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

Since the identification in 1996 of a "gain of function" missense mutation, R122H, in the cationic trypsinogen gene (PRSS1) as a cause of hereditary p ancreatitis, continued screening of this gene in both hereditary and sporad ic pancreatitis has found more disease-associated missense mutations than e xpected. In addition, functional analysis has yielded interesting findings regarding their underlying mechanisms resulting in a gain of trypsin. A cri tical review of these data, in the context of the complicated biogenesis an d complex autoactivation and autolysis of trypsin(ogen), highlights that PR SS1 mutations cause the disease by various mechanisms depending on which bi ochemical process they affect. The discovery of these mutations also modifi es the classical perception of the disease and, more importantly, reveals f ascinating new aspects of the molecular evolution and normal physiology of trypsinogen. First, activation peptide of trypsinogen is under strong selec tion 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, w e tentatively assign, in human cationic trypsinogen, the strongly selected activation peptide as the first-line and the R122 autolysis site as the sec ond-line of the built-in defensive mechanisms against premature trypsin act ivation within the pancreas, respectively, and the positively selected aspa ragine at residue 29 as an "amplifier" to the R122 "fail-safe" mechanism.