Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) 1 and the pancreatic secretory trypsin inhibitor (SPINK1) 2 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.

Witt, H., Sahin Toth, M., Landt, O., Chen, J., Kahne, T., Drenth, J., et al. (2006). A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. NATURE GENETICS, 38(6), 668-673 [10.1038/ng1797].

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

RICKARDS, OLGA;
2006-01-01

Abstract

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) 1 and the pancreatic secretory trypsin inhibitor (SPINK1) 2 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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/18 - Genetica
English
Con Impact Factor ISI
arginine; cationic trypsinogen prss1; enteropeptidase; glycine; pancreatic secretory trypsin inhibitor spink1; trypsin; trypsin inhibitor; trypsinogen; unclassified drug; adult; article; catalysis; chronic pancreatitis; codon; controlled study; disease predisposition; enzyme activity; female; gene; genetic risk; genetic susceptibility; human; major clinical study; male; nucleotide sequence; priority journal; protection; protein degradation; proteinosis; PRSS1 gene; risk factor; Base Sequence; Chronic Disease; DNA Primers; Haplotypes; Humans; Hydrolysis; Models, Molecular; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Trypsin; Trypsinogen
Witt, H., Sahin Toth, M., Landt, O., Chen, J., Kahne, T., Drenth, J., et al. (2006). A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. NATURE GENETICS, 38(6), 668-673 [10.1038/ng1797].
Witt, H; Sahin Toth, M; Landt, O; Chen, J; Kahne, T; Drenth, J; Kukor, Z; Szepessy, E; Halangk, W; Dahm, S; Rohde, K; Schulz, H; Le Marechal, C; Akar, N; Ammann, R; Truninger, K; Bargetzi, M; Bhatia, E; Castellani, C; Cavestro, G; Cerny, M; Destro Bisol, G; Spedini, G; Eiberg, H; Jansen, J; Koudova, M; Rausova, E; Macek, M; Malats, N; Real, F; Menzel, H; Moral, P; Galavotti, R; Pignatti, P; Rickards, O; Spicak, J; Zarnescu, N; Bock, W; Gress, T; Friess, H; Ockenga, J; Schmidt, H; Pfutzer, R; Lohr, M; Simon, P; Weiss, F; Lerch, M; Teich, N; Keim, V; Berg, T; Wiedenmann, B; Luck, W; Groneberg, D; Becker, M; Keil, T; Kage, A; Bernardova, J; Braun, M; Guldner, C; Halangk, J; Rosendahl, J; Witt, U; Treiber, M; Nickel, R; Ferec, C
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/38857
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