Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis

Background and aims: Mutations in the cationic trypsinogen (protease, serine, 1 (trypsin 1); PRSS1) gene are causally associated with recurrent acute and chronic pancreatitis. We investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, Kazal type I; SPINK1) mutations, the role of SPINK1 mutations in these patients was also analysed. Subjects and methods: The coding regions of PRSS1 and SPINK1 genes were sequenced in 290 controls and 198 patients, of whom 120 were diagnosed as idiopathic (ICP), 41 as alcoholic (ACP), and 37 as hereditary pancreatitis (HP). Twenty four unaffected relatives of HP probands were also analysed and genotype-phenotype correlations and statistical analyses were performed. Results: No mutations in the PRSS1 gene were detected in any of the patients, including HP patients, while the N34S mutation was observed in the SPINK1 gene in the majority of HP patients (73%). Similarly, 26.8% of ACP (11 of 41) and 32.5% (39 of 120) of ICP patients also had SPINK1 mutations. The N34S mutation was observed in both homozygous and heterozygous conditions. In comparison, only 2.76% of the control population had the N34S allele (p<0.001). The P55S mutation was observed in one ICP and one ACP patient, and in three normal individuals. Genotype-phenotype correlations did not suggest any significant difference in the age of onset, severity of disease, or pancreatic endocrine insufficiency in patients with or without mutated SPINK1 and irrespective of the allelic status of N34S SPINK1. Conclusions: Irrespective of the aetiology, mutations in the PRSS1 gene are not associated with chronic pancreatitis, including HP. In contrast, the N34S mutation in the SPINK1 gene shows a significant correlation in these patients. A comparable phenotype in terms of age of onset, diabetes mellitus, and other phenotypic features in patients with or without SPINK1 mutations and N34S homozygotes and heterozygotes suggests that there may still be involvement of other genetic or environmental factors.

[1]  M. Löhr,et al.  Autoimmune Pancreatitis: Pathological, Clinical, and Immunological Features , 2003, Pancreas.

[2]  M. Ohmuraya,et al.  From acute to chronic pancreatitis: the role of mutations in the pancreatic secretory trypsin inhibitor gene. , 2003, JOP : Journal of the pancreas.

[3]  A. Andriulli,et al.  On the role of CFTR, PSSR1 and PST1/SPINK1 in idiopathic chronic pancreatitis , 2003, European Journal of Human Genetics.

[4]  Alan E. Jackson,et al.  SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent. , 2002, American journal of human genetics.

[5]  A. Kage,et al.  Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. , 2002, Gastroenterology.

[6]  L. Singh,et al.  Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis , 2002, Journal of medical genetics.

[7]  A. Andrén-sandberg,et al.  The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease , 2002, Gut.

[8]  B. Seifert,et al.  Mutations of the serine protease inhibitor, Kazal type 1 gene, in patients with idiopathic chronic pancreatitis , 2002, American Journal of Gastroenterology.

[9]  J. Neoptolemos,et al.  Novel cationic trypsinogen (PRSS1) N29T and R122C mutations cause autosomal dominant hereditary pancreatitis , 2002, Gut.

[10]  C. Férec,et al.  Determination of the relative contribution of three genes–the cystic fibrosis transmembrane conductance regulator gene, the cationic trypsinogen gene, and the pancreatic secretory trypsin inhibitor gene–to the etiology of idiopathic chronic pancreatitis , 2002, European Journal of Human Genetics.

[11]  V. Keim,et al.  Relevance of Variants in Serum Antiproteinases for the Course of Chronic Pancreatitis , 2002, Scandinavian journal of gastroenterology.

[12]  A. Kage,et al.  α 1 -Antitrypsin Genotypes in Patients with Chronic Pancreatitis , 2002 .

[13]  M. Knowles,et al.  Cystic fibrosis gene mutations and pancreatitis risk: relation to epithelial ion transport and trypsin inhibitor gene mutations. , 2001, Gastroenterology.

[14]  C. Férec,et al.  Discrimination of three mutational events that result in a disruption of the R122 primary autolysis site of the human cationic trypsinogen (PRSS1) by denaturing high performance liquid chromatography , 2001, BMC Genetics.

[15]  D. Whitcomb,et al.  SPINK1 Mutations Are Associated with Multiple Phenotypes , 2001, Pancreatology.

[16]  H. Witt.  Gene Mutations in Children with Chronic Pancreatitis , 2001, Pancreatology.

[17]  H. Blum,et al.  Mutations of the cystic fibrosis gene in patients with chronic pancreatitis , 2001, American Journal of Gastroenterology.

