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

Heiko Witt, Miklós Sahin-Tóth, Olfert Landt, Jian Min Chen, Thilo Kähne, Joost P.H. Drenth, Zoltán Kukor, Edit Szepessy, Walter Halangk, Stefan Dahm, Klaus Rohde, Hans Ulrich Schulz, Cédric Le Maréchal, Nejat Akar, Rudolf W. Ammann, Kaspar Truninger, Mario Bargetzi, Eesh Bhatia, Carlo Castellani, Giulia Martina CavestroMilos Cerny, Giovanni Destro-Bisol, Gabriella Spedini, Hans Eiberg, Jan B.M.J. Jansen, Monika Koudova, Eva Rausova, Milan Macek, Núria Malats, Francisco X. Real, Hans Jürgen Menzel, Pedro Moral, Roberta Galavotti, Pier Franco Pignatti, Olga Rickards, Julius Spicak, Narcis Octavian Zarnescu, Wolfgang Böck, Thomas M. Gress, Helmut Friess, Johann Ockenga, Hartmut Schmidt, Roland Pfützer, Matthias Löhr, Peter Simon, Frank Ulrich Weiss, Markus M. Lerch, Niels Teich, Volker Keim, Thomas Berg, Bertram Wiedenmann, Werner Luck, David Alexander Groneberg, Michael Becker, Thomas Keil, Andreas Kage, Jana Bernardova, Markus Braun, Claudia Güldner, Juliane Halangk, Jonas Rosendahl, Ulrike Witt, Matthias Treiber, Renate Nickel, Claude Férec

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Abstract

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 × 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.

Original languageEnglish
Pages (from-to)668-673
Number of pages6
JournalNature genetics
Volume38
Issue number6
DOIs
Publication statusPublished - Jun 2006

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ASJC Scopus subject areas

  • Genetics

Cite this

Witt, H., Sahin-Tóth, M., Landt, O., Chen, J. M., Kähne, T., Drenth, J. P. H., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H. U., Le Maréchal, C., Akar, N., Ammann, R. W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., ... Férec, C. (2006). A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nature genetics, 38(6), 668-673. https://doi.org/10.1038/ng1797