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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Nature genetics Vol. 38; no. 6; pp. 668 - 673
Main Authors:	Real, Francisco X, Koudova, Monika, Le Maréchal, Cédric, Ammann, Rudolf W, Weiss, Frank Ulrich, Pfützer, Roland, Löhr, Matthias, Berg, Thomas, Halangk, Juliane, Böck, Wolfgang, Galavotti, Roberta, Chen, Jian-Min, Cavestro, Giulia Martina, Truninger, Kaspar, Keil, Thomas, Güldner, Claudia, Wiedenmann, Bertram, Bargetzi, Mario, Gress, Thomas M, Cerny, Milos, Friess, Helmut, Menzel, Hans-Jürgen, Dahm, Stefan, Rohde, Klaus, Kukor, Zoltán, Moral, Pedro, Spicak, Julius, Bernardova, Jana, Witt, Heiko, Sahin-Tóth, Miklós, Becker, Michael, Akar, Nejat, Destro-Bisol, Giovanni, Ockenga, Johann, Kähne, Thilo, Férec, Claude, Teich, Niels, Schulz, Hans-Ulrich, Macek, Milan, Keim, Volker, Witt, Ulrike, Luck, Werner, Bhatia, Eesh, Kage, Andreas, Rickards, Olga, Halangk, Walter, Landt, Olfert, Eiberg, Hans, Nickel, Renate, Jansen, Jan B M J, Treiber, Matthias, Pignatti, Pier Franco, Rosendahl, Jonas, Rausova, Eva, Simon, Peter, Drenth, Joost PH, Castellani, Carlo, Schmidt, Hartmut, Groneberg, David Alexander, Spedini, Gabriella, Malats, Núria, Zarnescu, Narcis Octavian, Lerch, Markus M, Braun, Markus, Szepessy, Edit
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group 01-06-2006 Nature Research
Subjects:	Base Sequence Biological and medical sciences Causes of Chronic Disease Chronic illnesses DNA Primers Fundamental and applied biological sciences. Psychology Gastroenterology. Liver. Pancreas. Abdomen Gene expression Genetic aspects Genetic variation Genetics of eukaryotes. Biological and molecular evolution Genètica Haplotypes Health aspects Humans Hydrolysis Inflammatory diseases Liver. Biliary tract. Portal circulation. Exocrine pancreas Medical sciences Models, Molecular Mutation Other diseases. Semiology Pancreas Pancreatitis Physiological aspects Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Tripsina Tripsinogen Trypsin - chemistry Trypsin - genetics Trypsin - metabolism Trypsinogen Trypsinogen - chemistry Trypsinogen - genetics Trypsinogen - metabolism Germany Degradation Variant Chronic Trypsinogen Pancreatitis Digestive diseases Pancreatic disease
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally. Correspondence: Heiko Witt, MD, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Charité, Campus Virchow-Klinikum, Universitätsmedizin Berlin, Augustenburger Platz 1, D-13353 Berlin, Germany, Phone: +49 30 450566663, Fax: +49 30 450559951, email: heiko.witt@charite.de
ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng1797