SPINK1 mutations and phenotypic expression in patients with pancreatitis associated with trypsinogen mutations

Hereditary pancreatitis (HP) is an inborn disorder which leads to recurrent episodes of pancreatitis in children and young adults and is associated with exocrine pancreatic insufficiency and secondary diabetes. 1- 3 Several germline mutations in the cationic trypsinogen (PRSS1) gene have been found to be associated with the disease phenotype, the most common of which are the R122H, N29I, and A16V mutations. 4- 6 The clinical significance of various other PRSS1 mutations that have been reported from isolated patients or single families is as yet unclear. 7, 8 In many families with HP some relatives who carry the mutation relevant to the disease will never develop pancreatitis. [...]mutations in the gene encoding the most abundant physiological inhibitor of digestive proteases, the serine protease inhibitor Kazal type 1 (SPINK1), also referred to as pancreatic secretory trypsin inhibitor (PSTI), have been found to be associated with idiopathic chronic pancreatitis. 10, 11 Although the biochemical role of SPINK1 in the onset of disease remains to be elucidated, SPINK1 mutations are clearly involved in the pathogenesis of different varieties of pancreatitis 12- 14 including alcohol induced pancreatitis. 15 One possible explanation for this association is that trypsin seems to be critically involved in the premature activation of other digestive proteases 16, 17 and SPINK1 is its most potent endogenous inhibitor.