Gain‐ and Loss‐of‐function Mutations in Trypsinogen

Abstract

Abstract Historically, trypsinogen has been among the most extensively studied models of protein structure and function. It has received renewed attention since the identification of a gain‐of‐function missense mutation in the cationic trypsinogen gene ( PRSS1 ) as a cause of hereditary pancreatitis in 1996; a finding gave strong support to the then century‐old hypothesis that pancreatitis is an autodigestive disease in which prematurely activated trypsin within the pancreas was thought to play a pivotal role. Whereas gain‐of‐function PRSS1 missense mutations cause chronic pancreatitis through a negative effect on trypsin lysis and a positive effect on trypsinogen autoactivation, duplication and triplication copy number mutations of the trypsinogen locus cause the disease through a gene‐dosage effect. By contrast, loss‐of‐function variations in the PRSS1 and PRSS2 (encoding anionic trypsinogen) genes protect against chronic pancreatitis. The study of pathogenic PRSS1 mutations also shed lights on the evolution of trypsinogen genes. Key Concepts: More than 100 years ago, pancreatitis was hypothesised to be an autodigestive disease in which prematurely activated trypsin within the pancreas was thought to play a pivotal role. The century‐old hypothesis was given strong support when a gain‐of‐function missense mutation (R122H) in the cationic trypsinogen gene ( PRSS1 ) was identified as a cause of hereditary pancreatitis in 1996. Gain‐of‐function PRSS1 missense mutations are characterised by a negative effect on trypsin lysis and a positive effect on trypsinogen autoactivation. Duplication and triplication copy number mutations of the trypsinogen locus cause a gain of trypsin through a gene‐dosage effect. Gain‐of‐function PRSS1 mutations can be generated from diverse mutational mechanisms such as CpG substitution, gene conversion, nonallelic homologous recombination (NAHR) and microhomology‐mediated replication‐dependent recombination (MMRDR). Whereas gain‐of‐function PRSS1 mutations predispose to chronic pancreatitis, loss‐of‐function variations in the PRSS1 and PRSS2 (encoding anionic trypsinogen) genes protect against chronic pancreatitis. The study of pathogenic PRSS1 mutations also shed lights on the evolution of trypsinogen genes.