HEREDITARY PANCREATITIS IS CAUSED BY A MUTATION IN THE CATIONIC TRYPSINOGEN GENE

Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder c haracterized by epigastric pain and often more serious complications, We now report that an Arg-His substitution at residue 117 of the catio nic trypsinogen gene is associated with the HP phenotype. This mutatio n was observed in all HP affected individuals and obligate carriers fr om five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, m olecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated wi thin the pancreas, may be inactivated; loss of this cleavage site woul d permit autodigestion resulting in pancreatitis.