Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis

Abstract

Chronic pancreatitis (CP) is a continuing or relapsing inflammatory disease of the pancreas. In approximately one-third of all cases, no aetiological factor can be found, and these patients are classified as having idiopathic disease. Pathophysiologically, autodigestion and inflammation may be caused by either increased proteolytic activity or decreased protease inhibition. Several studies have demonstrated mutations in the cationic trypsinogen gene (PRSS1) in patients with hereditary1,2,3 or idiopathic4 CP. It is thought that these mutations result in increased trypsin activity within the pancreatic parenchyma. Most patients with idiopathic or hereditary CP, however, do not have mutations in PRSS1 (ref. 4). Here we analysed 96 unrelated children and adolescents with CP for mutations in the gene encoding the serine protease inhibitor, Kazal type 1 (SPINK1), a pancreatic trypsin inhibitor. We found mutations in 23% of the patients. In 18 patients, 6 of whom were homozygous, we detected a missense mutation of codon 34 (N34S). We also found four other sequence variants. Our results indicate that mutations in SPINK1 are associated with chronic pancreatitis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Schematic presentation of SPINK1 genomic structure, and length and position of the five amplified fragments for analysis of the intronic sequences.
Figure 2: Multi-locus haplotype relative risk (HRR) lod scores plotted against the map position on chromosome 5.
Figure 3: Schematic presentation of the SPINK1 genomic structure and sequence variations found in CP patients.
Figure 4: Model of chronic pancreatitis.

References

  1. Whitcomb, D.C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genet. 14, 141– 145 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Gorry, M.C. et al. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology 113, 1063–1068 ( 1997).

    Article  CAS  PubMed  Google Scholar 

  3. Ferec, C. et al. Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis. J. Med. Genet. 36, 228–232 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Witt, H., Luck, W. & Becker, M. A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis. Gastroenterology 117, 7–10 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Horii, A. et al. Primary structure of human pancreatic secretory trypsin inhibitor (PSTI) gene. Biochem. Biophys. Res. Commun. 149, 635–641 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Bartelt, D.C., Shapanka, R. & Greene, L.J. The primary structure of the human pancreatic secretory trypsin inhibitor. Amino acid sequence of the reduced S-aminoethylated protein . Arch. Biochem. Biophys. 179, 189– 199 (1977).

    Article  CAS  PubMed  Google Scholar 

  7. Marchbank, T., Freeman, T.C. & Playford, R.J. Human pancreatic secretory trypsin inhibitor. Digestion 59, 167–174 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  8. Rinderknecht, H. Pancreatic secretory enzymes. in The Pancreas: Biology, Pathobiology, and Disease (eds Go, V.L.W. et al.) 219– 251 (Raven, New York, 1993).

    Google Scholar 

  9. Spielman, R.S., McGinnis, R.E. & Ewens, W.J. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am. J. Hum. Genet. 52, 506–516 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Falk, C.T. & Rubinstein, P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations . Ann. Hum. Genet. 51, 227– 233 (1987).

    Article  CAS  PubMed  Google Scholar 

  11. Terwilliger, J.D. A powerful likelihood method for the analysis of linkage disequilibrium between trait loci and one or more polymorphic marker loci. Am. J. Hum. Genet. 56, 777–787 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Laskowski, M. Jr & Kato, I. Protein inhibitors of proteinases. Annu. Rev. Biochem. 49, 593–626 (1980).

    Article  CAS  PubMed  Google Scholar 

  13. Rinderknecht, H. Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig. Dis. Sci. 31, 314–321 (1986).

    Article  CAS  PubMed  Google Scholar 

  14. Sharer, N. et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N. Engl. J. Med. 339, 645– 652 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Cohn, J.A. et al. Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis. N. Engl. J. Med. 339, 653–658 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152– 154 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the families for participation; the members of the Gesellschaft für Pädiatrische Gastroenterologie und Ernährung for providing clinical data and blood samples; C. Güldner and I. Liebner for technical assistance; and F. Rüschendorf for support in computer science.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Heiko Witt.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Witt, H., Luck, W., Hennies, H. et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 25, 213–216 (2000). https://doi.org/10.1038/76088

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/76088

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing