title: Gene conversion between cationic trypsinogen (PRSS1) and the pseudogene trypsinogen 6 (PRSS3P2) in patients with chronic pancreatitis.
abstract: Mutations of the human cationic trypsinogen gene (PRSS1) are frequently found in association with hereditary pancreatitis. The most frequent variants p.N29I and p.R122H 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.R122H 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.343T>A (p.S115T), c.347G>C (p.R116P), and c.365_366delinsAT (p.R122H). 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.R122H mutant. In addition, cellular secretion of the triple mutant from transfected HEK 293T cells was increased about twofold and this effect was attributable to mutation p.R116P. 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.
authors.affiliation: Department of Medical Genetics, Institute of Mother and Child Warsaw, Warsaw, Poland.
authors.forename: Agnieszka Magdalena
authors.initials: AM
authors.lastname: Rygiel
authors.forename: Sebastian
authors.initials: S
authors.lastname: Beer
authors.forename: Peter
authors.initials: P
authors.lastname: Simon
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wertheim-Tysarowska
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Oracz
authors.forename: Torsten
authors.initials: T
authors.lastname: Kucharzik
authors.forename: Andrzej
authors.initials: A
authors.lastname: Tysarowski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Niepokój
authors.forename: Jarosław
authors.initials: J
authors.lastname: Kierkus
authors.forename: Marta
authors.initials: M
authors.lastname: Jurek
authors.forename: Paweł
authors.initials: P
authors.lastname: Gawliński
authors.forename: Jarosław
authors.initials: J
authors.lastname: Poznański
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bal
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Miklós
authors.initials: M
authors.lastname: Sahin-Tóth
authors.forename: Frank Ulrich
authors.initials: FU
authors.lastname: Weiss
mesh_terms: D000483:Alleles; D002460:Cell Line; D002648:Child; D005260:Female; D005785:Gene Conversion; D006801:Humans; D008297:Male; D050500:Pancreatitis, Chronic / Q000235:genetics*; D011544:Pseudogenes; D014357:Trypsin / Q000235:genetics*; D055815:Young Adult
chemical_list: C489303:PRSS1 protein, human; D014357:Trypsin
keywords: autoactivation; gene conversion; genetic risk; hereditary pancreatitis; trypsinogen