ELECTRONIC LETTER 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. 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. The clinical significance of various other PRSS1 mutations that have been reported from isolated patients or single families is as yet unclear. 8 In many families with HP some relatives who carry the mutation relevant to the disease will never develop pancreatitis. The prevalence of these healthy carriers varies from between 20% and 30% in families with the common R122H and N29I mutations, 5 and may rise to nearly 80% in families with the A16V mutation. 9 The underlying cause for this variable penetrance remains unknown, but environmental as well as genetic factors might be involved. More recently, 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. 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 including alcohol induced pancreatitis. One possible explanation for this association is that trypsin seems to be critically involved in the premature activation of other digestive proteases 17 and SPINK1 is its most potent endogenous inhibitor. Structural alterations in SPINK1 could thus affect the protease/antiprotease balance within the pancreas and this may be of particular importance in HP where the premature activation of digestive proteases is thought to play a predominant role. 16 We have tested this hypothesis and studied whether SPINK1 mutations (1) segregate with known HP relevant trypsin mutations, (2) if present, aggravate the disease phenotype or increase the prevalence of secondary diabetes, and (3) determine the disease penetrance of HP. We also investigated whether onset of disease in early childhood would aggravate the severity of the clinical course of the disease or prevalence of diabetes.