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 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 approximately 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.
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PMID:Hereditary pancreatitis caused by triplication of the trypsinogen locus. 1707 18

Hereditary pancreatitis should be assumed if other risk factors for the disease can not been identified and if the patient has a family history for recurrent pancreatitis, chronic pancreatitis or pancreatic cancer. Since patients with chronic pancreatitis due to mutations in the cationic trypsinogen-gene have a much higher lifetime risk of developing pancreatic cancer, specifically if they are smokers, an adequate long-term follow up in specialized centers is recommended. The most frequent genetic changes in patients with hereditary pancreatitis are mutations in the cationic trypsinogen gene. Mutations in the CFTR-gene or SPINK1-gene have been reported in patients with idiopathic pancreatitis. The clinical relevance and the therapeutic consequences of these mutations is still controversial. Genetic testing is recommended when a patient with idiopathic pancreatitis is under 25 years at diagnosis or when one or more family members have either pancreatitis or pancreatic cancer. Genetic analysis of asymptomatic family members should only be offered after adequate genetic counselling. Prenatal diagnostic is not recommended.
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PMID:[Hereditary pancreatitis]. 1711 46

Trypsin activity is properly suppressed by pancreatic secretory trypsin inhibitor (PSTI), which is also known as serine protease inhibitor Kazal type 1 (SPINK1), thereby preventing damage to pancreatic acinar cells as a first line of defence. However, if trypsin activation exceeds the capacity of PSTI/SPINK1, a subsequent cascade of events leads to the activation of various proteases that damage cells. Five mutations (R122H, N29I, A16V, D22G and K23R) in cationic trypsinogen and two mutations (N34S and M1T) in the PSTI/SPINK1 gene have been found to correlate significantly with the onset of pancreatitis. From analyses of hereditary pancreatitis and the phenotype of PSTI/SPINK1 (Spink3) knockout mice, we showed that the imbalance of trypsin activation and its inhibition by PSTI/SPINK1 would lead to the development of pancreatitis.
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PMID:Genetic background of pancreatitis. 1714 97

Hereditary pancreatitis is a rare, autosomal dominant, inherited disease characterized by recurrent attacks of acute pancreatitis with the development of chronic pancreatitis and an increased risk of pancreatic cancer. R122H or N29I mutation in cationic trypsinogen (protease serine 1, PRSS1) gene causes hereditary pancreatitis. R122H mutation is the most common mutation that causes pancreatitis by preventing deactivation of trypsin within the pancreas and prolonging its action. Three members of the family, the patient, her elder son, and her niece experienced recurrent attacks of pancreatitis. We analyzed five exons of the PRSS1 gene in DNA samples of five family members including her husband and younger son who were asymptomatic. We found out that four members of the family, the patient, her two sons, and her niece, had R122H mutation in the exon 3 of PRSS1 gene. Finally, we diagnosed hereditary pancreatitis in two households in the same family.
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PMID:[Three cases of hereditary pancreatitis in two households in the same family associated with R122H mutation in cationic trypsinogen gene]. 1764 59

There was remarkable progress in the understanding of the role genetic risk factors in chronic pancreatitis. These factors seem to be much more important than thought in the past. The rare autosomal-dominant mutations N29I and R122H of PRSS1 (cationic trypsinogen) as well as the variant N34S of SPINK1 (pancreatic secretory trypsin inhibitor) are associated to a disease onset in childhood or youth. Compared to chronic alcoholic pancreatitis the progression is slow so that for a long time only signs of acute-recurrent pancreatitis are found. Only at later time points (more than 10-15 years) there is evidence for chronic pancreatitis in the majority of patients. Acute recurrent pancreatitis may therefore be regarded as a transition state until definite signs of chronic pancreatitis are detectable.
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PMID:Role of genetic disorders in acute recurrent pancreatitis. 1828 80

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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PMID:Hereditary pancreatitis caused by a double gain-of-function trypsinogen mutation. 1846 67

Though amply described, alcoholic pancreatitis continues to stir controversy. One of the most debated points is whether it is a chronic disease since onset or progresses to a chronic form after repeated episodes of acute pancreatitis. Histologic studies on patients with pancreatitis have clearly shown that it is chronic since onset and that if necrotic acute pancreatitis develops in an alcoholic, it occurs in a pancreas damaged by chronic lesions. While the possibility cannot be wholly excluded that alcohol-related acute pancreatitis may develop in the absence of chronic lesions, such an occurrence would be rare. In addition to alcoholism, genetic factors play a determinant role in the pathogenesis of the disease. Genetic studies have suggested that in hereditary pancreatitis mutation of the cationic trypsinogen gene and serine peptidase inhibitor, Kazal type 1 (SPINK1) genes mutations of the may have pathogenetic importance; however, studies on alcoholic pancreatitis have produced disappointing results so far.
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PMID:Alcoholic pancreatitis: new pathogenetic insights. 1866 46

