Complete analysis of the human mesotrypsinogen gene (PRSS3) in patients with chronic pancreatitis.
OBJECTIVE
A sustained imbalance of pancreatic proteases and their inhibitors seems to be important for the development of chronic pancreatitis (CP). Mesotrypsin (PRSS3) can degrade intrapancreatic trypsin inhibitors that protect against CP. Genetic variants that cause higher mesotrypsin activity might increase the risk for CP.


METHODS
We analyzed all 5 exons and the adjacent non-coding sequences of PRSS3 by direct sequencing of 313 CP patients and 327 controls. Additionally, exon 4 was investigated in 855 patients and 1,294 controls and a c.454+191G>A variant in 855 patients and 1,467 controls. The c.499A>G (p.T167A) variant was analyzed functionally using transiently transfected HEK 293T cells.


RESULTS
In the exonic regions, the previously described common c.94_96delGAG (p.E32del) variant and a novel p.T167A non-synonymous alteration were identified. Extended analysis of the p.T167A variant revealed no association to CP and in functional assays p.T167A showed normal secretion and activity. Variants of the intronic regions, including the extensively analyzed c.454+191G>A alteration, were not associated with the disease. Haplotype reconstruction using variants with a minor allele frequency of >1% revealed no CP-associated haplotype.


CONCLUSIONS
Although the trypsin inhibitor-degrading activity qualified PRSS3 as a candidate for a novel CP susceptibility gene, we found no association between a specific variant or haplotype and CP in our cohort with a high suspicion of genetically determined disease.
Rosendahl
Jonas
J
Department of Gastroenterology and Hepatology, University of Leipzig, Leipzig, Germany. jonas.rosendahl@medizin.uni-leipzig.de
Teich
Niels
N
Kovacs
Peter
P
Szmola
Richard
R
Blüher
Matthias
M
Gress
Thomas M
TM
Hoffmeister
Albrecht
A
Keim
Volker
V
Löhr
Matthias
M
Mössner
Joachim
J
Nickel
Renate
R
Ockenga
Johann
J
Pfützer
Roland
R
Schulz
Hans-Ulrich
HU
Stumvoll
Michael
M
Wittenburg
Henning
H
Sahin-Tóth
Miklós
M
Witt
Heiko
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D009154:Mutation; D050500:Pancreatitis, Chronic / Q000235:genetics*; D014357:Trypsin / Q000235:genetics*
C040749:PRSS3 protein, human; D014357:Trypsin