Genetic background of pancreatitis.
Trypsin activity is properly suppressed by pancreatic secretory trypsin inhibitor (PSTI), which is also known as serine protease inhibitor Kazal type 1 (SPINK1), thereby preventing damage to pancreatic acinar cells as a first line of defence. However, if trypsin activation exceeds the capacity of PSTI/SPINK1, a subsequent cascade of events leads to the activation of various proteases that damage cells. Five mutations (R122H, N29I, A16V, D22G and K23R) in cationic trypsinogen and two mutations (N34S and M1T) in the PSTI/SPINK1 gene have been found to correlate significantly with the onset of pancreatitis. From analyses of hereditary pancreatitis and the phenotype of PSTI/SPINK1 (Spink3) knockout mice, we showed that the imbalance of trypsin activation and its inhibition by PSTI/SPINK1 would lead to the development of pancreatitis.
Hirota
Masahiko
M
Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, Honjo, Kumamoto-City, Kumamoto 860-0811, Japan. hdobaba@kaiju.medic.kumamoto-u.ac.jp
Ohmuraya
Masaki
M
Baba
Hideo
H
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D010195:Pancreatitis / Q000235:genetics*; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen / Q000235:genetics
C505032:CFTR protein, human; D002352:Carrier Proteins; C486642:SPINK1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014362:Trypsinogen