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 which 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 non-synonymous 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 two-fold 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.

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

“…DNA exchange by gene conversion is of paramount importance for the evolution of gene families but it can also cause human diseases [18] including CP and other pancreatic pathologies. Gene conversion events between PRSS1 and PRSS2 or between PRSS1 and the pseudogene PRSS3P2 were shown to generate pathogenic alleles that cause hereditary pancreatitis [19,20,21]. More recently, a recombination allele of the carboxyl ester lipase gene ( CEL ) and its pseudogene CELP was described as a novel genetic risk factor for CP [22].…”

Clinical chronic pancreatitis

“…Two highlighted the importance of specific promoter variants in SPINK1 (8), and chymotrypsin C (CTRC) as a risk factor for CP. (9) Another reported on the importance of gene conversion events leading to phenotypes similar to established genetic mutation variants in PRSS1 (10). A validation genome wide association study (GWAS) of CP confirmed a protective effect of a PRSS1-PRSS2 SNP, and an increased risk in variants of the CLDN2-MORC2 loci in alcoholic CP.…”

Genetic determination of pancreatitis

“…In PRSS1 hybrid alleles such as PRSS1-PRSS2 [66] and PRSS1-PRSS3P2 [67] generated by gene conversion events, although rare, are causative mutations in chronic pancreatitis.…”