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Editor—Hereditary pancreatitis (HP) is an autosomal dominant disease with about 80% penetrance that mainly afflicts white families.1 Although pancreatitis was hypothesised to result from inappropriate activation of pancreatic zymogens by Chiara2 in 1896, and the genetic nature of HP was identified by Comfort et al 3 in 1952, the precise mechanism underlying the pathogenesis of HP has remained a mystery until recently. By familial linkage analysis, a genetic defect was mapped to chromosome 7q35 by Le Bodic et al,4 and independently confirmed by two other groups in 1996.5 6 Soon after, a single G to A mutation resulting in an arginine (R) to histidine (H) substitution (R117H) in the third exon of the cationic trypsinogen gene was identified as being associated with HP by Whitcombet al.7
Trypsinogen is synthesised in the acinar cells of the pancreas and is activated into trypsin upon cleavage of the activation peptide by enterokinase. Trypsin plays a central role in pancreatic exocrine physiology by acting as the trigger enzyme which leads to the activation of all the pancreatic digestive proenzymes as well as trypsinogen itself. When the R117H mutation was identified, Whitcombet al 7 concluded that this mutation did not affect the tertiary structure of trypsin, nor alter its catalytic activity or interfere with trypsin inhibitor binding, since the three dimensional position of R117 was located on the opposite surface of the trypsin molecule to the catalytic and trypsin inhibitor binding sites. They hypothesised instead that the R117H mutation eliminated a “fail safe” mechanism for the inactivation of trypsin by abolishing an important autolytic site. Thus, the stabilised mutant enzyme would disrupt the trypsin activation/inhibition balance and trigger the pancreatic autodigestion process which results in pancreatitis under certain conditions. This model coincided with Chiara's …
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