Gain-of-function mutations associated with hereditary pancreatitis enhanceautoactivation of human cationic trypsinogen

Hereditary pancreatitis (HP), an autosomal dominant disorder, has been asso ciated with mutations in the cationic trypsinogen gene. Here we demonstrate that the two most frequent HP mutations, Arg117 --> His and Asn21 --> Ile, significantly enhance autoactivation of human cationic trypsinogen in vitr o, in a manner that correlates with the severity of clinical symptoms in HP . In addition, mutation Arg117 --> His inhibits autocatalytic inactivation of trypsin, while mutation Asn21 --> Ile has no such effect. The findings s trongly argue that increased trypsinogen activation in the pancreas is the common initiating step in both forms of HP, whereas trypsin stabilization m ight also contribute to HP associated with the Arg117 --> His mutation. (C) 2000 Academic Press.