Genetic risk in chronic pancreatitis: the misfolding-dependent pathway

Current Opinion in Gastroenterology - Tập 33 Số 5 - Trang 390-395 - 2017
Miklós Sahin‐Tóth1,2,3,4
1Department of Molecular and Cell Biology, Center for Exocrine Disorders, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts, USA
2e-mail: [email protected]
3fax: +1 617 414 1041
4to Miklós Sahin-Tóth, Department of Molecular and Cell Biology, Center for Exocrine Disorders, Boston University Henry M. Goldman School of Dental Medicine, 72 East Concord Street, Evans-433, Boston, MA 02118, USA. Tel: +1 617 414 1070

Tóm tắt

Purpose of review Genetic risk in chronic pancreatitis is partly due to mutations that cause misfolding of digestive enzymes and elicit endoplasmic reticulum stress. This review examines recent developments in this concept. Recent findings The best characterized misfolding variants in the highly expressed digestive proteases cationic trypsinogen (PRSS1) and carboxypeptidase A1 (CPA1) are strong, causative risk factors for chronic pancreatitis and may be associated with autosomal dominant hereditary pancreatitis. Summary Properties of misfolding digestive enzyme mutants indicate that endoplasmic reticulum stress is a highly relevant pathological mechanism and a potential therapeutic target in chronic pancreatitis.

Từ khóa


Tài liệu tham khảo

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

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

Walter, 2011, The unfolded protein response: from stress pathway to homeostatic regulation, Science, 334, 1081, 10.1126/science.1209038

Tabas, 2011, Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress, Nat Cell Biol, 13, 184, 10.1038/ncb0311-184

Oakes, 2015, The role of endoplasmic reticulum stress in human pathology, Annu Rev Pathol, 10, 173, 10.1146/annurev-pathol-012513-104649

Grootjans, 2016, The unfolded protein response in immunity and inflammation, Nat Rev Immunol, 16, 469, 10.1038/nri.2016.62

Wang, 2016, Protein misfolding in the endoplasmic reticulum as a conduit to human disease, Nature, 529, 326, 10.1038/nature17041

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

Balázs, 2016, Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis, Am J Physiol Gastrointest Liver Physiol, 310, G477, 10.1152/ajpgi.00444.2015

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

Tautermann, 2001, R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis, Digestion, 64, 226, 10.1159/000048866

Le Maréchal, 2001, Identification of a novel pancreatitis-associated missense mutation, R116C, in the human cationic trypsinogen gene (PRSS1), Mol Genet Metab, 74, 342, 10.1006/mgme.2001.3246

Teich, 2002, Mutational screening of patients with nonalcoholic chronic pancreatitis: identification of further trypsinogen variants, Am J Gastroenterol, 97, 341

Pho-Iam, 2005, A Thai family with hereditary pancreatitis and increased cancer risk due to a mutation in PRSS1 gene, World J Gastroenterol, 11, 1634, 10.3748/wjg.v11.i11.1634

Rebours, 2009, The natural history of hereditary pancreatitis: a national series, Gut, 58, 97, 10.1136/gut.2008.149179

Chang, 2009, Association and differential role of PRSS1 and SPINK1 mutation in early-onset and late-onset idiopathic chronic pancreatitis in Chinese subjects, Gut, 58, 885, 10.1136/gut.2007.129916

Joergensen, 2010, Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark, Am J Gastroenterol, 105, 1876, 10.1038/ajg.2010.193

Joergensen, 2010, Incidence, etiology and prognosis of first-time acute pancreatitis in young patients: a population-based cohort study, Pancreatology, 10, 453, 10.1159/000260666

Sultan, 2012, Genetic prevalence and characteristics in children with recurrent pancreatitis, J Pediatr Gastroenterol Nutr, 54, 645, 10.1097/MPG.0b013e31823f0269

Rosendahl, 2013, CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated?, Gut, 62, 582, 10.1136/gutjnl-2011-300645

Chang, 2014, Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis, J Gastroenterol Hepatol, 29, 2038, 10.1111/jgh.12649

Keiles, 2006, Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis, Pancreas, 33, 221, 10.1097/01.mpa.0000232014.94974.75

Liu, 2009, Prevalence of pancreatic diabetes in patients carrying mutations or polymorphisms of the PRSS1 gene in the Han population, Diabetes Technol Ther, 11, 799, 10.1089/dia.2009.0051

