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 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
Heiko
H
Department of Hepatology and Gastroenterology, Charité University Hospital, Augustenburger Platz 1, 13353 Berlin, Germany. heiko.witt@charite.de
Sahin-Tóth
Miklós
M
Landt
Olfert
O
Chen
Jian-Min
JM
Kähne
Thilo
T
Drenth
Joost Ph
JP
Kukor
Zoltán
Z
Szepessy
Edit
E
Halangk
Walter
W
Dahm
Stefan
S
Rohde
Klaus
K
Schulz
Hans-Ulrich
HU
Le Maréchal
Cédric
C
Akar
Nejat
N
Ammann
Rudolf W
RW
Truninger
Kaspar
K
Bargetzi
Mario
M
Bhatia
Eesh
E
Castellani
Carlo
C
Cavestro
Giulia Martina
GM
Cerny
Milos
M
Destro-Bisol
Giovanni
G
Spedini
Gabriella
G
Eiberg
Hans
H
Jansen
Jan B M J
JB
Koudova
Monika
M
Rausova
Eva
E
Macek
Milan
M
Malats
Núria
N
Real
Francisco X
FX
Menzel
Hans-Jürgen
HJ
Moral
Pedro
P
Galavotti
Roberta
R
Pignatti
Pier Franco
PF
Rickards
Olga
O
Spicak
Julius
J
Zarnescu
Narcis Octavian
NO
Böck
Wolfgang
W
Gress
Thomas M
TM
Friess
Helmut
H
Ockenga
Johann
J
Schmidt
Hartmut
H
Pfützer
Roland
R
Löhr
Matthias
M
Simon
Peter
P
Weiss
Frank Ulrich
FU
Lerch
Markus M
MM
Teich
Niels
N
Keim
Volker
V
Berg
Thomas
T
Wiedenmann
Bertram
B
Luck
Werner
W
Groneberg
David Alexander
DA
Becker
Michael
M
Keil
Thomas
T
Kage
Andreas
A
Bernardova
Jana
J
Braun
Markus
M
Güldner
Claudia
C
Halangk
Juliane
J
Rosendahl
Jonas
J
Witt
Ulrike
U
Treiber
Matthias
M
Nickel
Renate
R
Férec
Claude
C
D001483:Base Sequence; D002908:Chronic Disease; D017931:DNA Primers; D006239:Haplotypes; D006801:Humans; D006868:Hydrolysis; D008958:Models, Molecular; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014357:Trypsin / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014362:Trypsinogen / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; C064831:PRSS2 protein, human; D014362:Trypsinogen; D014357:Trypsin