Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
Pancreatitis is considered to be an autodigestive disease due to premature activation of trypsinogen inside the pancreas. Its genetic basis has recently been established with the identification of causal mutations in cationic trypsinogen gene (PRSS1) in patients with hereditary1 and non-hereditary pancreatitis.2 Mutations in other genes such as SPINK1 (encoding pancreatic secretory trypsin inhibitor)3 and cystic fibrosis transmembrane conductance regulator (CFTR)4,5 genes have also been associated with the disease. Tropical calcific pancreatitis is a type of idiopathic pancreatitis, reported particularly in the tropics. Recently, we and others demonstrated absence of PRSS1 mutations but significant prevalence of the N34S mutation in the SPINK1 gene in these patients.6–8 However, our study raised two important questions: firstly, the exact role of SPINK1 mutations in disease causation as cationic trypsinogen is normal with an intact autolysis site; and secondly, the cause of the disease in the remaining patients negative for both PRSS1 and SPINK1 mutations.
Of the nine members of the human trypsinogen gene family, only PRSS1, PRSS2, and PRSS3 are functional genes coding for cationic, anionic, and meso-trypsinogen isoforms, respectively. The anionic form accounts for about one third of the total trypsins in pancreatic juice. We investigated whether mutations in the anionic trypsinogen gene may contribute to the pathogenesis of tropical calcific pancreatitis. Of 20 mutations reported to date in the PRSS1 gene, 17 are clustered in exons 2 and 3 only. The remaining three are in the promoter region but reported in isolated patients. Hence we initially screened exons 2 and 3 of the anionic trypsinogen gene in 68 well characterised Indian patients with tropical calcific pancreatitis.6 Subsequently, we also sequenced the promoter, complete coding region, and the flanking region in an attempt to look for any novel mutation.
Owing to the extremely high sequence homology between PRSS1 and PRSS2, a nested polymerase chain reaction (PCR) was used to ensure specificity. The primers were selected from the published study of Chen and colleagues9 and all of the exons of PRSS2 were PCR amplified, purified, and sequenced on both alleles using internal sequencing primers and the Big Dye terminator cycle sequencing approach. However, we did not find any of the reported or any novel mutations in the coding region or in the splice site junctions, except a synonymous polymorphism A90A (GCA>GCG) in exon 3 of the anionic trypsinogen gene. This variation was observed in both the heterozygous and homozygous states with a mutant allele frequency of 0.58 (9 AA, 20 GG, and 39 AG) and was comparable with 0.61 in 50 controls (7 AA, 18 GG and 25 AG) analysed.
Our results thus exclude any association of mutations in the anionic trypsinogen gene in tropical calcific pancreatitis and suggest a role for other genetic or non-genetic factors in the pathogenesis of the disease. Screening of genes such as CFTR may explain the disease in the remaining patients. It also affirms the importance of the N34S mutation in SPINK1 as the major genetic factor for this type of pancreatitis.