Hereditary Pancreatitis Is Caused by a Mutation in the Cationic Trypsinogen Gene

Nat Genet. 1996 Oct;14(2):141-5. doi: 10.1038/ng1096-141.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arginine / physiology
  • Chromosomes, Human, Pair 7
  • DNA Mutational Analysis
  • Enzyme Activation
  • Exons / genetics
  • Female
  • Genes / genetics*
  • Heterozygote
  • Humans
  • Male
  • Models, Molecular
  • Pancreatitis / genetics*
  • Pedigree
  • Point Mutation / genetics*
  • Polymorphism, Restriction Fragment Length
  • Protein Conformation
  • Protein Structure, Tertiary
  • Trypsin / metabolism
  • Trypsinogen / chemistry
  • Trypsinogen / genetics*

Substances

  • Trypsinogen
  • Arginine
  • Trypsin

Associated data

  • GENBANK/U70137