Genetic Risk in Chronic Pancreatitis: The Trypsin-Dependent Pathway

Abstract

Genetic investigations have provided unique insight into the mechanism of chronic pancreatitis in humans and firmly established that uncontrolled trypsin activity is a central pathogenic factor. Mutations in the PRSS1, SPINK1, and CTRC genes promote increased activation of trypsinogen to trypsin by stimulation of autoactivation or by impairing protective trypsinogen degradation and/or trypsin inhibition. Here we review key genetic and biochemical features of the trypsin-dependent pathological pathway in chronic pancreatitis.

Genetic determination of pancreatitis

“…The CTRC mutations may predispose for CP by ineffective degradation of trypsinogen/trypsin, ineffective activation of carboxypeptidase, and induction of the endoplasmic reticulum [82]. The degradation of trypsinogen with participation of CTRC takes place after the exhaustion of the protective mechanisms dependent on SPINK1 [84]. Pathogenic CTRC variants (p.A73T, p.V235I, p.R254W, and p.K247_R254del) were found in patients with CP, as well as healthy controls; therefore, they should be considered as risk factors [85].…”

“…The frequent CTRC variant c.180T may exert an effect on the modification of the progression from RAP to CP, especially in patients with CFTR or SPINK1 variant, who consume alcohol and are tobacco smokers [88]. The presence of the SPINK1 and CTRC mutations causes a high risk of contracting pancreatitis and may be responsible for a more severe course of acute pancreatitis [84,87].…”

Novel PRSS1 Mutation p.P17T Validates Pathogenic Relevance of CTRC-Mediated Processing of the Trypsinogen Activation Peptide in Chronic Pancreatitis

“…Mutations in PRSS1 cause hereditary pancreatitis by reducing chymotrypsin C (CTRC)-dependent degradation of cationic trypsinogen and thereby promoting trypsinogen autoactivation [1, 2]. An interesting exception is mutation p.A16V, which does not affect trypsinogen degradation.…”

“…An interesting exception is mutation p.A16V, which does not affect trypsinogen degradation. Instead, it increases CTRC-mediated processing of the trypsinogen activation peptide to a shorter form (Figure 1A), which, in turn, results in accelerated autoactivation [1–3]. Mutation p.A16V exhibits variable penetrance, indicating that disease onset requires additional risk factors [4, 5].…”

Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice

“…Onset and progression of a single episode of acute pancreatitis towards chronic pancreatitis is often determined by underlying genetic risk factors associated with digestive proteases or their inhibitor. Mutations in PRSS1 (cationic trypsinogen), SPINK1 (serine protease inhibitor Kazal type 1), CTRC (chymotrypsin C) increase activation of trypsinogen to trypsin in the pancreas and thereby result in acinar cell damage and inflammation 2. A protective mutation in PRSS2 (anionic trypsinogen) and an inversion at the CTRB1-CTRB2 (chymotrypsin B1-B2) locus also modify trypsin levels and pancreatitis risk 3 4.…”