Trypsinogen stabilization by mutation Arg117 -> His: A unifying pathomechanism for hereditary pancreatitis?

Mutations Arg117-->His and Asn21-->Ile of the human cationic trypsinogen ha ve been recently identified in patients affected by hereditary pancreatitis (HP). The Arg117-->His substitution is believed to cause pancreatitis by e liminating an essential autolytic cleavage site in trypsin, thereby renderi ng the protease resistant to inactivation through autolysis. Here we demons trate that the Arg117-->His mutation also significantly inhibits autocataly tic trypsinogen breakdown under Ca2+-free conditions and stabilizes the zym ogen form of rat trypsin. Taken together with recent findings demonstrating that the Asn21-->Ile mutation stabilizes rat trypsinogen against autoactiv ation and consequent autocatalytic degradation, the observations suggest a unifying molecular pathomechanism for HP in which zymogen stabilization pla ys a central role. (C) 1999 Academic Press.