Trypsinogen Copy Number Mutations in Patients With Idiopathic Chronic Pancreatitis

Background & Aims: We have recently reported that the triplication of a ∼605 kilobase segment containing the PRSS1 (encoding cationic trypsinogen) and PRSS2 (encoding anionic trypsinogen) genes causes hereditary pancreatitis. Here we went further to investigate whether this copy number mutation could account for some unidentified French white patients with idiopathic chronic pancreatitis (ICP) or familial chronic pancreatitis (FCP) as well as Indian patients with tropical calcific pancreatitis (TCP). Methods: Patients and controls were screened by means of previously described quantitative fluorescent multiplex polymerase chain reaction and/or genotyping of the microsatellite marker rs3222967. Results: The ∼605 kilobase triplication and a novel duplication (confirmed by fluorescence in situ hybridization) of the trypsinogen locus were detected in 10 and 2 of 202 ICP patients, respectively (age of disease onset, ≤20 years) but were absent in 282 French controls. In addition, the duplication mutation was found in 2 of 1044 ICP patients whose age of disease onset was >20 years. However, the 2 trypsinogen copy number mutations were observed in neither 103 FCP patients nor 268 Indian TCP patients. Conclusions: Our findings revealed the molecular basis of 6% of the young ICP patients and further demonstrated that chronic pancreatitis is a genomic disorder. Our findings also add to the mounting evidence showing that trypsinogen gene mutations do not appear to play an important role in the pathogenesis of TCP in the Indian population. Finally, a dividend of this study is that we have provided convincing evidence to show that all 5 previously described copy number variations involving PRSS1 or/and PRSS2 are artifacts.

Abbreviations used in this paper: CNM, copy number mutation, CNV, copy number variation, FCP, familial chronic pancreatitis, FISH, fluorescence in situ hybridization, ICP, idiopathic chronic pancreatitis, kb, kilobase, QFM-PCR, quantitative fluorescent multiplex polymerase chain reaction, TCP, tropical calcific pancreatitis