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Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene

D C Whitcomb1, M C Gorry, R A Preston

  • 1Dept of Medicine, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.

Nature Genetics
|October 1, 1996
PubMed

Insights

A genetic mutation in the cationic trypsinogen gene causes hereditary pancreatitis (HP), a rare early-onset disorder. This Arg-His substitution at residue 117 disrupts a trypsin-sensitive site, leading to pancreatic autodigestion and HP.

Area of Science:

  • Genetics
  • Biochemistry
  • Molecular Biology

Background:

  • Hereditary pancreatitis (HP) is a rare genetic disorder causing early-onset epigastric pain and severe complications.
  • The genetic basis of HP is not fully understood, necessitating further research into causative mutations.

Purpose of the Study:

  • To identify the specific genetic mutation associated with hereditary pancreatitis.
  • To elucidate the molecular mechanism by which the identified mutation leads to pancreatitis.

Main Methods:

  • Genetic analysis of five kindreds with hereditary pancreatitis.
  • X-ray crystal structure analysis of the mutated trypsinogen.
  • Molecular modeling and protein digest experiments.

Main Results:

  • An Arg-His substitution at residue 117 of the cationic trypsinogen gene was identified in all affected individuals and carriers.
  • This mutation was absent in unrelated individuals and spouses.
  • Structural and functional analyses revealed that Arg 117 is a trypsin-sensitive site crucial for trypsin inactivation.

Conclusions:

  • The Arg-His substitution at residue 117 of cationic trypsinogen is strongly associated with hereditary pancreatitis.
  • Loss of this trypsin-sensitive site impairs trypsin inactivation, leading to pancreatic autodigestion and the HP phenotype.

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