[Significance of trypsinogen gene mutations in the etiology of hereditary pancreatitis].
Hereditary, chronic pancreatitis is an autosomal dominant genetic disorder, frequently associated with two point mutations in the cationic trypsinogen gene. The mutations result in characteristic changes in the amino-acid sequence of trypsinogen: an arginine residue at position 117 is changed to histidine (Arg117-->His) or an asparagine residue at position 21 is replaced by isoleucine (Asn21-->Ile). Current opinion on the pathogenesis of hereditary pancreatitis suggests that the mutations lead to increased trypsin activity in the pancreatic tissue as a result of enhanced autoactivation of trypsinogen or decreased autocatalytic degradation (autolysis) of trypsin. To investigate the relationship between the altered properties of mutant trypsinogens and the pathomechanism of pancreatitis, wild-type and two mutant forms of recombinant human cationic trypsinogen were produced and autoactivation of trypsinogens and autolysis of trypsins were studied. The results indicate that trypsin stabilization (i.e. decreased autolysis) caused by the Arg117-->His mutation may contribute to the development of pancreatitis, however, the Asn21-->Ile mutation has no such effect. In contrast, enhanced autoactivation of mutant trypsinogens may contribute to the pathogenesis of both forms of hereditary pancreatitis. This notion is strongly supported by the clear correlation between the autoactivation rates of mutant trypsinogens and the severity of clinical symptoms.
Sahin-Tóth
M
M
Department of Physiology, University of California Los Angeles, Los Angeles, California, USA.
Tóth
M
M
D001120:Arginine / Q000235:genetics; D001216:Asparagine / Q000235:genetics; D002908:Chronic Disease; D004790:Enzyme Induction; D006639:Histidine / Q000235:genetics; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D009154:Mutation; D010195:Pancreatitis / Q000201:enzymology* / Q000235:genetics*; D014362:Trypsinogen / Q000096:biosynthesis* / Q000235:genetics*
D007532:Isoleucine; D006639:Histidine; D001216:Asparagine; D014362:Trypsinogen; D001120:Arginine