18–22 Finally, the pG191R variant in the serine protease 2 (PRSS

18–22 Finally, the p.G191R variant in the serine protease 2 (PRSS2) gene encoding anionic trypsinogen was shown to afford protection against chronic pancreatitis.23 Taken together, the genetic studies indicate that chronic pancreatitis is a multigenic disease, and the balance between risk and protective genetic factors determines susceptibility. The genetics http://www.selleckchem.com/products/AZD1152-HQPA.html of PRSS1, PRSS2, SPINK1, and CFTR mutations in chronic pancreatitis has been the subject of excellent reviews.2,3,14,15,24,25 Functional studies with mutant cationic trypsinogens demonstrated that

the most frequently and consistently found phenotypic change was an increased propensity for trypsin-mediated trypsinogen activation, also referred to as autoactivation.26–30 On the basis of these findings, we proposed that most PRSS1 variants are gain-of-function mutations that cause chronic pancreatitis by promoting premature Selleck EGFR inhibitor trypsinogen activation in the pancreas. We and others showed that genetic variants in the SPINK1 gene are loss-of-function

mutations that diminish the expression of the inhibitor, either at the mRNA or at the protein level, thereby impairing its protective function.31–35 Finally, in contrast to the pathogenic PRSS1 and SPINK1 mutations, we found that the p.G191R variant in PRSS2 results in rapid autodegradation of anionic trypsinogen, and thereby affords protection against chronic pancreatitis.23 Conceptually, the properties of p.G191R are noteworthy because they highlight the protective

role of trypsinogen degradation against chronic pancreatitis. Taken together, the genetic and biochemical evidence defines a pathological pathway in which the imbalance between intrapancreatic trypsinogen activation, trypsinogen degradation, and trypsin inhibition increases the risk for the development of chronic pancreatitis (Fig. 1). In 2007, an international team of scientists reported that loss-of-function variants in the chymotrypsin C (CTRC) gene are risk factors for chronic pancreatitis, and this finding was replicated by an independent study published shortly thereafter.36,37 Screening of CTRC in patients affected by chronic pancreatitis was stimulated by second biochemical studies from our laboratory, which demonstrated that CTRC plays an important role in regulating trypsinogen activation and degradation. The initial genetic experiments took place at the University of Leipzig in Germany, where Niels Teich and Jonas Rosendahl used direct DNA sequencing to investigate 100 patients with idiopathic and hereditary chronic pancreatitis and found variants in four patients. The senior author of this review visited Leipzig in 2006 and still recalls the palpable excitement these initial observations elicited.

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