Molecular pathology and evolutionary and physiological implications of pancreatitis-associated cationic trypsinogen mutations

Abstract

Since the identification in 1996 of a "gain of function" missense mutation, R122H, in the cationic trypsinogen gene (PRSS1) as a cause of hereditary pancreatitis, continued screening of this gene in both hereditary and sporadic pancreatitis has found more disease-associated missense mutations than expected. In addition, functional analysis has yielded interesting findings regarding their underlying mechanisms resulting in a gain of trypsin. A critical review of these data, in the context of the complicated biogenesis and complex autoactivation and autolysis of trypsin(ogen), highlights that PRSS1 mutations cause the disease by various mechanisms depending on which biochemical process they affect. The discovery of these mutations also modifies the classical perception of the disease and, more importantly, reveals fascinating new aspects of the molecular evolution and normal physiology of trypsinogen. First, activation peptide of trypsinogen is under strong selection pressure to minimize autoactivation in higher vertebrates. Second, the R122 primary autolysis site has further evolved in mammalian trypsinogens. Third, evolutionary divergence from threonine to asparagine at residue 29 in human cationic trypsinogen provides additional advantage. Accordingly, we tentatively assign, in human cationic trypsinogen, the strongly selected activation peptide as the first-line and the R122 autolysis site as the second-line of the built-in defensive mechanisms against premature trypsin activation within the pancreas, respectively, and the positively selected asparagine at residue 29 as an "amplifier" to the R122 "fail-safe" mechanism.

Gene conversion cetween functional trypsinogen genesPRSS1andPRSS2associated with chronic pancreatitis in a six-year-old girl

“…A region comprising parts of exon 2 and intron 2 of the PRSS1 acceptor gene is converted by the PRSS2 donor gene. The PRSS2 gene remains unaltered (adapted from Chen et al, 2001). Autocatalytic activation of wild type (PRSS1), single-mutant (N29I) and double-mutant (N29I-N54S) cationic trypsinogen.…”

A Thai family with hereditary pancreatitis and increased cancer risk due to a mutation inPRSS1gene

“…It is autoactivated to trypsin by cleavage of 8 amino acids, from alanine 16 to lysine 23 residues (APFDDDDK) next to the N-terminal signal peptide of 15 residues. The activated trypsin can then autolyze itself at the primary autolysis site, arginine 122 [6,7] . Most of the 17 PRSS1 mutations discovered, to date, occur within or near important enzymatic domains of CT and locate only in exons 2 and 3, and the promoter region of the PRSS1 gene (http://uwcmml1s.uwcm.ac.uk/uwcm/ mg/search/119620.html).…”

“…The precise mechanism by which these PRSS1 mutations cause HP disease remains unclear. However, it is believed to be a gain-of-function due to increased activity or stability of trypsin and/or decreased trypsin inactivation [7,16,17] , leading to autolysis of the pancreatic tissue. Thus, the possible mechanisms may be: (1) enhanced autoactivation of trypsinogen by mutations at the autoactivation site (A16V, D22G, K23R) [9,13,15] , (2) stabilization of trypsin by N29I [16] , and (3) disruption of the trypsin hydrolytic recognition site by R122H [16] .…”

Determination of the relative contribution of three genes–the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene–to the etiology of idiopathic chronic pancreatitis

“…To date, most of the relevant studies performed mutational analysis of only a single gene, that is, the CFTR gene, 3,4,11 ± 14 the PRSS1 gene (see a recent review 15 ), or the PSTI gene. 6,7,16 ± 20 Moreover, due to differences in the selection of participants, the number of participants analysed, and the mutation screening method used, the reported frequency of mutations in a given gene varied significantly among different studies.…”