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Gene Review

SPINK1  -  serine peptidase inhibitor, Kazal type 1

Homo sapiens

Synonyms: PCTT, PSTI, Pancreatic secretory trypsin inhibitor, Serine protease inhibitor Kazal-type 1, Spink3, ...
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Disease relevance of SPINK1


Psychiatry related information on SPINK1

  • CONCLUSIONS: The decrease in tissue PSTI levels associated with gastric atrophy probably represents a permanent reduction in one of the mucosal defense mechanisms [8].
  • A correlation coefficient of 0.85 between the speech discrimination score in quiet and the PSTI was obtained [9].

High impact information on SPINK1


Chemical compound and disease context of SPINK1

  • The median (range) concentration of PSTI in basal gastric juice from 13 patients with duodenal ulcers was 9 (3-21) micrograms/l and did not change during stimulation with pentagastrin [14].
  • The maximum increase of TATI was from a mean basal value of 8.51 +/- 5.58 micrograms l-1 in subjects with normal renal function to 107.27 +/- 63.34 micrograms l-1 in patients with renal failure; beta 2M increased from 1.45 +/- 0.38 to 11.16 +/- 5.73 mg l-1 and creatinine from 1.05 +/- 0.17 to 5.07 +/- 1.93 mg dl-1 [15].
  • The Ser-170 residue of a trypsin-like enzyme from Streptomyces fradiae (SFT), which is considered to be the active-site serine, was replaced with alanine by site-directed mutagenesis to improve the affinity chromatography step for a Kazal-type trypsin inhibitor pancreatic secretory trypsin inhibitor (PSTI) [16].
  • Concentrations of pancreatic secretory trypsin inhibitor (PSTI), acute phase proteins, and neopterin in Crohn's disease. Comparison with clinical disease activity and endoscopical findings [17].
  • Twelve of 30 (40%) cases in the MP group and 24 of 30 (80%) cases in the FL + PSTI group showed clinical improvement in macular edema according to the stereoscopic evaluation of fundus and fluorescein angiography (P = 0.003) [18].

Biological context of SPINK1

  • Neither compound heterozygotes for CFTR nor trans-heterozygotes for CFTR/SPINK1 were found [19].
  • The remaining issues are of how wide to cast the net of investigation in patients with unexplained pancreatitis, particularly looking for mutations in the CFTR and lower penetrance genes such as PSTI/SPINK1 [4].
  • The four exons and their flanking sequences of the SPINK1 gene were screened by denaturing high performance liquid chromatography analysis (DHPLC); and mutations were identified by direct sequencing [20].
  • Since the N34S variant of the SPINK1 trypsin inhibitor gene has been found to partially account for genetic susceptibility to chronic pancreatitis, we used a family-based and case-control approach in two separate ethnic groups from the Indian subcontinent, to determine whether N34S was associated with susceptibility to FCPD [21].
  • Remarkably, the same mutation endowed mesotrypsin with a novel and unique function: mesotrypsin rapidly hydrolyzed the reactive-site peptide bond of the Kunitz-type trypsin inhibitor SBTI, and irreversibly degraded the Kazal-type temporary inhibitor SPINK1 [22].

Anatomical context of SPINK1

  • In summary, SPINK1 is thought to play an important role in protecting the pancreas against excessive trypsinogen activation [2].
  • MAIN OUTCOME MEASURES: In patients with mutations of PRSS1 (N29I, R122H) and SPINK1 (N34S) the parameters such as calcification, dilatation of the main pancreatic duct, diabetes mellitus, hospital treatments, and surgery were recorded [23].
  • RESULTS: The SPINK1 gene is transcribed in the parotid gland [24].
  • The median concentration of TAT-2 was higher in mucinous than in serous cyst fluid as has been found previously for the specific trypsin inhibitor, tumor-associated trypsin inhibitor [25].
  • Immunolabeling of the original tissue with antibodies against these two genes confirmed overexpression, validating our strategy: 67LR was not expressed in the normal urothelium but was present in the tumor, whereas TATI expression was confined to umbrella cells in the normal urothelium, but extended to all cell layers in the tumor [26].

