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Gene Conversion Between Cationic Trypsinogen ( PRSS1 ) and the Pseudogene Trypsinogen 6 ( PRSS3P2 ) in Patients with Chronic Pancreatitis
Author(s) -
Rygiel Agnieszka Magdalena,
Beer Sebastian,
Simon Peter,
WertheimTysarowska Katarzyna,
Oracz Grzegorz,
Kucharzik Torsten,
Tysarowski Andrzej,
Niepokój Katarzyna,
Kierkus Jarosław,
Jurek Marta,
Gawliński Paweł,
Poznański Jarosław,
Bal Jerzy,
Lerch Markus M.,
SahinTóth Miklós,
Weiss Frank Ulrich
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22747
Subject(s) - trypsinogen , biology , exon , hereditary pancreatitis , genetics , pseudogene , mutation , gene , pancreatitis , mutant , allele , microbiology and biotechnology , trypsin , medicine , biochemistry , enzyme , genome
Mutations of the human cationic trypsinogen gene ( PRSS1 ) are frequently found in association with hereditary pancreatitis. The most frequent variants p. N 29 I and p. R 122 H are recognized as disease‐causing mutations. Three pseudogene paralogs in the human trypsinogen family, including trypsinogen 6 ( PRSS3P2 ), carry sequence variations in exon 3 that mimic the p. R 122 H mutation. In routine genetic testing of patients with chronic pancreatitis, we identified in two unrelated individuals similar gene conversion events of 24–71 nucleotides length between exon 3 of the PRSS1 (acceptor) and PRSS3P2 (donor) genes. The converted allele resulted in three nonsynonymous alterations c.343 T > A (p. S 115 T ), c.347 G > C (p. R 116 P ), and c.365_366delins AT (p. R 122 H ). Functional analysis of the conversion triple mutant revealed markedly increased autoactivation resulting in high and sustained trypsin activity in the presence of chymotrypsin C . This activation phenotype was identical to that of the p. R 122 H mutant. In addition, cellular secretion of the triple mutant from transfected HEK 293 T cells was increased about twofold and this effect was attributable to mutation p. R 116 P . Our observations confirm and extend the notion that recombination events between members of the trypsinogen family can generate high‐risk PRSS1 alleles. The pathogenic phenotype of the novel conversion is explained by a unique combination of increased trypsinogen activation and secretion.