A signal peptide cleavage site mutation in the cationic trypsinogen gene is strongly associated with chronic pancreatitis

Background & Aims: In pancreatitis, a key role has been attributed to the i nappropriate conversion of trypsinogen to trypsin. Recently, two mutations of the cationic trypsinogen gene were found in families with hereditary pan creatitis. This study was conducted to determine the spectrum and frequency of cationic trypsinogen mutations in unrelated patients with idiopathic or hereditary chronic pancreatitis (CP). Methods: DNA samples from 44 unrelat ed children and adolescents with CP (30 patients with idiopathic CP and 14 with hereditary CP) and from 56 family members were investigated. The catio nic trypsinogen gene was screened for mutations by single-strand conformati on polymorphism analysis and DNA sequencing. Results: A mutation in the cat ionic trypsinogen gene was detected in 5 patients: in 2 patients with a fam ily history of CP and in 3 patients with idiopathic CP. In 1 patient the fo rmerly described R122H mutation was detected. In 4 patients a hitherto unkn own mutation was found at the signal peptide cleavage site leading to an al anine to valine exchange in codon 16. The mutations were inherited in all c ases. In 95 unrelated control individuals the A16V mutation was not found. Conclusions: Heterozygosity for the A16V mutation is strongly associated wi th CP. These results indicate that a significant percentage of patients wit h idiopathic CP may have a genetic basis for their disorder; therefore, gen etic testing should be included in the diagnostic evaluation of these patie nts.