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Trypsinogen and other digestive zymogens are synthesised in the acinar cells of the exocrine pancreas. The serine protease inhibitor Kazal-type 1 (SPINK1), more commonly known as pancreatic secretory trypsin inhibitor (PSTI), is also synthesised in these cells. Because of its ability to inhibit approximately 20% of the potential trypsin activity within the pancreas, PSTI has long been thought to be one of the defensive mechanisms against a prematurely activated trypsin-driven digestive zymogen activation cascade leading to pancreatic autodigestion.1 Given that gain-of-function missense mutations in the cationic trypsinogen gene (PRSS1) have been found to cause hereditary pancreatitis,2 3 SPINK1 was analysed by a candidate gene approach in 2000,4 5 and, since then, some 40 variants have been reported. In particular, 14 variants, all of which were exclusively found in chronic pancreatitis patients but not in controls, are clear or experimentally demonstrated loss-of-function mutations (table 1).5–17 These findings support the hypothesis that PSTI is a key negative regulator of prematurely activated trypsin within the pancreatic acinar cells.
Two key questions, among others, have arisen from the association of SPINK1 variations with chronic pancreatitis. The first concerns the role of PSTI (ie, disease causing vs disease modifying) in the aetiology of the disease. We suggested that this question be discussed in the context of specific variations.6 Thus, mutations resulting in a complete functional loss of the involved alleles and that are found in cases with familial or hereditary pancreatitis—exemplified by the c.27delC mutation …
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