Nature Genetics
14, 141 - 145 (1996)
doi:10.1038/ng1096-141
Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen geneDavid C. Whitcomb1, 2, 3, Michael C. Gorry3, 4, Robert A. Preston3, 4, William Furey5, Michael J. Sossenheimer1, Charles D. Ulrich6, Stephen P. Martin6, Lawrence K. Gates Jr.7, Stephen T. Amann8, Phillip P. Toskes8, Roger Liddle9, Kevin McGrath9, G. Uomo10, J. C. Post3, 11, 12
& Garth D. Ehrlich3, 4, 11, 12, 13
1Dept of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
2Depts of Medicine, Pittsburgh Veterans Affairs Medical Center (VAMC), Pittsburgh, Pennsylvania 15240, USA
3Center for Genomic Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
4Dept of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
5Crystallography, Pittsburgh Veterans Affairs Medical Center (VAMC), Pittsburgh, Pennsylvania 15240, USA
6Division of Digestive Diseases at the University of Cincinnati, Cincinnati, Ohio 45267-0595, USA
7University of Kentucky Medical Center, Lexington, Kentucky 40536-0084, USA
8Depts of Gastroenterology, Hepatology and Nutrition at the University of Florida School of Medicine, Gainsville, Florida 32610-0214, USA
9Dept of Medicine at Duke University Medical Center, Durham, North Carolina 27710, USA
10XXXI Internal Medicine Unit, Ospedale Cardarelli, Naples, Italy
11Dept of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
12Dept of Pediatric Otolaryngology Children's Hospital of Pittsburgh (CUP) Pittsburgh, Pennsylvania 15213, USA
13737 Scaife Hall, 3350 Terrace Street, Dept of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA email: ehr@med.pitt.edu 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.
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