Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma
Paul C. Moore, … , Mark S. Anderson, Scott A. Oakes
Paul C. Moore, … , Mark S. Anderson, Scott A. Oakes
Published November 1, 2019; First published August 1, 2019
Citation Information: J Clin Invest. 2019;129(11):4676-4681. https://doi.org/10.1172/JCI129961.
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Categories: Concise Communication Cell biology Gastroenterology

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

Abstract

Although 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 prompted 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 pancreatic proteases have been previously linked to hereditary pancreatitis, to our knowledge, this is the first known instance of a mutation in CELA3B and a defect in translational control contributing to this disease.

Authors

Paul C. Moore, Jessica T. Cortez, Chester E. Chamberlain, Diana Alba, Amy C. Berger, Zoe Quandt, Alice Chan, Mickie H. Cheng, Jhoanne L. Bautista, Justin Peng, Michael S. German, Mark S. Anderson, Scott A. Oakes

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Figure 1

Identification of a pathogenic mutation in a family with hereditary pancreatitis.

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Identification of a pathogenic mutation in a family with hereditary panc...
(A) Pedigree of the study family. Squares indicate males; circles indicate females. Shapes were partitioned and colored to indicate conditions (green: pancreatitis, blue: diabetes, red: pancreatic cancer). Generations I–IV were previously reported (10), whereas generation V is newly reported here. Teal branches indicate family members who participated in this study to identify the CELA3B p.R90C mutation, and black branches indicate previously reported individuals. The proband is indicated by an arrow and labeled with a “P.” The mutation status confirmed by sequencing is indicated below the shapes and labeled with “C/C,” indicating WT individuals, or “C/T,” indicating individuals who harbor the CELA3B c.268C>T (p.R90C) variant. (B) Map of human CELA3B showing known domains and key amino acid residues.