Associations of SPINK1 with chemical compounds

  • Chronic ethanol consumption induces gene expression of pancreatic monitor peptide, but not SPINK1/PSTI-56, in rats [27].
  • Variants of the human pancreatic secretory trypsin inhibitor (PSTI) have been created during a protein design project to generate a high-affinity inhibitor with respect to some serine proteases other than trypsin [28].
  • METHODS AND RESULTS: Using a monoclonal anti-TATI antibody, immunohistochemistry was performed on formalin-fixed paraffin-embedded tumour specimens from 336 patients [29].
  • However, when the small bowel juice had been pre-incubated with soybean trypsin inhibitor 3 g/l, casein 5 g/l or lactalbumin 30 g/l, the hydrolysis of PSTI diminished so that 95%, 32%, and 33% respectively, now eluted in the characteristic position of free (i.e. intact and not bound to an enzyme) PSTI [30].
  • The 1.0 kilobase pairs of PSTI 5'-flanking sequence directed preferential expression of a linked reporter chloramphenicol acetyltransferase, which was active in a PSTI-expressing pancreatic cell line (AR42j) but not in a PSTI-nonexpressing fibroblast cell line (XC) [31].

Regulatory relationships of SPINK1

  • Heterozygous SPINK1 mutations were detected in eight ICP patients (15% v 1% in controls) but only one also carried an additional mild CFTR mutation [32].

