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Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 1999 Mar;36(3):228–232.

Mutations in the cationic trypsinogen gene and evidence for genetic heterogeneity in hereditary pancreatitis

C Ferec 1, O Raguenes 1, R Salomon 1, C Roche 1, J Bernard 1, M Guillot 1, I Quere 1, C Faure 1, B Mercier 1, M Audrezet 1, P Guillausseau 1, C Dupont 1, A Munnich 1, J Bignon 1, L Le Bodic 1
PMCID: PMC1734328  PMID: 10204851

Abstract

Hereditary pancreatitis (HP) is a rare inherited disorder, characterised by recurrent episodes of pancreatitis often beginning in early childhood. The mode of inheritance suggests an autosomal dominant trait with incomplete penetrance. The gene, or at least one of the genes, responsible for hereditary pancreatitis has been mapped to the long arm of chromosome 7 and a missense mutation, an arginine to histidine substitution at residue 117 in the trypsinogen cationic gene (try4) has been shown to segregate with the HP phenotype. The aim of this work was to investigate the molecular basis of hereditary pancreatitis. This study was performed on 14 HP families. The five exons of the trypsinogen cationic gene were studied using a specific gene amplification assay combined with denaturing gradient gel electrophoresis (DGGE). The present paper describes three novel mutations, namely K23R and N29I and a deletion -28delTCC in the promoter region. We also found a polymorphism in exon 4, D162D. In eight of these families we found a mutation which segregates with the disease. A segregation analysis using microsatellite markers carried out on the other families suggests genetic heterogeneity in at least one of them. Our findings confirm the implication of the cationic trypsinogen gene in HP and highlight allelic diversity associated with this phenotype. We also show that the pattern of inheritance of HP is probably complex and that other genes may be involved in this genetic disease.


Keywords: hereditary pancreatitis; mutation analysis; cationic trypsinogen

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Selected References

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  1. Antonarakis S. E. Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat. 1998;11(1):1–3. doi: 10.1002/(SICI)1098-1004(1998)11:1<1::AID-HUMU1>3.0.CO;2-O. [DOI] [PubMed] [Google Scholar]
  2. COMFORT M. W., STEINBERG A. G. Pedigree of a family with hereditary chronic relapsing pancreatitis. Gastroenterology. 1952 May;21(1):54–63. [PubMed] [Google Scholar]
  3. Férec C., Audrezet M. P., Mercier B., Guillermit H., Moullier P., Quere I., Verlingue C. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet. 1992 Jun;1(3):188–191. doi: 10.1038/ng0692-188. [DOI] [PubMed] [Google Scholar]
  4. Gorry M. C., Gabbaizedeh D., Furey W., Gates L. K., Jr, Preston R. A., Aston C. E., Zhang Y., Ulrich C., Ehrlich G. D., Whitcomb D. C. Mutations in the cationic trypsinogen gene are associated with recurrent acute and chronic pancreatitis. Gastroenterology. 1997 Oct;113(4):1063–1068. doi: 10.1053/gast.1997.v113.pm9322498. [DOI] [PubMed] [Google Scholar]
  5. Laskowski M., Jr, Kato I. Protein inhibitors of proteinases. Annu Rev Biochem. 1980;49:593–626. doi: 10.1146/annurev.bi.49.070180.003113. [DOI] [PubMed] [Google Scholar]
  6. Le Bodic L., Bignon J. D., Raguénès O., Mercier B., Georgelin T., Schnee M., Soulard F., Gagne K., Bonneville F., Muller J. Y. The hereditary pancreatitis gene maps to long arm of chromosome 7. Hum Mol Genet. 1996 Apr;5(4):549–554. doi: 10.1093/hmg/5.4.549. [DOI] [PubMed] [Google Scholar]
  7. Lerman L. S., Silverstein K. Computational simulation of DNA melting and its application to denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:482–501. doi: 10.1016/0076-6879(87)55032-7. [DOI] [PubMed] [Google Scholar]
  8. Myers R. M., Maniatis T., Lerman L. S. Detection and localization of single base changes by denaturing gradient gel electrophoresis. Methods Enzymol. 1987;155:501–527. doi: 10.1016/0076-6879(87)55033-9. [DOI] [PubMed] [Google Scholar]
  9. Perrault J. Hereditary pancreatitis. Gastroenterol Clin North Am. 1994 Dec;23(4):743–752. [PubMed] [Google Scholar]
  10. Rowen L., Koop B. F., Hood L. The complete 685-kilobase DNA sequence of the human beta T cell receptor locus. Science. 1996 Jun 21;272(5269):1755–1762. doi: 10.1126/science.272.5269.1755. [DOI] [PubMed] [Google Scholar]
  11. Sato T., Saito Y. Familial chronic pancreatitis associated with pancreatic lithiasis. Am J Surg. 1974 May;127(5):511–517. doi: 10.1016/0002-9610(74)90307-9. [DOI] [PubMed] [Google Scholar]
  12. Whitcomb D. C., Gorry M. C., Preston R. A., Furey W., Sossenheimer M. J., Ulrich C. D., Martin S. P., Gates L. K., Jr, Amann S. T., Toskes P. P. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996 Oct;14(2):141–145. doi: 10.1038/ng1096-141. [DOI] [PubMed] [Google Scholar]
  13. Yamamoto T., Nakamura Y., Nishide J., Emi M., Ogawa M., Mori T., Matsubara K. Molecular cloning and nucleotide sequence of human pancreatic secretory trypsin inhibitor (PSTI) cDNA. Biochem Biophys Res Commun. 1985 Oct 30;132(2):605–612. doi: 10.1016/0006-291x(85)91176-3. [DOI] [PubMed] [Google Scholar]

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