INT12240
From wiki-pain
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Sentences Mentioned In
Key: | Protein | Mutation | Event | Anatomy | Negation | Speculation | Pain term | Disease term |
In contrast to this attractive hypothesis of gain-of-function trypsins in hereditary pancreatitis, recent in vitro studies have challenged these assumptions and suggested that a loss of trypsin function could impair the inactivation of other (more pancreatotoxic?) | |||||||||||||||
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The mild phenotype in these animals is probably caused by a low expression level of R122H mutated trypsinogen. | |||||||||||||||
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However, the absence of trypsinogen in the stones from two of the 13 patients also suggests that trypsinogen is not the sole protein initiating precipitate formation. | |||||||||||||||
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SPINK1 is a potent protease inhibitor thought to be a specific inactivation factor of intrapancreatic trypsin activity. | |||||||||||||||
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These in vivo results underline the hypothesis that enhanced inhibitory capacity of trypsin protects against pancreatitis. | |||||||||||||||
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The analysis of the recombinantly expressed G191R variant revealed a complete loss of trypsin activity due to the introduction of a novel tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. | |||||||||||||||
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These new insights suggest, that structural alterations, which impair the function of trypsin, could eliminate a protective mechanism rather than triggering an aggressive mechanism in initiating pancreatitis. | |||||||||||||||
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Thus, this animal model, which gives a significant expression level of R122H mutated trypsinogen, seems to recapitulate the human disease. | |||||||||||||||
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Transgenic expression of SPINK1 did not hinder trypsinogen activation, but reduced trypsin activity after supramaximal stimulation with cerulein. | |||||||||||||||
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However, we hypothesize that in the case of the SPINK1 N34S high-risk haplotype, the variation in reported effect sizes may be a result of differences in the proportion of subjects with pathogenic pathways linking environmental stressors to pancreatic stellate cell (PSC) activation through recurrent trypsinogen activation and inadequate trypsin inhibition by SPINK1. | |||||||||||||||
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These may predispose to acute pancreatitis by eliminating one of the fail-safe mechanisms used by the pancreas to eliminate prematurely activated trypsin. | |||||||||||||||
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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. | |||||||||||||||
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Results from a mouse with targeted disruption of the pancreatic secretory trypsin inhibitor are puzzling [69]. | |||||||||||||||
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Results from a mouse with targeted disruption of the pancreatic secretory trypsin inhibitor are puzzling [69]. | |||||||||||||||
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Lastly, we identified two loss-of-function copy number mutations (deletions) in the SPINK1 gene, which encodes pancreatic secretory trypsin inhibitor (PSTI). | |||||||||||||||
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In an actual study of 2466 patients with chronic pancreatitis (including 1857 with hereditary or idiopathic pancreatitis) and 6459 controls by Witt et al., the G191R variant of the anionic trypsinogen was over represented in controls (32 vs. 220, odds ratio 0.37; P = 1.1 × 10-8). | |||||||||||||||
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"Loss of function" mutations in the cationic trypsinogen gene (PRSS1) may act as a protective factor against pancreatitis. | |||||||||||||||
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These findings in genetically determined forms of chronic pancreatitis indicate that an imbalance between trypsin activity and trypsin inhibition in favour of enhanced proteolytic activity is the central pathogenetic factor in pancreatitis. | |||||||||||||||
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Effects of trypsin were largely reduced by low Cl(-), by basolateral bumetanide, and in the presence of barium or clotrimazole, but not by tetrodotoxin. | |||||||||||||||
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BACKGROUND: Mutations of the pancreatic serine protease inhibitor, Kazal type 1 (SPINK1), the cationic trypsinogen (PRSS1) and the cystic fibrosis transmembrane conductance regulator (CFTR) were reported to be genetic risk factors of chronic pancreatitis (CP). | |||||||||||||||
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General Comments
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