Other interactions of SPINK1


Analytical, diagnostic and therapeutic context of SPINK1


  1. Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Drenth, J.P., te Morsche, R., Jansen, J.B. Gut (2002) [Pubmed]
  2. Serine protease inhibitor Kazal type 1 mutations and pancreatitis. Schneider, A. Gastroenterol. Clin. North Am. (2004) [Pubmed]
  3. Hereditary pancreatitis as the premalignant disease: a Japanese case of pancreatic cancer involving the SPINK1 gene mutation N34S. Masamune, A., Mizutamari, H., Kume, K., Asakura, T., Satoh, K., Shimosegawa, T. Pancreas (2004) [Pubmed]
  4. Genetic counseling for hereditary pancreatitis--the role of molecular genetics testing for the cationic trypsinogen gene, cystic fibrosis and serine protease inhibitor Kazal type 1. Ellis, I. Gastroenterol. Clin. North Am. (2004) [Pubmed]
  5. SPINK1/PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh. Schneider, A., Suman, A., Rossi, L., Barmada, M.M., Beglinger, C., Parvin, S., Sattar, S., Ali, L., Khan, A.K., Gyr, N., Whitcomb, D.C. Gastroenterology (2002) [Pubmed]
  6. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Király, O., Wartmann, T., Sahin-Tóth, M. Gut (2007) [Pubmed]
  7. Association of SPINK1 expression and TMPRSS2:ERG fusion with prognosis in endocrine-treated prostate cancer. Leinonen, K.A., Tolonen, T.T., Bracken, H., Stenman, U.H., Tammela, T.L., Saramäki, O.R., Visakorpi, T. Clin. Cancer Res. (2010) [Pubmed]
  8. Influence of inflammation and atrophy on pancreatic secretory trypsin inhibitor levels within the gastric mucosa. Playford, R.J., Hanby, A.M., Quinn, C., Calam, J. Gastroenterology (1994) [Pubmed]
  9. Relations between speech intelligibility and psychoacoustical modulation transfer function (PMTF). Hagerman, B., Olofsson, A., Lindblad, A.C. Scandinavian audiology. (1987) [Pubmed]
  10. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Witt, H., Sahin-Tóth, M., Landt, O., Chen, J.M., Kähne, T., Drenth, J.P., Kukor, Z., Szepessy, E., Halangk, W., Dahm, S., Rohde, K., Schulz, H.U., Le Maréchal, C., Akar, N., Ammann, R.W., Truninger, K., Bargetzi, M., Bhatia, E., Castellani, C., Cavestro, G.M., Cerny, M., Destro-Bisol, G., Spedini, G., Eiberg, H., Jansen, J.B., Koudova, M., Rausova, E., Macek, M., Malats, N., Real, F.X., Menzel, H.J., Moral, P., Galavotti, R., Pignatti, P.F., Rickards, O., Spicak, J., Zarnescu, N.O., Böck, W., Gress, T.M., Friess, H., Ockenga, J., Schmidt, H., Pfützer, R., Löhr, M., Simon, P., Weiss, F.U., Lerch, M.M., Teich, N., Keim, V., Berg, T., Wiedenmann, B., Luck, W., Groneberg, D.A., Becker, M., Keil, T., Kage, A., Bernardova, J., Braun, M., Güldner, C., Halangk, J., Rosendahl, J., Witt, U., Treiber, M., Nickel, R., Férec, C. Nat. Genet. (2006) [Pubmed]
  11. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Witt, H., Luck, W., Hennies, H.C., Classen, M., Kage, A., Lass, U., Landt, O., Becker, M. Nat. Genet. (2000) [Pubmed]
  12. Autophagic cell death of pancreatic acinar cells in serine protease inhibitor Kazal type 3-deficient mice. Ohmuraya, M., Hirota, M., Araki, M., Mizushima, N., Matsui, M., Mizumoto, T., Haruna, K., Kume, S., Takeya, M., Ogawa, M., Araki, K., Yamamura, K. Gastroenterology (2005) [Pubmed]
  13. Tropical calcific pancreatitis: strong association with SPINK1 trypsin inhibitor mutations. Bhatia, E., Choudhuri, G., Sikora, S.S., Landt, O., Kage, A., Becker, M., Witt, H. Gastroenterology (2002) [Pubmed]
  14. Pancreatic secretory trypsin inhibitor in gastrointestinal mucosa and gastric juice. Freeman, T.C., Playford, R.J., Quinn, C., Beardshall, K., Poulter, L., Young, J., Calam, J. Gut (1990) [Pubmed]
  15. Serum tumour-associated trypsin inhibitor (TATI) and renal function. Tramonti, G., Donadio, C., Ferdeghini, M., Annichiarico, C., Norpoth, M., Bianchi, R., Bianchi, C. Scand. J. Clin. Lab. Invest. (1996) [Pubmed]
  16. A mutant trypsin-like enzyme from Streptomyces fradiae, created by site-directed mutagenesis, improves affinity chromatography for protein trypsin inhibitors. Katoh, T., Kikuchi, N., Nagata, K., Yoshida, N. Appl. Microbiol. Biotechnol. (1996) [Pubmed]