[18]  M. McKenna,et al.  Sequence Analysis of COL1A1 and COL1A2 Genes in Clinical Otosclerosis: No Evidence for Mutations in the Coding Regions of the Genes , 2001, Oto-Rhino-Laryngologia Nova.

[19]  W. Knoefel,et al.  Mutation in the SPINK1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. , 2001, JAMA.

[20]  J. Drenth,et al.  Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. , 2001, Gut.

[21]  T. Dörk,et al.  Low prevalence of SPINK1 gene mutations in adult patients with chronic idiopathic pancreatitis , 2001, Journal of medical genetics.

[22]  C. Férec,et al.  Mutations of the pancreatic secretory trypsin inhibitor (PSTI) gene in idiopathic chronic pancreatitis. , 2001, Gastroenterology.

[23]  D. Whitcomb,et al.  Chronic pancreatitis: diagnosis, classification, and new genetic developments. , 2001, Gastroenterology.

[24]  C. Férec,et al.  A CGC>CAT gene conversion-like event resulting in the R122H mutation in the cationic trypsinogen gene and its implication in the genotyping of pancreatitis , 2000, Journal of medical genetics.

[25]  G. Feldman,et al.  Mutation analysis of the cystic fibrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis. , 2000, American journal of medical genetics.

[26]  M. Barmada,et al.  SPINK1/PSTI polymorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. , 2000, Gastroenterology.

[27]  M. Manns,et al.  Chronic pancreatitis associated with an activation peptide mutation that facilitates trypsin activation. , 2000, Gastroenterology.

[28]  Olfert Landt,et al.  Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis , 2000, Nature Genetics.

[29]  C. Férec,et al.  Mutational analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene in hereditary and sporadic chronic pancreatitis , 2000, Journal of medical genetics.

[30]  D. Whitcomb,et al.  Trypsinogen mutations in chronic pancreatitis. , 1999, Gastroenterology.

[31]  A. Curtis,et al.  Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis , 1999, The Lancet.

[32]  H. Witt,et al.  A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. , 1999, Gastroenterology.

[33]  M. Korsten,et al.  Racial factors and the risk of chronic pancreatitis , 1999, American Journal of Gastroenterology.

[34]  A. Munnich,et al.  Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis , 1999, Journal of medical genetics.

[35]  S. Onishi,et al.  Mutations in exons 2 and 3 of the cationic trypsinogen gene in Japanese families with hereditary pancreatitis , 1999, Gut.

[36]  P. Raskin,et al.  Report of the expert committee on the diagnosis and classification of diabetes mellitus. , 1999, Diabetes care.

[37]  M. Knowles,et al.  Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. , 1998, The New England journal of medicine.

[38]  Daniel L. Koller,et al.  Heterogeneity in hereditary pancreatitis. , 1998, American journal of medical genetics.

[39]  M. Gorry,et al.  Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. , 1997, Gastroenterology.

[40]  T. Frick.  Drug-associated pancreatitis: facts and fiction. , 1997, Pancreas.

[41]  M. Fantone,et al.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus , 1997, Diabetes Care.

[42]  R. Ammann.  A clinically based classification system for alcoholic chronic pancreatitis: summary of an international workshop on chronic pancreatitis. , 1997, Pancreas.

[43]  M. Gorry,et al.  Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene , 1996, Nature Genetics.

[44]  P. Lévy,et al.  [Natural history of chronic pancreatitis]. , 1996, La Revue du praticien.

[45]  G. Hitman,et al.  Familial Aggregation in Tropical Fibrocalculous Pancreatic Diabetes , 1989, Pancreas.

[46]  N. Tomita,et al.  Primary structure of human pancreatic secretory trypsin inhibitor (PSTI) gene. , 1987, Biochemical and biophysical research communications.

[47]  A. Bisceglie,et al.  Cirrhosis and chronic pancreatitis in alcoholics. , 1984, Journal of clinical gastroenterology.

[48]  H. Rinderknecht,et al.  Effects of chronic alcohol abuse on exocrine pancreatic secretion in man , 2005, Digestive Diseases and Sciences.

[49]  S. Pandol,et al.  Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats. , 2002, Gastroenterology.

[50]  A. Kage,et al.  Alpha1-antitrypsin genotypes in patients with chronic pancreatitis. , 2002, Scandinavian journal of gastroenterology.

[51]  T. Furukawa,et al.  Analysis of the human pancreatic secretory trypsin inhibitor (PSTI) gene mutations in Japanese patients with chronic pancreatitis , 2001, Journal of Human Genetics.

[52]  P. Lankisch.  [Chronic pancreatitis]. , 1991, Der Internist.

[53]  J. Haynes,et al.  Hereditary pancreatitis. , 1982, American family physician.