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A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis


Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1)1 and the pancreatic secretory trypsin inhibitor (SPINK1)2 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 × 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.

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Figure 1: Haploview graph of the pairwise linkage disequilibrium (LD) among 17 SNPs around the PRSS2 locus.
Figure 2: Ribbon diagram of human cationic trypsin (Protein Data Bank file 1TRN) showing Gly191 (chymotrypsin numbering (chymo#) Gly187) mutated to Arg (in red).
Figure 3: Activation of wild-type and Arg191 mutant anionic trypsinogens.
Figure 4: Mass spectrometric analysis of trypsinogen activation.

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We thank the many patients who have participated in this study. We are especially grateful to V. Kielstein (Magdeburg, Germany) and L. Klomp (University Medical Center Utrecht, Utrecht, The Netherlands) for providing blood samples from control subjects. 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.).

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Correspondence to Heiko Witt.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Distribution of G191R in the different patient groups. (PDF 49 kb)

Supplementary Table 2

Characteristics of patients. (PDF 59 kb)

Supplementary Methods (PDF 82 kb)

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Witt, H., Sahin-Tóth, M., Landt, O. et al. A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis. Nat Genet 38, 668–673 (2006).

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