LETTER TO JMG Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis


Pancreatitis is a global health care problem with varied aetiologies. Alcoholism is responsible in the majority of patients while other causes, such as heredity, gallstones, hyperlipidaemia, hypercalcaemia, and idiopathic pancreatitis, are relatively rare. 2 The causal factor in 20-30% of such cases is still not known and they fall into the category of idiopathic chronic pancreatitis (ICP). 2 Although the exact pathogenesis is not clear, autodigestion secondary to aberrant intraductal activation of zymogens by trypsin is a primary common event. A genetic basis was reported in 1996 by familial linkage analysis and confirmed by detection of missense mutations, namely R122H and N29I, in the cationic trypsinogen gene (PRSS1) in hereditary pancreatitis (HP) patients. 7 HP is a relatively rare autosomal dominant disorder where typical acute attacks in childhood and frequent progression to chronic pancreatitis are seen to occur in two or more subjects or generations. Subsequent studies from other parts of the world have also reported the two common mutations 9 and other mutations in the PRSS1 gene in both HP and ICP patients. 10 11 However, only about 60% cases of HP and less than 20% with a diagnosis of ICP have a mutated PRSS1 gene, suggesting the presence of other candidate genes. Pancreatic secretory trypsin inhibitor (PSTI/SPINK1) is a potent protease inhibitor and thought to be a major protective mechanism preventing inappropriate activation of pancreatic digestive enzyme cascade by inhibiting up to 20% of potential trypsin activity. The human SPINK1 gene on chromosome 5 is approximately 7.5 kb long with four exons and codes for a product of 79 amino acids including a signal peptide of 23 amino acids. Since the inhibitor molecule provides the first line of defence against prematurely activated trypsinogen within the pancreas, it has recently attracted attention as a possible cause of chronic pancreatitis. A causal role for the SPINK1 gene was ruled out initially, but a significant correlation between mutated SPINK1 and chronic pancreatitis was first shown by Witt et al and subsequently supported by Pfutzer et al. A founder mutation N34S was detected in the majority of patients, while another variant P55S was identified in only a few. In contrast, two recent analyses have reported a very low prevalence of SPINK1 gene mutations. Five (three with N34S) out of 32 Japanese patients and only two (one with N34S) out of 20 German adult patients with idiopathic chronic pancreatitis had a mutated SPINK1 gene. Tropical calcific pancreatitis (TCP) is an idiopathic, juvenile, non-alcoholic form of chronic pancreatitis widely prevalent in several tropical countries, and fibrocalculous pancreatic diabetes (FCPD) is a form of diabetes secondary to TCP. The disease differs from alcoholic pancreatitis by a much younger age of onset, pancreatic calcification, a high incidence of insulin dependent but ketosis resistant diabetes mellitus, and an exceptionally high incidence of pancreatic cancer. Although two studies have reported a lack of common mutations in PRSS1 in FCPD patients, neither of them analysed the whole PRSS1 gene. 21 The genetic basis of TCP without diabetes has also not been fully investigated. A recent study based on analysis of eight FCPD and four TCP patients (without diabetes) has shown that SPINK1 mutations are associated with FCPD but not with TCP. We have analysed 68 clinically and radiologically confirmed TCP patients (24 FCPD and 44 TCP patients without diabetes mellitus) for mutations in the cationic trypsinogen and pancreatic secretory trypsin inhibitor genes in an attempt to understand their respective roles in the pathogenesis of tropical calcific pancreatitis in our population.

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@inproceedings{Chandak2002LETTERTJ, title={LETTER TO JMG Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis}, author={Giriraj Ratan Chandak and Mohammed M. Idris and Duvvur Nageshwar Reddy and Seema Bhaskar and Parupudi V. J. Sriram and Lalji Singh}, year={2002} }