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Mutations in PRSS1 cause hereditary pancreatitis by altering cleavage of regulatory nick sites by chymotrypsin C (CTRC) resulting in reduced trypsinogen degradation and increased autoactivation.

Despite 90% identity with PRSS1 and a strong propensity for autoactivation, mutations in PRSS2 are not found in hereditary pancreatitis suggesting that activation of this isoform is more tightly regulated.

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However, genetic studies failed to identify PRSS2 mutations in hereditary pancreatitis families or in association with sporadic chronic pancreatitis (14–16).

Interestingly, a polymorphic variant, G191R, was found with higher frequency in healthy controls (3.4%) pancreatitis patients (1.3%), indicating an ∼2.7-fold protective effect, as judged by the odds ratio in the largest cohort studied (14).

Taken together with the lack of pathogenic PRSS2 mutations, the observations to date led us to hypothesize that anionic trypsinogen may be more tightly regulated by CTRC, possibly preventing natural mutations from causing significantly increased activation of this isoform.

Amino acid residues in human trypsinogen isoforms were numbered starting with the initiator methionine of the primary translation product, according to the recommendations of the Human Genome Variation Society.

The human pancreas secretes three isoforms as follows: cationic trypsinogen, anionic trypsinogen, and mesotrypsinogen, which are encoded by the genes, respectively (1).

Cationic and anionic trypsinogen constitute more than 95% of total trypsinogen in the pancreatic juice, with a slight preponderance of the cationic isoform (2–4).The digestive enzyme CTRC cleaves at Leu-81 in the calcium binding loop, which together with an autolytic cleavage at Arg-122 by trypsin results in trypsinogen degradation (Fig. A secondary CTRC-mediated cleavage at Leu-41 was also observed.Active cationic trypsin is also degraded by this mechanism but at a much slower rate due to unusual thermodynamic stability of the regulatory nick sites (11, 12).Finally, processing of the trypsinogen activation peptide at Phe-18 by CTRC inhibited autoactivation of anionic trypsinogen, although cationic trypsinogen was strongly stimulated.Taken together, the observations indicate that human anionic trypsinogen is controlled by CTRC in a manner that individual natural mutations are unlikely to increase stability enough to promote intra-pancreatic activation.The discovery of the association of PRSS1 mutations and hereditary pancreatitis stimulated a number of investigations into the potential role of PRSS2 in chronic pancreatitis (14–16).

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