Molecular Genetics of Chronic Pancreatitis

Richard Szmola, Boston University Medical Center, Boston, Massachusetts, USA
David C Whitcomb, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Published online: March 2009

DOI: 10.1002/9780470015902.a0021481

Chronic pancreatitis is a progressive inflammatory condition of the pancreas that results in impairment of both exocrine and endocrine functions of the gland. The finding that a mutation in the cationic trypsinogen gene (PRSS1) causes hereditary pancreatitis was a major breakthrough that stimulated intensive research into the genetics of chronic pancreatitis. Further disease-causing mutations were identified in the PRSS1 gene, and mutations in novel genes (SPINK1, CFTR, CTRC, CASR) have been described in patients with idiopathic chronic pancreatitis. Genetic and biochemical studies highlighted the importance of the tightly regulated balance between trypsin activation and inactivation in the pathogenesis of pancreatitis.

Keywords: chronic pancreatitis; hereditary pancreatitis; cationic trypsinogen; SPINK1; CTRC

Figure 1. The trypsin-dependent pathological model of chronic pancreatitis. Early activation of trypsinogen to trypsin within the pancreas plays a crucial role in the development of pancreatitis (red arrow). Trypsinogen activation is prevented in normal zymogen granules, promoted in trypsinogen (PRSS1) mutations, and in trypsin in the presence of calcium. There are two early defence mechanisms to protect the organ against intracellular trypsin activity: trypsin degradation within the acinar cell and trypsin secretion into the duct. Trypsin will degrade itself in low calcium in the presence of CTRC. Thus calcium levels play a key regulatory role, and calcium is regulated by CASR and alcohol (EtOH). If trypsin is secreted, the rapid flushing of trypsin out of the duct is facilitated by CFTR. If trypsin activity is retained to that point that significant injury occurs, then an acute inflammatory response (AIR) is generated. The AIR upregulates SPINK1, which will inhibit trypsin directly, both inside and outside of the acinar cell (green lines, stimulation; red lines, inhibition; dashed lines, stimulation in the absence of inhibition). Figure by Dr. Whitcomb, all rights reserved.
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 References
    Aoun E, Chang CC, Greer JB et al. (2008) Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis. PLoS ONE 3(4): e2003.
    Applebaum SE, O'Connell JA, Aston CE and Whitcomb DC (2001) Motivations and concerns of patients with access to genetic testing for hereditary pancreatitis. American Journal of Gastroenterology 96(5): 1610–1617.
    Applebaum-Shapiro SE, Finch R, Pfützer RH et al. (2001) Hereditary pancreatitis in North America: the Pittsburgh-Midwest Multi-Center Pancreatic Study Group Study. Pancreatology 1(5): 439–443.
    Bhatia E, Choudhuri G, Sikora SS et al. (2002) Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. Gastroenterology 123(4): 1020–1025.
    Boulling A, Le Marechal C, Trouve P et al. (2007). Functional analysis of pancreatitis-associated missense mutations in the pancreatic secretory trypsin inhibitor (SPINK1) gene. European Journal of Human Genetics 15(9): 936–942.
    Bruce JI, Yang X, Ferguson CJ et al. (1999) Molecular and functional identification of a Ca2+ (polyvalent cation)-sensing receptor in rat pancreas. Journal of Biological Chemistry 274(29): 20561–20568.
    Chiari H (1896) Über die Selbstverdauung des menschlichen Pankreas. Zeitschrift für Heilkunde 17: 69–96.
    Cohn JA, Friedman KJ, Noone PG et al. (1998) Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. New England Journal of Medicine 339(10): 653–658.
    Comfort MW and Steinberg AG (1952) Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology 21: 54–63.
    Criddle DN, Murphy J, Fistetto G et al. (2006) Fatty acid ethyl esters cause pancreatic calcium toxicity via inositol trisphosphate receptors and loss of ATP synthesis. Gastroenterology 130(3): 781–793.
    Criddle DN, Raraty MG, Neoptolemos JP et al. (2004) Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites. Proceedings of the National Academy of Sciences of the USA 101(29): 10738–10743.
