Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis

Abstract

Variations in the serine protease 1 (PRSS1) gene encoding human cationic trypsinogen have been conclusively associated with autosomal dominant hereditary pancreatitis and sporadic nonalcoholic chronic pancreatitis. Most high-penetrance PRSS1 variants increase intrapancreatic trypsin activity by stimulating trypsinogen autoactivation and/or by inhibiting chymotrypsin C-dependent trypsinogen degradation. Alternatively, some PRSS1 variants can cause trypsinogen misfolding, which results in intracellular retention and degradation with consequent endoplasmic reticulum stress. However, not all PRSS1 variants are pathogenic, and clinical relevance of rare variants is often difficult to ascertain. Here we review the PRSS1 variants published since 1996 and discuss their functional properties and role in chronic pancreatitis.

Fig. 1.

Effect of pancreatitis-associated PRSS1 mutations on the chymotrypsin C (CTRC)-dependent activation and degradation of human cationic trypsinogen. CTRC cleaves the Leu81-Glu82 peptide bond and trypsin cleaves the Arg122-Val123 peptide bond; these 2 cleavages result in the eventual degradation of trypsinogen. CTRC also stimulates autoactivation of cationic trypsinogen by cleaving the Phe18-Asp19 peptide bond in the activation peptide. The shortened activation peptide is more susceptible to trypsin-mediated activation at the Lys23-Ile24 peptide bond. The dominant effect of CTRC is degradation. A: PRSS1 mutations can increase conversion of trypsinogen to trypsin by inhibition of CTRC-dependent trypsinogen degradation (red arrow) or by increasing CTRC-dependent stimulation of autoactivation (green arrow). See text for further details. B: proteolytic cleavage of human cationic trypsinogen by CTRC and trypsin. Primary structure of trypsinogen with disulfide bonds is shown. CTRC cleavage sites are highlighted in orange and trypsin cleavage sites are shown in blue. The activation peptide is in green. Note the yellow peptide segment not stabilized by disulfide bonds between the Leu81 and Arg122 cleavage sites. B is modified from Ref. , copyright by the National Academy of Sciences of the United States of America.