Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

Abstract

Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G > A (p.R122 H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In the following years, further mutations of this gene were discovered in patients with hereditary or idiopathic chronic pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo. The clinical presentation is highly variable, but most affected mutation carriers have relatively mild disease. In this review, we summarize the current knowledge on trypsinogen mutations and their role in pancreatic diseases.

Figure 1

Linear map of pancreatitis-associated mutations within the primary structure of the human cationic trypsinogen. The 18 amino-acid positions affected by the pancreatitis-associated PRSS1 variants (see Table 1) are denoted by asterisks. The positions of the most frequent N29I and R122H mutations are indicated. The gray call-out demonstrates the sequence of the trypsinogen activation peptide (TAP) and the mutations found in this region. The highly conserved tetra-aspartate motif in the activation peptide is underlined.