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

Heiko Witt^1, 2, 39, Miklós Sahin-Tóth^3, 39, Olfert Landt⁴, Jian-Min Chen⁵, Thilo Kähne⁶, Joost PH Drenth⁷, Zoltán Kukor³, Edit Szepessy³, Walter Halangk⁸, Stefan Dahm⁹, Klaus Rohde⁹, Hans-Ulrich Schulz⁸, Cédric Le Maréchal⁵, Nejat Akar¹⁰, Rudolf W Ammann¹¹, Kaspar Truninger^11, 12, Mario Bargetzi¹³, Eesh Bhatia¹⁴, Carlo Castellani¹⁵, Giulia Martina Cavestro¹⁶, Milos Cerny¹⁷, Giovanni Destro-Bisol¹⁸, Gabriella Spedini¹⁸, Hans Eiberg¹⁹, Jan B M J Jansen⁷, Monika Koudova²⁰, Eva Rausova²⁰, Milan Macek Jr²⁰, Núria Malats²¹, Francisco X Real²¹, Hans-Jürgen Menzel²², Pedro Moral²³, Roberta Galavotti²⁴, Pier Franco Pignatti²⁴, Olga Rickards²⁵, Julius Spicak²⁶, Narcis Octavian Zarnescu²⁷, Wolfgang Böck²⁸, Thomas M Gress²⁸, Helmut Friess²⁹, Johann Ockenga³⁰, Hartmut Schmidt^30, 31, Roland Pfützer³², Matthias Löhr³², Peter Simon³³, Frank Ulrich Weiss³³, Markus M Lerch³³, Niels Teich³⁴, Volker Keim³⁴, Thomas Berg¹, Bertram Wiedenmann¹, Werner Luck², David Alexander Groneberg², Michael Becker³⁵, Thomas Keil³⁶, Andreas Kage³⁷, Jana Bernardova^1, 2, Markus Braun^1, 2, Claudia Güldner^1, 2, Juliane Halangk¹, Jonas Rosendahl^2, 34, Ulrike Witt³⁸, Matthias Treiber^1, 2, Renate Nickel² & Claude Férec⁵

¹  Department of Hepatology and Gastroenterology, Charité University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany.

²  Department of Pediatrics, Charité University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany.

³  Department of Molecular and Cell Biology, Boston University Goldman School of Dental Medicine, 715 Albany Street, Boston, Massachusetts 02118, USA.

⁴  TIB MOLBIOL, Eresburgstrasse 22-23, 12103 Berlin, Germany.

⁵  Institut National de la Santé et de la Recherche Médicale (INSERM), U613, Brest, F-29220 France; Université de Bretagne Occidentale, Faculté de Médecine de Brest et des Sciences de la Santé, F-29238 France; Etablissement Français du Sang-Bretagne, Brest and Centre Hospitalier Régional Universitaire (CHRU) Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire et d'Histocompatibilité, Brest, F-29220 France.

⁶  Institute of Experimental Internal Medicine, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany.

⁷  Department of Medicine, Division of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands.

⁸  Department of Surgery, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany.

⁹  Department of Bioinformatics, Max-Delbrück-Centrum, 13092 Berlin, Germany.

¹⁰  Department of Pediatric Molecular Genetics, Ankara University Medical School, Konutkent-2, Mudanya Sokak C-1 Blok B-2, 06530 Cayyolu, Ankara, Turkey.

¹¹  Department of Medicine, Division of Gastroenterology, University Hospital, Rämistrasse 100, 8092 Zurich, Switzerland.

¹²  Department of Medicine, Division of Gastroenterology, Kantonsspital Aarau, Tellstrasse, CH-5001 Aarau, Switzerland.

¹³  Department of Medicine, Center of Oncology/Hematology, Kantonsspital Aarau, Tellstrasse, CH-5001 Aarau, Switzerland.

¹⁴  Department of Endocrinology, Sanjay Gandhi Postgraduate Institute, Lucknow 226014, India.

¹⁵  Cystic Fibrosis Centre, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126 Verona, Italy.

¹⁶  Gastroenterology Section, Department of Clinical Sciences, University of Parma, Via Gramsci 14, 43100 Parma, Italy.

¹⁷  Clinic of Obstetrics and Gynecology, Neonatology Department, University Hospital Motol and Second Medical School, Charles University Prague, V Uvalu 84, 103 Prague 5, Czech Republic.

¹⁸  Department of Human and Animal Biology, Section of Anthropology, University of Rome "La Sapienza", Via della Ricerca Scientifica 1, 00133 Rome, Italy.

¹⁹  Department of Medical Biochemistry and Genetics, Panum Instistute, University of Copenhagen, IMBG-G Build 24.4, Blegdamsvej 3, DK 2200, Copenhagen, Denmark.

²⁰  Institute of Biology and Medical Genetics–Cystic Fibrosis Center, University Hospital Motol and Second School of Medicine of Charles University, V Uvalu 84, Prague 5, CZ 150 06, Czech Republic.

²¹  Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer Dr. Aiguader 80, 08003 Barcelona, Spain.

²²  Institute of Medical Biology and Human Genetics, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria.

²³  Unitat d'Antropologia, Departament de Biologia Animal, Universitat de Barcelona, Av. Diagonal 645, 08028 Barcelona, Spain.

²⁴  Department Maternal Infantile and of Biology-Genetics (DMIBG), Section of Biology and Genetics, University of Verona, Strada le Grazie 37134 Verona, Italy.

²⁵  Department of Biology, University of Rome "Tor Vergata", Piazzale A. Moro 5, 00185 Rome, Italy.

²⁶  Clinic of Hepatogastroenterology, Institute for Clinical and Experimental Medicine (IKEM), Videnska 1958/9, 14021 Prague 4, Czech Republic.

²⁷  Second Department of Surgery, University Emergency Hospital, 72435 Bucharest, Romania.

²⁸  Department of Internal Medicine I, University Hospital Ulm, Robert Koch Str. 8, 89081 Ulm, Germany.

²⁹  Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.

³⁰  Department of Gastroenterology, Hepatology & Endocrinology, Charité University Hospital, 10008 Berlin, Germany.

³¹  Transplant Hepatology, University Hospital Münster, Albert-Schweitzer-Strasse 33 48149 Münster, Germany.

³²  Department of Medicine II (Gastroenterology/Hepatology/Infectious Diseases), University of Heidelberg, Medical Faculty of Mannheim, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany.

³³  Department of Gastroenterology, Endocrinology and Nutrition, Ernst-Moritz-Arndt University, Friedrich-Loeffler-Str. 23A, 17487 Greifswald, Germany.

³⁴  Department of Gastroenterology and Hepatology, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany.

³⁵  Department of Pediatric Gastroenterology, Deutsches Rotes Kreuz Kliniken Westend, Spandauer Damm 130, 14050 Berlin, Germany.

³⁶  Institute for Social Medicine and Epidemiology, Charité University Hospital, 10008 Berlin, Germany.

³⁷  Institute of Laboratory Medicine and Pathobiochemistry, Charité University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany.

³⁸  Department of Surgery, Charité University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany.

³⁹  These authors contributed equally to this work.

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 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.

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