  17. Concentrations of pancreatic secretory trypsin inhibitor (PSTI), acute phase proteins, and neopterin in Crohn's disease. Comparison with clinical disease activity and endoscopical findings. Halme, L., von Smitten, K., Stenman, S., Turpeinen, U., Stenman, U.H. Scand. J. Clin. Lab. Invest. (1993) [Pubmed]
  18. Posterior sub-Tenon's capsule triamcinolone injection combined with focal laser photocoagulation for diabetic macular edema. Tunc, M., Onder, H.I., Kaya, M. Ophthalmology (2005) [Pubmed]
  19. Mutation analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, the cationic trypsinogen (PRSS1) gene, and the serine protease inhibitor, Kazal type 1 (SPINK1) gene in patients with alcoholic chronic pancreatitis. Perri, F., Piepoli, A., Stanziale, P., Merla, A., Zelante, L., Andriulli, A. Eur. J. Hum. Genet. (2003) [Pubmed]
  20. Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis. Le Maréchal, C., Chen, J.M., Le Gall, C., Plessis, G., Chipponi, J., Chuzhanova, N.A., Raguénès, O., Férec, C. Hum. Mutat. (2004) [Pubmed]
  21. SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in subjects from the Indian subcontinent. Hassan, Z., Mohan, V., Ali, L., Allotey, R., Barakat, K., Faruque, M.O., Deepa, R., McDermott, M.F., Jackson, A.E., Cassell, P., Curtis, D., Gelding, S.V., Vijayaravaghan, S., Gyr, N., Whitcomb, D.C., Khan, A.K., Hitman, G.A. Am. J. Hum. Genet. (2002) [Pubmed]
  22. Human mesotrypsin is a unique digestive protease specialized for the degradation of trypsin inhibitors. Szmola, R., Kukor, Z., Sahin-Tóth, M. J. Biol. Chem. (2003) [Pubmed]
  23. The course of genetically determined chronic pancreatitis. Keim, V., Witt, H., Bauer, N., Bodeker, H., Rosendahl, J., Teich, N., Mossner, J. JOP (2003) [Pubmed]
  24. Chronic parotitis: not another SPINKosis. Gundling, F., Reitmeier, F., Tannapfel, A., Schutz, A., Weber, A., Ussmuller, J., Keim, V., Mossner, J., Teich, N. Digestive diseases (Basel, Switzerland) (2004) [Pubmed]
  25. Cyst fluid of ovarian cancer patients contains high concentrations of trypsinogen-2. Koivunen, E., Itkonen, O., Halila, H., Stenman, U.H. Cancer Res. (1990) [Pubmed]
  26. Identification of genes up-regulated in urothelial tumors: the 67-kd laminin receptor and tumor-associated trypsin inhibitor. Diggle, C.P., Cruickshank, S., Olsburgh, J.D., Pellegrin, S., Smith, B., Banks, R.E., Selby, P.J., Knowles, M.A., Southgate, J., Harnden, P. Am. J. Pathol. (2003) [Pubmed]
  27. Chronic ethanol consumption induces gene expression of pancreatic monitor peptide, but not SPINK1/PSTI-56, in rats. Li, H.S., Deng, X.Y., Thompson, B.S., Zhang, J.Y., Wood, P.G., Eagon, P.K., Whitcomb, D.C. Pancreas (2001) [Pubmed]
  28. Three-dimensional structure of the complexes between bovine chymotrypsinogen A and two recombinant variants of human pancreatic secretory trypsin inhibitor (Kazal-type). Hecht, H.J., Szardenings, M., Collins, J., Schomburg, D. J. Mol. Biol. (1991) [Pubmed]
  29. High tissue expression of tumour-associated trypsin inhibitor (TATI) associates with a more favourable prognosis in gastric cancer. Wiksten, J.P., Lundin, J., Nordling, S., Kokkola, A., Stenman, U.H., Haglund, C. Histopathology (2005) [Pubmed]
  30. Interactions of pancreatic secretory trypsin inhibitor in small intestinal juice: its hydrolysis and protection by intraluminal factors. Freeman, T.C., Davies, R., Calam, J. Clin. Chim. Acta (1990) [Pubmed]
  31. Identification of novel pancreas-specific regulatory sequences in the promoter region of human pancreatic secretory trypsin inhibitor gene. Yasuda, T., Yasuda, T., Ohmachi, Y., Katsuki, M., Yokoyama, M., Murata, A., Monden, M., Matsubara, K. J. Biol. Chem. (1998) [Pubmed]
  32. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Weiss, F.U., Simon, P., Bogdanova, N., Mayerle, J., Dworniczak, B., Horst, J., Lerch, M.M. Gut (2005) [Pubmed]
  33. Association of rare SPINK1 gene mutation with another base substitution in chronic pancreatitis patients. Kalinin, V.N., Kaifi, J.T., Schwarzenbach, H., Sergeyev, A.S., Link, B.C., Bogoevski, D., Vashist, Y., Izbicki, J.R., Yekebas, E.F. World J. Gastroenterol. (2006) [Pubmed]
  34. Expression of pancreatic secretory trypsin inhibitor gene in neoplastic tissues. Tomita, N., Horii, A., Yamamoto, T., Ogawa, M., Mori, T., Matsubara, K. FEBS Lett. (1987) [Pubmed]
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