Sofia, 2016, Extensive molecular analysis suggested the strong genetic heterogeneity of idiopathic chronic pancreatitis, Mol Med, 22, 300, 10.2119/molmed.2016.00010

Németh, 2016, Misfolding cationic trypsinogen variant p.L104P causes hereditary pancreatitis, Gut

Chen, 2001, Mutational screening of the cationic trypsinogen gene in a large cohort of subjects with idiopathic chronic pancreatitis, Clin Genet, 59, 189, 10.1034/j.1399-0004.2001.590308.x

Hamoir, 2013, Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants, Digestion, 87, 229, 10.1159/000348439

Masson, 2013, Characterization of two deletions of the CTRC locus, Mol Genet Metab, 109, 296, 10.1016/j.ymgme.2013.04.022

Lee, 2011, High incidence of PRSS1 and SPINK1 mutations in Korean children with acute recurrent and chronic pancreatitis, J Pediatr Gastroenterol Nutr, 52, 478, 10.1097/MPG.0b013e31820e2126

Masamune, 2014, PRSS1 c.623G>C (p. G208A) variant is associated with pancreatitis in Japan, Gut, 63, 366, 10.1136/gutjnl-2013-304925

Lee, 2015, The PRSS1 c.623G>C (p. G208A) mutation is the most common PRSS1 mutation in Korean children with hereditary pancreatitis, Gut, 64, 359, 10.1136/gutjnl-2014-307256

Cho, 2016, PRSS1, SPINK1, CFTR, and CTRC pathogenic variants in Korean patients with idiopathic pancreatitis, Ann Lab Med, 36, 555, 10.3343/alm.2016.36.6.555

Saito, 2016, Genetic analysis of Japanese children with acute recurrent and chronic pancreatitis, J Pediatr Gastroenterol Nutr, 63, 431, 10.1097/MPG.0000000000001320

Hegyi, 2014, Chronic pancreatitis associated with the p.G208A variant of PRSS1 gene in a European patient, JOP, 15, 49

Kereszturi, 2009, Intracellular autoactivation of human cationic trypsinogen mutants causes reduced trypsinogen secretion and acinar cell death, J Biol Chem, 284, 33392, 10.1074/jbc.M109.056812

Joergensen, 2011, Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis, Pancreas, 40, 540, 10.1097/MPA.0b013e3182152fdf

Geisz, 2013, Robust autoactivation, chymotrypsin C independence and diminished secretion define a subset of hereditary pancreatitis-associated cationic trypsinogen mutants, FEBS J, 280, 2888, 10.1111/febs.12292

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

Wu, 2017, No significant enrichment of rare functionally defective CPA1 variants in a large Chinese idiopathic chronic pancreatitis cohort, Hum Mutat, 38, 959, 10.1002/humu.23254

Kujko, 2017, A novel p.Ser282Pro CPA1 variant is associated with autosomal dominant hereditary pancreatitis, Gut, 10.1136/gutjnl-2017-313816

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

Beer, 2013, Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk, Gut, 62, 1616, 10.1136/gutjnl-2012-303090

Szmola, 2010, Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells, Gut, 59, 365, 10.1136/gut.2009.198903

Scheele, 1981, Characterization of human exocrine pancreatic proteins by two-dimensional isoelectric focusing/sodium dodecyl sulfate gel electrophoresis, Gastroenterology, 80, 461, 10.1016/0016-5085(81)90007-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

Király, 2007, Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation, Gut, 56, 1433, 10.1136/gut.2006.115725

Boulling, 2007, Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene, Eur J Hum Genet, 15, 936, 10.1038/sj.ejhg.5201873

Boulling, 2012, Functional analysis of eight missense mutations in the SPINK1 gene, Pancreas, 41, 329, 10.1097/MPA.0b013e3182277b83

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

Johansson, 2011, Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease, J Biol Chem, 286, 34593, 10.1074/jbc.M111.222679

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

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

Behar, 2014, Identification of a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency, J Lipid Res, 55, 307, 10.1194/jlr.P041103

Szabó, 2015, A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding, Biochim Biophys Acta, 1852, 1372, 10.1016/j.bbadis.2015.04.002

Cao, 2003, DNA polymorphisms of lipase related genes, J Hum Genet, 48, 443, 10.1007/s10038-003-0051-1

Xiao, 2011, Pancreatic lipase-related protein-2 (PLRP2) can contribute to dietary fat digestion in human newborns, J Biol Chem, 286, 26353, 10.1074/jbc.M111.249813