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: D C Whitcomb, M C Gorry, R A Preston, W Furey, M J Sossenheimer, C D Ulrich, S P Martin, L K Gates Jr, S T Amann, P P Toskes, R Liddle, K McGrath, G Uomo, J C Post, G D Ehrlich
• Journal: Nature genetics (Nat Genet) Vol. 14 Issue 2 Pg. 141-5 (Oct 1996) ISSN: 1061-4036 [Print] United States
• PMID: 8841182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Trypsinogen
• Arginine
• Trypsin

Topics

• 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, genetics)