Wild-Type Human PRSS2 and PRSS1R122H Cooperatively Initiate Spontaneous Hereditary Pancreatitis in Transgenic Mice

Premature digestive enzyme activation in the pancreas is a major cause of pancreatitis. This concept is supported by the observation that intrapancreatic trypsinogen activation is one of the earliest events in experimental pancreatitis models. 1 Saluja A. et al. Gastroenterology. 2019; 156: 1979-1993 Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar Genetic expression of "super-active" murine trypsin mutants induces pancreatitis. 2 Gaiser S. et al. Gut. 2011; 60: 1379-1388 Crossref PubMed Scopus (85) Google Scholar ,3 Geisz A. et al. Nat Commun. 2018; 9: 5033 Crossref PubMed Scopus (44) Google Scholar Most importantly, the gain-of-function trypsinogen PRSS1 gene mutations are linked to the development of human hereditary pancreatitis with >80% penetrance, a significant risk factor for pancreatic cancer. 4 Whitcomb D.C. et al. Nat Genet. 1996; 14: 141-145 Crossref PubMed Scopus (1329) Google Scholar ,5 Szabo A. et al. J Biol Chem. 2012; 287: 20701-20710 Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar However, since the discovery 25 years ago of PRSS1R122H—the most common mutation in human hereditary pancreatitis 4 Whitcomb D.C. et al. Nat Genet. 1996; 14: 141-145 Crossref PubMed Scopus (1329) Google Scholar —the many attempts to develop a genetic mouse model for hereditary pancreatitis by transgenic expression of human PRSS1R122H have yielded limited success. 6 Athwal T. et al. Cell Death Dis. 2014; 5: e1165 Crossref PubMed Scopus (27) Google Scholar , 7 Gui F. et al. J Clin Invest. 2020; 130: 189-202 Crossref PubMed Scopus (30) Google Scholar , 8 Huang H. et al. Gastroenterology. 2020; 158: 1072-1082.e7 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Some of these transgenic models can substantially worsen cerulein-indued pancreatitis; however, none of these models showed evidence of spontaneous pancreatitis. 6 Athwal T. et al. Cell Death Dis. 2014; 5: e1165 Crossref PubMed Scopus (27) Google Scholar , 7 Gui F. et al. J Clin Invest. 2020; 130: 189-202 Crossref PubMed Scopus (30) Google Scholar , 8 Huang H. et al. Gastroenterology. 2020; 158: 1072-1082.e7 Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The underlying reasons are unclear.