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

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Item Type:	Article
Title:	A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis
Creators Name:	Witt, H., Sahin-Toth, M., Landt, O., Chen, J.M., Kaehne, T., Drenth, J.P., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.U., Le Marechal, C., Akar, N., Ammann, R.W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., Cavestro, G.M., Cerny, M., Destro-Bisol, G., Spedini, G., Eiberg, H., Jansen, J.B., Koudova, M., Rausova, E., Macek, M., Malats, N., Real, F.X., Menzel, H.J., Moral, P., Galavotti, R., Pignatti, P.F., Rickards, O., Spicak, J., Zarnescu, N.O., Boeck, W., Gress, T.M., Friess, H., Ockenga, J., Schmidt, H., Pfuetzer, R., Loehr, M., Simon, P., Weiss, F.U., Lerch, M.M., Teich, N., Keim, V., Berg, T., Wiedenmann, B., Luck, W., Groneberg, D.A., Becker, M., Keil, T., Kage, A., Bernardova, J., Braun, M., Gueldner, C., Halangk, J., Rosendahl, J., Witt, U., Treiber, M., 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
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	38
Number:	6
Page Range:	668-673
Date:	June 2006
Official Publication:	https://doi.org/10.1038/ng1797
PubMed:	View item in PubMed

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