1. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis
- Author
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Heiko, Witt, Miklos Sahin Toth, Olfert, Landt, Jian Min Chen, Thilo, Kahne, Drenth, Joost P. H., Zoltan, Kukor, Edit, Szepessy, Walter, Halangk, Stefan, Dahm, Klaus, Rohde, Hans Ulrich Schulz, Cedric Le Marechal, Nejat, Akar, Ammann, Rudolf W., Kaspar, Truninger, Mario, Bargetzi, Eesh, Bhatia, Carlo, Castellani, Giulia Martina Cavestro, Milos, Cerny, DESTRO-BISOL, Giovanni, Spedini, Gabriella, Hans, Eiberg, Jansen, Jan B. M. J., Monika, Koudova, Eva, Rausova, Milan, Macek, Macek Jr, M., Nuria, Malats, Real, Francisco X., Hans Jurgen Menzel, Pedro, Moral, Roberta, Galavotti, Pier Franco Pignatti, Olga, Rickards, Julius, Spicak, Narcis Octavian Zarnescu, Wolfgang, Bock, Gress, Thomas M., Helmut, Friess, Johann, Ockenga, Hartmut, Schmidt, Roland, Pfutzer, Matthias, Lohr, Peter, Simon, Frank Ulrich Weiss, Lerch, Markus M., Niels, Teich, Volker, Keim, Thomas, Berg, Bertram, Wiedenmann, Werner, Luck, David Alexander Groneberg, Michael, Becker, Thomas, Keil, Andreas, Kage, Jana, Bernardova, Markus, Braun, Claudia, Guldner, Juliane, Halangk, Jonas, Rosendahl, Ulrike, Witt, Matthias, Treiber, Renate, Nickel, Claude, Ferec, Witt, H, SAHIN TOTH, M, Landt, O, Chen, Jm, Kahne, T, Drenth, Jp, Kukor, Z, Szepessy, E, Halangk, W, Dahm, S, Rohde, K, Schulz, Hu, LE MARECHAL, C, Akar, N, Ammann, Rw, Truninger, K, Bargetzi, M, Bhatia, E, Castellani, C, Cavestro, GIULIA MARTINA, Cerny, M, DESTRO BISOL, G, Spedini, G, Eiberg, H, Jansen, Jb, Koudova, M, Rausova, E, MACEK M., Jr, Malats, N, Real, Fx, Menzel, Hj, Moral, P, Galavotti, R, Pignatti, Pf, Rickards, O, Spicak, J, Zarnescu, No, Bock, W, Gress, Tm, Friess, H, Ockenga, J, Schmidt, H, Pfutzer, R, Lohr, M, Simon, P, Weiss, Fu, Lerch, Mm, Teich, N, Keim, V, Berg, T, Wiedenmann, B, Luck, W, Groneberg, Da, Becker, M, Keil, T, Kage, A, Bernardova, J, Braun, M, Guldner, C, Halangk, J, Rosendahl, J, Witt, U, Treiber, M, Nickel, R, and Ferec, C.
- Subjects
trypsin inhibitor ,Models, Molecular ,Enteropeptidase ,Pancreatic disease ,Membrane transport and intracellular motility [NCMLS 5] ,arginine ,genetic risk ,chemistry.chemical_compound ,Models ,proteinosis ,Trypsin ,Pancreatic Secretory Trypsin Inhibitor ,PRSS1 gene ,enteropeptidase ,medicine.diagnostic_test ,adult ,Hydrolysis ,cationic trypsinogen ,protection ,unclassified drug ,enzyme activity ,female ,priority journal ,risk factor ,CHRONIC PANCREATITIS ,protein degradation ,Trypsinogen ,medicine.drug ,medicine.medical_specialty ,anionic trypsinogen ,Proteolysis ,Biology ,Article ,male ,Internal medicine ,Genetics ,medicine ,Matrix-Assisted Laser Desorption-Ionization ,Humans ,PRSS2 ,controlled study ,human ,Molecular gastro-enterology and hepatology [IGMD 2] ,gene ,DNA Primers ,Genetic polymorphism ,catalysis ,Base Sequence ,Spectrometry ,disease predisposition ,Molecular ,cationic trypsinogen prss1 ,glycine ,pancreatic secretory trypsin inhibitor spink1 ,trypsin ,trypsinogen ,article ,chronic pancreatitis ,codon ,genetic susceptibility ,major clinical study ,nucleotide sequence ,Chronic Disease ,Haplotypes ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Mass ,medicine.disease ,Tripsinogen ,Tripsina ,Settore BIO/18 - Genetica ,Endocrinology ,Genetic defects of metabolism [UMCN 5.1] ,Pancreatitis ,chemistry ,Genètica - 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. The initial experiments were supported by the DFG (Wi 2036/1-1). This work was supported by the Sonnenfeld-Stiftung, Berlin, Germany (to H.W.), the US National Institutes of Health (NIH) (grant DK058088 to M.S.-T.), INSERM (Institut National de la Santé et de la Recherche Médicale) and the Programme Hospitalier de Recherche Clinique (grant PHRC R 08-04 to C.F.)
- Published
- 2006
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