Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma

J Clin Invest. 2019 Aug 1;129(11):4676-4681. doi: 10.1172/JCI129961.


While improvements in genetic analysis have greatly enhanced our understanding of the mechanisms behind pancreatitis, it continues to afflict many families for whom the hereditary factors remain unknown. Recent evaluation of a patient with a strong family history of pancreatitis sparked us to reexamine a large kindred originally reported over 50 years ago with an autosomal dominant inheritance pattern of chronic pancreatitis, diabetes and pancreatic adenocarcinoma. Whole exome sequencing analysis identified a rare missense mutation in the gene encoding pancreas-specific protease Elastase 3B (CELA3B) that cosegregates with disease. Studies of the mutant protein in vitro, in cell lines and in CRISPR-Cas9 engineered mice indicate that this mutation causes translational upregulation of CELA3B, which upon secretion and activation by trypsin leads to uncontrolled proteolysis and recurrent pancreatitis. Although lesions in several other pancreatitic proteases have been previously linked to hereditary pancreatitis, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.

Keywords: Cell Biology; Gastroenterology; Genetic diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Animals
  • Exome Sequencing
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genetic Diseases, Inborn / enzymology
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / pathology
  • Genetic Predisposition to Disease*
  • Humans
  • Mice
  • Mutation*
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Pancreatic Elastase / biosynthesis
  • Pancreatic Elastase / genetics*
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Pancreatitis / enzymology
  • Pancreatitis / genetics*
  • Pancreatitis / pathology
  • Up-Regulation


  • Neoplasm Proteins
  • CELA3B protein, human
  • Pancreatic Elastase

Supplementary concepts

  • Pancreatic Carcinoma