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

Item Type:Article
Title:A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis
Creators Name:Witt, H. and Sahin-Toth, M. and Landt, O. and Chen, J.M. and Kaehne, T. and Drenth, J.P. and Kukor, Z. and Szepessy, E. and Halangk, W. and Dahm, S. and Rohde, K. and Schulz, H.U. and Le Marechal, C. and Akar, N. and Ammann, R.W. and Truninger, K. and Bargetzi, M. and Bhatia, E. and Castellani, C. and Cavestro, G.M. and Cerny, M. and Destro-Bisol, G. and Spedini, G. and Eiberg, H. and Jansen, J.B. and Koudova, M. and Rausova, E. and Macek, M. and Malats, N. and Real, F.X. and Menzel, H.J. and Moral, P. and Galavotti, R. and Pignatti, P.F. and Rickards, O. and Spicak, J. and Zarnescu, N.O. and Boeck, W. and Gress, T.M. and Friess, H. and Ockenga, J. and Schmidt, H. and Pfuetzer, R. and Loehr, M. and Simon, P. and Weiss, F.U. and Lerch, M.M. and Teich, N. and Keim, V. and Berg, T. and Wiedenmann, B. and Luck, W. and Groneberg, D.A. and Becker, M. and Keil, T. and Kage, A. and Bernardova, J. and Braun, M. and Gueldner, C. and Halangk, J. and Rosendahl, J. and Witt, U. and Treiber, M. and Nickel, R. and Ferec, C.
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 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.
Keywords:Base Sequence, Chronic Disease, DNA Primers, Haplotypes, Hydrolysis, Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry, Molecular Models, Trypsin, Trypsinogen
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:668-673
Date:June 2006
Official Publication:https://doi.org/10.1038/ng1797
PubMed:View item in PubMed

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