Interaction between Trypsinogen Isoforms in Genetically Determined Pancreatitis: Mutation E79K in Cationic Trypsin (PRSS1) Causes Increased Transactivation of Anionic Trypsinogen (PRSS2)

Niels Teich, Cédric Le Maréchal, Z. Kukor, Karel Caca, Helmut Witzigmann, Jian Min Chen, Miklós Tóth, Joachim Mössner, Volker Keim, Claude Férec, Miklós Sahin-Tóth

Research output: Contribution to journalArticle

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Abstract

The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis-associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild-type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. Furthermore, in contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N291 had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis.

Original languageEnglish
Pages (from-to)22-31
Number of pages10
JournalHuman Mutation
Volume23
Issue number1
DOIs
Publication statusPublished - 2004

Fingerprint

Trypsinogen
Pancreatitis
Trypsin
Transcriptional Activation
Protein Isoforms
Mutation
Chronic Pancreatitis
Kazal Pancreatic Trypsin Inhibitor
Autolysis
Genes
Pancreas
Peptide Hydrolases

Keywords

  • Anionic trypsinogen
  • Cationic trypsinogen
  • Chronic pancreatitis
  • Hereditary pancreatitis
  • PRSS1
  • PRSS2
  • SPINK1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Interaction between Trypsinogen Isoforms in Genetically Determined Pancreatitis : Mutation E79K in Cationic Trypsin (PRSS1) Causes Increased Transactivation of Anionic Trypsinogen (PRSS2). / Teich, Niels; Le Maréchal, Cédric; Kukor, Z.; Caca, Karel; Witzigmann, Helmut; Chen, Jian Min; Tóth, Miklós; Mössner, Joachim; Keim, Volker; Férec, Claude; Sahin-Tóth, Miklós.

In: Human Mutation, Vol. 23, No. 1, 2004, p. 22-31.

Research output: Contribution to journalArticle

Teich, Niels ; Le Maréchal, Cédric ; Kukor, Z. ; Caca, Karel ; Witzigmann, Helmut ; Chen, Jian Min ; Tóth, Miklós ; Mössner, Joachim ; Keim, Volker ; Férec, Claude ; Sahin-Tóth, Miklós. / Interaction between Trypsinogen Isoforms in Genetically Determined Pancreatitis : Mutation E79K in Cationic Trypsin (PRSS1) Causes Increased Transactivation of Anionic Trypsinogen (PRSS2). In: Human Mutation. 2004 ; Vol. 23, No. 1. pp. 22-31.
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abstract = "The human pancreas secretes two major trypsinogen isoforms, cationic and anionic trypsinogen. To date, 19 genetic variants have been identified in the cationic trypsinogen gene (PRSS1) of patients with hereditary, familial, or sporadic chronic pancreatitis. A common feature of cationic trypsinogen mutants studied so far is an increased propensity for autocatalytic activation (autoactivation). This is thought to lead to premature intrapancreatic digestive protease activation. In contrast, no pancreatitis-associated mutations have been found in the anionic trypsinogen gene (PRSS2), suggesting that this isoform might play a relatively unimportant role in pancreatitis. To challenge this notion, here we describe the unique properties of the E79K cationic trypsinogen mutation (c.235G>A), which was identified in three European families affected by sporadic or familial pancreatitis cases. In vitro analysis of recombinant wild-type and mutant enzymes revealed that catalytic activity of E79K trypsin was normal, and its inhibition by pancreatic secretory trypsin inhibitor was unaffected. Although the E79K mutation introduces a potential new tryptic cleavage site, autocatalytic degradation (autolysis) of E79K-trypsin was also unchanged. Furthermore, in contrast to previously characterized disease-causing mutations, E79K markedly inhibited autoactivation of cationic trypsinogen. Remarkably, however, E79K trypsin activated anionic trypsinogen two-fold better than wild-type cationic trypsin did, while the common pancreatitis-associated mutants R122H or N291 had no such effect. The observations not only suggest a novel mechanism of action for pancreatitis-associated trypsinogen mutations, but also highlight the importance of interactions between the two major trypsinogen isoforms in the development of genetically determined chronic pancreatitis.",
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