    Felderbauer P, Hoffmann P, Einwachter H et al. (2003) A novel mutation of the calcium sensing receptor gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC Gastroenterology 3(1): 34.
    Felderbauer P, Schnekenburger J, Lebert R et al. (2008) A novel A121T mutation in human cationic trypsinogen associated with hereditary pancreatitis: functional data indicating a loss-of-function mutation influencing the R122 trypsin cleavage site. Journal of Medical Genetics 45(8): 507–512.
    Gorry MC, Gabbaizedeh D, Furey W et al. (1997) Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 113(4): 1063–1068.
    Howes N, Lerch MM, Greenhalf W et al. (2004) European Registry of Hereditary Pancreatitis and Pancreatic Cancer (EUROPAC). Clinical and genetic characteristics of hereditary pancreatitis in Europe. Clinical Gastroenterology and Hepatology 2(3): 252–261.
    Kazal LA, Sopicer DS and Brahinski RA (1948) Isolation of a crystalline trypsin inhibitor-anticoagulant protein from pancreas. Journal of the American Chemistry Society 70: 3034–3040.
    Keim V, Bauer N, Teich N et al. (2001) Clinical characterization of patients with hereditary pancreatitis and mutations in the cationic trypsinogen gene. American Journal of Medicine 111(8): 622–626.
    Keim V, Witt H, Bauer N et al. (2003) The course of genetically determined chronic pancreatitis. Journal of the Pancreas 4(4): 146–154.
    Khalid A, Finkelstein S, Thompson B et al. (2006) A 93 year old man with the PRSS1 R122H mutation, low SPINK1 expression, and no pancreatitis: insights into phenotypic non-penetrance. Gut 55(5): 728–731.
    Király O, Boulling A, Witt H et al. (2007a) Signal peptide variants that impair secretion of pancreatic secretory trypsin inhibitor (SPINK1) cause autosomal dominant hereditary pancreatitis. Human Mutation 28(5): 469–476.
    Király O, Wartmann T and Sahin-Tóth M (2007b) Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut 56(10): 1433–1438.
    Kume K, Masamune A, Kikuta K and Shimosegawa T (2006) [-215G>A; IVS3+2T>C] mutation in the SPINK1 gene causes exon 3 skipping and loss of the trypsin binding site. Gut 55(8): 1214.
    Kuwata K, Hirota M, Shimizu H et al. (2002) Functional analysis of recombinant pancreatic secretory trypsin inhibitor protein with amino-acid substitution. Journal of Gastroenterology 37(11): 928–934.
    Le Bodic L, Bignon JD, Raguenes O et al. (1996) The hereditary pancreatitis gene maps to long arm of chromosome 7. Human Molecular Genetics 5(4): 549–554.
    Le Maréchal C, Masson E, Chen JM et al. (2006) Hereditary pancreatitis caused by triplication of the trypsinogen locus. Nature Genetics 38(12): 1372–1374.
    Lowenfels AB, Maisonneuve P, DiMagno EP et al. (1997) Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. Journal of the National Cancer Institute 89(6): 442–446.
    Masson E, Chen JM, Scotet V, Le Maréchal C and Férec C (2008b) Association of rare chymotrypsinogen C (CTRC) gene variations in patients with idiopathic chronic pancreatitis. Human Genetics 123(1): 83–91.
    Masson E, Le Maréchal C, Chandak GR et al. (2008a) Trypsinogen copy number mutations in patients with idiopathic chronic pancreatitis. Clinical Gastroenterology and Hepatology 6(1): 82–88.
    Muddana V, Lamb J, Greer JB et al. (2008) Association between calcium sensing receptor gene polymorphisms and chronic pancreatitis in a US population: role of serine protease inhibitor Kazal 1type and alcohol. World Journal of Gastroenterolology 14(28): 4486–4491.
    Murugaian EE, Premkumar RM, Radhakrishnan L and Vallath B (2007) Novel mutations in the calcium sensing receptor gene in tropical chronic pancreatitis in India. Scandinavian Journal of Gastroenterology 14: 1–5.
    Pandya A, Blanton SH, Landa B et al. (1996) Linkage studies in a large kindred with hereditary pancreatitis confirms mapping of the gene to a 16-cM region on 7q. Genomics 38(2): 227–230.
    Pfützer RH, Barmada MM, Brunskill AP et al. (2000) SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology 119(3): 615–623.
    Pidasheva S, D'Souza-Li L, Canaff L, Cole DE and Hendy GN (2004) CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Human Mutation 24(2): 107–111.
