title: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.
abstract: Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg-His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular 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 within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.
authors.affiliation: Dept of Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Whitcomb
authors.forename: M C
authors.initials: MC
authors.lastname: Gorry
authors.forename: R A
authors.initials: RA
authors.lastname: Preston
authors.forename: W
authors.initials: W
authors.lastname: Furey
authors.forename: M J
authors.initials: MJ
authors.lastname: Sossenheimer
authors.forename: C D
authors.initials: CD
authors.lastname: Ulrich
authors.forename: S P
authors.initials: SP
authors.lastname: Martin
authors.forename: L K
authors.initials: LK
authors.lastname: Gates
authors.forename: S T
authors.initials: ST
authors.lastname: Amann
authors.forename: P P
authors.initials: PP
authors.lastname: Toskes
authors.forename: R
authors.initials: R
authors.lastname: Liddle
authors.forename: K
authors.initials: K
authors.lastname: McGrath
authors.forename: G
authors.initials: G
authors.lastname: Uomo
authors.forename: J C
authors.initials: JC
authors.lastname: Post
authors.forename: G D
authors.initials: GD
authors.lastname: Ehrlich
mesh_terms: D001120:Arginine / Q000502:physiology; D002897:Chromosomes, Human, Pair 7; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D005260:Female; D005796:Genes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D010195:Pancreatitis / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014357:Trypsin / Q000378:metabolism; D014362:Trypsinogen / Q000737:chemistry / Q000235:genetics*
chemical_list: D014362:Trypsinogen; D001120:Arginine; D014357:Trypsin