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Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are significantly associated with tropical calcific pancreatitis
  1. G R Chandak1,
  2. M M Idris1,
  3. D N Reddy2,
  4. S Bhaskar1,
  5. P V J Sriram2,
  6. L Singh1
  1. 1Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India
  2. 2Asian Institute of Gastroenterology, Medinova Diagnostic Services, Punjagutta, Hyderabad 500 082, India
  1. Correspondence to:
 Dr G R Chandak, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India;
 chandakgrc{at}gene.ccmbindia.org

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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.1,2 The causal factor in 20-30% of such cases is still not known and they fall into the category of idiopathic chronic pancreatitis (ICP).1,2 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 analysis3–5 and confirmed by detection of missense mutations, namely R122H and N29I, in the cationic trypsinogen gene (PRSS1) in hereditary pancreatitis (HP) patients.6,7 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 mutations8,9 and other mutations in the PRSS1 gene in both HP and ICP patients.8,10,11 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.12 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.13 Since the inhibitor molecule provides the first line of defence against prematurely activated trypsinogen within the pancreas, it has recently …

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