A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Witt, Heiko; Sahin-Tóth, Miklós; Landt, Olfert; Chen, Jian-Min; Kähne, Thilo; Drenth, Joost Ph; Kukor, Zoltán; Szepessy, Edit; Halangk, Walter; Dahm, Stefan; Rohde, Klaus; Schulz, Hans-Ulrich; Le Maréchal, Cédric; Akar, Nejat; Ammann, Rudolf W; Truninger, Kaspar; Bargetzi, Mario; Bhatia, Eesh; Castellani, Carlo; Cavestro, Giulia Martina; ... (2006). A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nature genetics, 38(6), pp. 668-73. New York, N.Y.: Nature America 10.1038/ng1797

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Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology

UniBE Contributor:

Truninger, Kaspar

ISSN:

1061-4036

ISBN:

16699518

Publisher:

Nature America

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:50

Last Modified:

17 Mar 2015 21:52

Publisher DOI:

10.1038/ng1797

PubMed ID:

16699518

Web of Science ID:

000237954800021

URI:

https://boris.unibe.ch/id/eprint/20878 (FactScience: 4672)

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