A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis
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- dc.contributor.author Witt, Heiko
- dc.contributor.author Malats i Riera, Núria
- dc.contributor.author Real, Francisco X.
- dc.contributor.author Férec, Claude
- dc.date.accessioned 2019-01-24T08:52:04Z
- dc.date.available 2019-01-24T08:52:04Z
- dc.date.issued 2006
- dc.description.abstract Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.
- dc.description.sponsorship The initial experiments were supported by the DFG (Wi 2036/1-1). This work was supported by the Sonnenfeld-Stiftung, Berlin, Germany (to H.W.), the US National Institutes of Health (NIH) (grant DK058088 to M.S.-T.), INSERM (Institut National de la Santé et de la Recherche Médicale) and the Programme Hospitalier de Recherche Clinique (grant PHRC R 08-04 to C.F.)
- dc.format.mimetype application/pdf
- dc.identifier.citation Witt H, Sahin-Tóth M, Landt O, Chen JM, Kähne T, Drenth JP et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet. 2006 Jun;38(6):668-73. DOI: 10.1038/ng1797
- dc.identifier.doi http://dx.doi.org/10.1038/ng1797
- dc.identifier.issn 1061-4036
- dc.identifier.uri http://hdl.handle.net/10230/36424
- dc.language.iso eng
- dc.publisher Nature Research
- dc.relation.ispartof Nature Genetics. 2006 Jun;38(6):668-73
- dc.rights © Springer Nature Publishing AG. Witt H, Sahin-Tóth M, Landt O, Chen JM, Kähne T, Drenth JP et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet. 2006 Jun;38(6):668-73. http://dx.doi.org/10.1038/ng1797
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.subject.other Tripsina
- dc.subject.other Tripsinogen
- dc.subject.other Pancreatitis
- dc.subject.other Genètica
- dc.title A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/acceptedVersion