We investigated the biochemical properties and cellular expression of the c.346C>T (p.R116C) human cationic trypsinogen (PRSS1) mutant, which we identified in a German family with autosomal dominant hereditary pancreatitis. This mutation leads to an unpaired Cys residue with the potential to interfere with protein folding via incorrect disulfide bond formation. Recombinantly expressed p.R116C trypsinogen exhibited a tendency for misfolding in vitro. Biochemical analysis of the correctly folded, purified p.R116C mutant revealed unchanged activation and degradation characteristics compared to wild type trypsinogen. Secretion of mutant p.R116C from transfected 293T cells was reduced to approximately 20% of wild type. A similar secretion defect was observed with another rare PRSS1 variant, p.C139S, whereas mutants p.A16V, p.N29I, p.N29T, p.E79K, p.R122C, and p.R122H were secreted normally. All mutants were detected in cell extracts at comparable levels but a large portion of mutant p.R116C was present in an insoluble, protease-sensitive form. Consistent with intracellular retention of misfolded trypsinogen, the endoplasmic reticulum (ER) stress markers immunoglobulin-binding protein (BiP) and the spliced form of the X-box binding protein-1 (XBP1s) were elevated in cells expressing mutant p.R116C. The results indicate that mutation-induced misfolding and intracellular retention of human cationic trypsinogen causes hereditary pancreatitis in carriers of the p.R116C mutation. ER stress triggered by trypsinogen misfolding represents a new potential disease mechanism for chronic pancreatitis.
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PMID:Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. 1919 23

In 1996, shortly after a locus for hereditary pancreatitis had been mapped to chromosome 7q35, an apparent gain-of-function missense mutation, p.R122H, in the cationic trypsinogen gene (PRSS1) was identified. Thereafter, the search for chronic pancreatitis-associated genetic factors has been largely focused on one form of genetic variation, namely, single nucleotide substitutions (SNSs). Only very recently has another type of genetic variation - copy number variations (CNVs) - been found to cause the disease. First, we identified duplication and triplication of an approximately 605 kb segment on chromosome 7q35 in French white patients with hereditary or idiopathic chronic pancreatitis. These alterations increased the copy number of PRSS1 as well as PRSS2, which encodes anionic trypsinogen. Second, we characterized a hybrid trypsinogen gene, in which exons 1 and 2 were derived from PRSS2 and exons 3 to 5 from PRSS1. Interestingly, this hybrid gene had two independent gain-of-function effects: increased trypsinogen gene copy number and it contained the p.N29I pancreatitis-causing missense mutation. Lastly, we identified two loss-of-function copy number mutations (deletions) in the SPINK1 gene, which encodes pancreatic secretory trypsin inhibitor (PSTI). Particularly, in one family with chronic pancreatitis, deletion of the complete SPINK1 gene was co-inherited with a CFTR missense mutation (p.L997F), revealing another layer of complexity between CNV and SNS interactions in the determination of a given disease phenotype. These findings represent a further demonstration of how studies of CNVs have altered the landscape of genetic research in the past few years and offer a fresh glimpse into the exciting realm of human CNVs.
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PMID:Copy number variations in chronic pancreatitis. 1928 44

Chronic alcohol intake accounts for 60-90% of the cases of chronic pancreatitis, but other etiologies have been recognized and described in the very recent years. Genetic causes include mutations of the cationic trypsinogen gene PRSS1 (100 families in France), of its inhibitor SPINK1 and of the CFTR gene involved in cystic fibrosis. Auto-immune pancreatitis is often part of an "IgG4-related systemic disease" involving the biliary tract, the salivary glands, the retroperitoneum and/or the kidneys. Diagnostic criteria are now well-defined (HISORt of the Mayo Clinic), with ductal and parenchymal lesions on imaging that may mimick pancreatic adenocarcinoma. Corticoids are efficacious but recurrences are frequent and long-term outcome is still poorly known.
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PMID:[From the chronic pancreatitis to chronic pancreatites]. 1971 57


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