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Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice
  1. Eszter Hegyi,
  2. Miklós Sahin-Tóth
  1. Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
  1. Correspondence to Dr Miklós Sahin-Tóth, Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA; miklos{at}


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 CPA1, 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 CPA1-associated chronic pancreatitis.

Design We knocked-in the most frequently occurring p.N256K human CPA1 mutation to the mouse Cpa1 locus. Mutant mice were characterised with respect to pancreas pathology and ER stress and compared with C57BL/6N and CPA1 null control mice.

Results In the CPA1 N256K 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 CPA1 null 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 Hspa5 (BiP) and Ddit3 (CHOP) both in cell culture and mutant mice.

Conclusion The results offer categorical evidence that CPA1 mutations elicit enzyme misfolding and cause chronic pancreatitis via an ER stress-related mechanism.

  • pancreatitis
  • pancreatic pathology
  • pancreatic fibrosis
  • pancreatic enzymes
  • pancreatic disease

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  • Contributors MST conceived and directed the study. EH and MST designed the experiments. EH performed the experiments. EH and MST analysed the data. EH and MST wrote the manuscript.

  • Funding This work was supported by the National Institutes of Health (NIH) grant R01 DK058088.

  • Competing interests MST is a consultant for Takeda Pharmaceuticals.

  • Patient consent Not required.

  • Ethics approval Institutional Animal Care and Use Committee (IACUC) of Boston University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it published Online First. The abstract has been corrected.

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