The CEL-HYB1 Hybrid Allele Promotes Digestive Enzyme Misfolding and Pancreatitis in Mice

Gardner, 2020, ACG clinical guideline: chronic pancreatitis, Am J Gastroenterol, 115, 322, 10.14309/ajg.0000000000000535

Chiari, 1896, Über die Selbstverdauung des menschlichen Pankreas, Z Heilkunde, 17, 69

Hegyi, 2017, Genetic risk in chronic pancreatitis: the trypsin-dependent pathway, Dig Dis Sci, 62, 1692, 10.1007/s10620-017-4601-3

Whitcomb, 1996, Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene, Nat Genet, 14, 141, 10.1038/ng1096-141

Le Maréchal, 2006, Hereditary pancreatitis caused by triplication of the trypsinogen locus, Nat Genet, 38, 1372, 10.1038/ng1904

Huang, 2020, Transgenic expression of PRSS1 R122H sensitizes mice to pancreatitis, Gastroenterology, 158, 1072, 10.1053/j.gastro.2019.08.016

Zou, 2022, Trypsinogen (PRSS1 and PRSS2) gene dosage correlates with pancreatitis risk across genetic and transgenic studies: a systematic review and re-analysis, Hum Genet, 10.1007/s00439-022-02436-x

Witt, 2000, Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis, Nat Genet, 25, 213, 10.1038/76088

Sun, 2020, Heterozygous Spink1 c.194+2T>C mutant mice spontaneously develop chronic pancreatitis, Gut, 69, 967, 10.1136/gutjnl-2019-318790

Rosendahl, 2008, Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis, Nat Genet, 40, 78, 10.1038/ng.2007.44

Rosendahl, 2018, all members of the PanEuropean Working group on ACP. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis, Gut, 67, 1855, 10.1136/gutjnl-2017-314454

Tang, 2018, The CTRB1-CTRB2 risk allele for chronic pancreatitis discovered in European populations does not contribute to disease risk variation in the Chinese population due to near allele fixation, Gut, 67, 1368, 10.1136/gutjnl-2017-315180

Witt, 2006, A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis, Nat Genet, 38, 668, 10.1038/ng1797

Sahin-Tóth, 2017, Genetic risk in chronic pancreatitis: the misfolding-dependent pathway, Curr Opin Gastroenterol, 33, 390, 10.1097/MOG.0000000000000380

Mayerle, 2019, Genetics, cell biology, and pathophysiology of pancreatitis, Gastroenterology, 156, 1951, 10.1053/j.gastro.2018.11.081

Kereszturi, 2009, Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism, Hum Mutat, 30, 575, 10.1002/humu.20853

Schnúr, 2014, Functional effects of 13 rare PRSS1 variants presumed to cause chronic pancreatitis, Gut, 63, 337, 10.1136/gutjnl-2012-304331

Witt, 2013, Variants in CPA1 are strongly associated with early onset chronic pancreatitis, Nat Genet, 45, 1216, 10.1038/ng.2730

Hegyi, 2019, Human CPA1 mutation causes digestive enzyme misfolding and chronic pancreatitis in mice, Gut, 68, 301, 10.1136/gutjnl-2018-315994

Fjeld, 2015, A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis, Nat Genet, 47, 518, 10.1038/ng.3249

Zou, 2016, No association between CEL-HYB hybrid allele and chronic pancreatitis in Asian populations, Gastroenterology, 150, 1558, 10.1053/j.gastro.2016.02.071

Oracz, 2019, The hybrid allele 1 of carboxyl-ester lipase (CEL-HYB1) in Polish pediatric patients with chronic pancreatitis, Pancreatology, 19, 531, 10.1016/j.pan.2019.04.006

Johansson, 2018, The role of the carboxyl ester lipase (CEL) gene in pancreatic disease, Pancreatology, 18, 12, 10.1016/j.pan.2017.12.001

Mao, 2021, Homozygosity of short VNTR lengths in the CEL gene may confer susceptibility to idiopathic chronic pancreatitis, Pancreatology, 21, 1311, 10.1016/j.pan.2021.09.001

Raeder, 2006, Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction, Nat Genet, 38, 54, 10.1038/ng1708

Cassidy, 2020, Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding, Hum Mutat, 41, 1967, 10.1002/humu.24105

Dalva, 2020, Pathogenic carboxyl ester lipase (CEL) variants interact with the normal CEL protein in pancreatic cells, Cells, 9, 244, 10.3390/cells9010244

Vesterhus, 2010, Pancreatic function in carboxyl-ester lipase knockout mice, Pancreatology, 10, 467, 10.1159/000266284

Holmes, 2011, Comparative structures and evolution of vertebrate carboxyl ester lipase (CEL) genes and proteins with a major role in reverse cholesterol transport, Cholesterol, 2011, 10.1155/2011/781643

Gravdal, 2021, The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity, J Biol Chem, 296, 10.1016/j.jbc.2021.100661

Tjora, 2021, Protein misfolding in combination with other risk factors in CEL-HYB1-mediated chronic pancreatitis, Eur J Gastroenterol Hepatol, 33, 839, 10.1097/MEG.0000000000001963

Xiao, 2016, A carboxyl ester lipase (CEL) mutant causes chronic pancreatitis by forming intracellular aggregates that activate apoptosis, J Biol Chem, 291, 23224, 10.1074/jbc.M116.734384

Lansbury, 1999, Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease, Proc Natl Acad Sci U S A, 96, 3342, 10.1073/pnas.96.7.3342

Diakopoulos, 2015, Impaired autophagy induces chronic atrophic pancreatitis in mice via sex- and nutrition-dependent processes, Gastroenterology, 148, 626, 10.1053/j.gastro.2014.12.003

Saluja, 2019, Early intra-acinar events in pathogenesis of pancreatitis, Gastroenterology, 156, 1979, 10.1053/j.gastro.2019.01.268

Molven, 2016, Lipase genetic variants in chronic pancreatitis: when the end is wrong, all’s not well, Gastroenterology, 150, 1515, 10.1053/j.gastro.2016.04.019

Ræder, 2013, Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young), PLoS One, 8, 10.1371/journal.pone.0060229

Wildi, 2007, Suppression of transforming growth factor beta signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations, Gut, 56, 685, 10.1136/gut.2006.105833

Zhang, 2017, P2X7R blockade prevents NLRP3 inflammasome activation and pancreatic fibrosis in a mouse model of chronic pancreatitis, Pancreas, 46, 1327, 10.1097/MPA.0000000000000928