterized familial syndroms like HNPCC or Peutz-Jeghers-syndrom. In a minority of the others a genetic factor may be found, too. In sporadic disease the development of the tumor is characterized by continued acquirement of genetic alterations described by the PanIN model (pancreatic intraepithelial neoplesia). This means that the evolution of the neoplasia progresses from normal tissue via epithelial hyperplasy (PanIN 1A), papillary hyperplasy without (PanIN 1B) and with dysplasy (PanIN 2) and carcinoma in situ (PanIN 3) to invasive pancreas cancer. The progression is associated with genetic alterations of the cells (mutations of ki-ras, p16, p53 etc.). This results in deterioration of control of the cell cycle and the apoptosis and explains the malignancy of the disease. These findings may be used in the future to develop newer therapeutic principles in order to improve the dismal prognosis of this disease.
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PMID:[Chronic pancreatitis--pancreas cancer: influence of genetic factors]. 1595 15

Mutations in the human cationic trypsinogen are associated with hereditary pancreatitis. The cDNA coding for human cationic trypsinogen was subcloned into the expression vector pcDNA3. The mutations R122H, N29I, A16V, D22G, and K23R were introduced by site directed mutagenesis. We constructed an expression vector coding for active trypsin by subcloning the cDNA of trypsin lacking the coding region for the trypsin activating peptide behind an appropriate signal peptide. Expression of protein was verified by Western blot and measurement of enzymatic activity. AR4-2J cells were transiently transfected with the different expression vectors and cell viability and intracellular caspase-3 activity were quantified. In contrast to wild-type trypsinogen, expression of active trypsin and mutated trypsinogens reduced cell viability of AR4-2J cells. Expression of trypsin and R122H trypsinogen induced caspase-3 activity. Acinar cells might react to intracellular trypsin activity by triggering apoptosis.
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PMID:Expression of mutated cationic trypsinogen reduces cellular viability in AR4-2J cells. 1603 33

There was some recent progress in the understanding of genetic risk factors in chronic pancreatitis. Due to this progress some of the traditional views of the subject will change. Today, genetic risk factors are attributed a much more important role that in the past. The frequency and strength of mutations were higher than expected. Strong variants were the rare autosomal-dominant mutations N29I and R122H of PRSS1 (cationic trypsinogen) and homozygous N34S of SPINK1 (pancreatic secretory trypsin inhibitor). Other mutations (heterozygous N34S, CFTR) were of lower relevance but still mediate a higher risk than alcohol consumption. The course of genetically determined pancreatitis is rather mild. In the long term pancreas cancer was found in some patients but apart from non-smoking no adequate prophylactic strategy is available up to now.
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PMID:Genetics of pancreatitis. 1611 Oct 90

Cystic fibrosis (CF) is a recessive disease caused by mutations of the CF transmembrane conductance regulator (CFTR) gene. The risk of idiopathic chronic pancreatitis (ICP) is increased in individuals who have CFTR genotypes containing a CF-causing mutation plus a second pathogenic allele. It is unknown whether the risk of ICP is increased in CF carriers who have one CF-causing mutation plus one normal allele. In this study, 52 sporadic cases of ICP were ascertained through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen mutations were excluded. DNA was comprehensively tested for CFTR mutations using a robotically enhanced, multiplexed, and highly redundant form of single-strand conformation polymorphism (SSCP) analysis followed by DNA sequencing. Fifteen subjects had a total of 18 pathogenic CFTR alleles. Eight subjects had common CF-causing mutations. This group included seven CF carriers in whom the second CFTR allele was normal (4.3 times the expected frequency, P=0.0002). Three subjects had compound heterozygotes genotypes containing two pathogenic alleles (31 times the expected frequency, P<0.0001). A variant allele of uncertain significance (p.R75Q) was detected in eight of the 52 ICP subjects and at a similar frequency (13/96) in random donors. ICP differs from other established CFTR-related conditions in that ICP risk is increased in CF carriers who have one documented normal CFTR allele. Having two CFTR mutations imparts a higher relative risk, while having only one mutation imparts a higher attributable risk.
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PMID:Increased risk of idiopathic chronic pancreatitis in cystic fibrosis carriers. 1613 71


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