Human mutation causes digestive enzyme misfolding and chronic pancreatitis in mice.

Objective: Chronic pancreatitis is a progressive, relapsing inflammatory disorder of the pancreas, which often develops in the background of genetic susceptibility. Recently, loss-of-function mutations in , which encodes the digestive enzyme carboxypeptidase A1, were described in sporadic early onset cases and in hereditary pancreatitis. Mutation-induced misfolding of CPA1 and associated endoplasmic reticulum (ER) stress was suggested as potential disease mechanism; however, in vivo evidence has been lacking. The objective of the present study was to create a mouse model that recapitulates features of -associated chronic pancreatitis.

Design: We knocked-in the most frequently occurring p.N256K human mutation to the mouse locus. Mutant mice were characterised with respect to pancreas pathology and ER stress and compared with C57BL/6N and control mice.

Results: In the mutant mice, we observed hallmarks of chronic pancreatitis that included progressive acinar cell atrophy, inflammatory cell infiltration, fibrosis and acinar-ductal metaplasia. In contrast, similarly to the C57BL/6N mice, the control strain exhibited no signs of pancreatic disease. Mutation p.N256K induced misfolding of mouse CPA1 and resulted in elevated expression of ER stress markers (BiP) and (CHOP) both in cell culture and mutant mice.

Conclusion: The results offer categorical evidence that mutations elicit enzyme misfolding and cause chronic pancreatitis via an ER stress-related mechanism.