Sequence analysis of the human tyrosylprotein sulfotransferase-2 gene in subjects with chronic pancreatitis.
OBJECTIVE
Human trypsinogens are post-translationally sulfated on Tyr154 by the Golgi resident enzyme tyrosylprotein sulfotransferase-2 (TPST2). Tyrosine sulfation stimulates the autoactivation of human cationic trypsinogen. Because increased trypsinogen autoactivation has been implicated as a pathogenic mechanism in chronic pancreatitis, we hypothesized that genetic variants of TPST2 might alter the risk for the disease.


METHODS
We sequenced the 4 protein-coding exons and the adjacent intronic sequences of TPST2 in 151 subjects with chronic pancreatitis and in 169 healthy controls. The functional effect of TPST2 variants on trypsinogen sulfation was analyzed in transfected HEK 293T cells.


RESULTS
We detected 10 common polymorphic variants, including 6 synonymous variants and 4 intronic variants, with similar frequencies in patients and controls. None of the 8 common haplotypes reconstructed from the frequent variants showed an association with chronic pancreatitis. In addition, we identified 5 rare TPST2 variants, which included 3 synonymous alterations, the c.458G>A (p.R153H) nonsynonymous variant and the c.-9C>T variant in the 5' untranslated region. The p.R153H variant was found in a family with hereditary pancreatitis; however, it did not segregate with the disease. In functional assays, both the p.R153H and c.-9C>T TPST2 variants catalyzed trypsinogen sulfation as well as wild-type TPST2.


CONCLUSIONS
Genetic variants of human TPST2 exert no influence on the risk of chronic pancreatitis.
Rosendahl
Jonas
J
Department of Gastroenterology and Hepatology,University of Leipzig, Leipzig, Germany. jonas.rosendahl@medizin.uni-leipzig.de
Rónai
Zsolt
Z
Kovacs
Peter
P
Teich
Niels
N
Wittenburg
Henning
H
Blüher
Matthias
M
Stumvoll
Michael
M
Mössner
Joachim
J
Keim
Volker
V
Bradbury
Andrew R M
AR
Sahin-Tóth
Miklós
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D050500:Pancreatitis, Chronic / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D015238:Sulfotransferases / Q000235:genetics*; D014362:Trypsinogen / Q000378:metabolism
D008565:Membrane Proteins; D014362:Trypsinogen; D015238:Sulfotransferases; C114740:TPST2 protein, human
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