    Rinderknecht H, Renner IG and Carmack C (1979) Trypsinogen variants in pancreatic juice of healthy volunteers, chronic alcoholics, and patients with pancreatitis and cancer of the pancreas. Gut 20(10): 886–891.
    Rosendahl J, Witt H, Szmola R et al. (2008) Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis. Nature Genetics 40(1): 78–82.
    Rossi L, Pfützer RH, Parvin S et al. (2001) SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh: a preliminary report. Pancreatology 1(3): 242–245.
    Sahin-Tóth M (2006) Biochemical models of hereditary pancreatitis. Endocrinology Metabolism Clinics of North America 35(2): 303–312.
    Santhosh S, Witt H, te Morsche RH et al. (2008) A loss of function polymorphism (G191R) of anionic trypsinogen (PRSS2) confers protection against chronic pancreatitis. Pancreas 36(3): 317–320.
    Sibert JR (1978) Hereditary pancreatitis in England and Wales. Journal of Medical Genetics 15(3): 189–201.
    Sossenheimer MJ, Aston CE, Preston RA et al. (1997) Clinical characteristics of hereditary pancreatitis in a large family, based on high-risk haplotype. The Midwest Multicenter Pancreatic Study Group (MMPSG). American Journal of Gastroenterology 92(7): 1113–1116.
    Szmola R, Kukor Z and Sahin-Tóth M (2003) Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. Journal of Biological Chemistry 278(49): 48580–48589.
    Szmola R and Sahin-Tóth M (2007) Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknecht's enzyme Y. Proceedings of the National Academy of Sciences of the USA 104(27): 11227–11232.
    Teich N, Rosendahl J, Toth M, Mossner J and Sahin-Tóth M (2006) Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis. Human Mutation 27(8): 721–730.
    Whitcomb DC (1999) Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 45: 317–322.
    Whitcomb DC (2004a) Mechanisms of disease: advances in understanding the mechanisms leading to chronic pancreatitis. Nature Clinical Practice Gastroenterology & Hepatology 1(1): 46–52.
    Whitcomb DC (2004b) Value of genetic testing in management of pancreatitis. Gut 53(11): 1710–1717.
    Whitcomb DC and Barmada MM (2007) A systems biology approach to genetic studies of pancreatitis and other complex diseases. Cellular and Molecular Life Sciences 64(14): 1763–1777.
    Whitcomb DC, Gorry MC, Preston RA et al. (1996b) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genetics 14(2): 141–145.
    Whitcomb DC, Preston RA, Aston CE et al. (1996a) A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110(6): 1975–1980.
    Witt H, Luck W and Becker M (1999) A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology 117(1): 7–10.
    Witt H, Luck W, Becker M et al. (2001) Mutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. Journal of the American Medical Association 285(21): 2716–2717.
    Witt H, Luck W, Hennies HC et al. (2000) Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nature Genetics 25(2): 213–216.
    Witt H, Sahin-Toth M, Landt O et al. (2006) A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nature Genetics 38(6): 668–673.
 Further Reading
    Deng X, Wang L, Elm MS et al. (2005) Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats. American Journal of Pathology 166(1): 93–106.
    Ruthenbürger M, Mayerle J and Lerch MM (2006) Cell biology of pancreatic proteases. Endocrinology Metabolism Clinics of North America 35(2): 313–331.
    Teich N and Mossner J (2008) Hereditary chronic pancreatitis. Best Practice & Research. Clinical Gastroenterology 22(1): 115–130.
    Whitcomb DC (2006) Polygenetic traits in pancreatic disorders. Endocrinology Metabolism Clinics of North America 35(2): 255–269.
    Witt H, Apte MV, Keim V and Wilson JS (2007) Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 132(4): 1557–1573.

Related Sub-Topics:

Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Posttranslational Modification | Proteins: Structure, Function, Metabolism | Enzymes: Structure and Action Mechanism
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Article Title: Molecular Genetics of Chronic Pancreatitis
 
How to Cite close
Szmola, Richard, and Whitcomb, David C(Mar 2009) Molecular Genetics of Chronic Pancreatitis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021481]