Copy number variations in chronic pancreatitis

In 1996, shortly after a locus for hereditary pancreatitis had been mapped to chromosome 7q35, an apparent gain-of-function missense mutation, p.R122H, in the cationic trypsinogen gene (PRSS1) was identified. Thereafter, the search for chronic pancreatitis-associated genetic factors has been largely focused on one form of genetic variation, namely, single nucleotide substitutions (SNSs). Only very recently has another type of genetic variation - copy number variations (CNVs) - been found to cause the disease. First, we identified duplication and triplication of an approximately 605 kb segment on chromosome 7q35 in French white patients with hereditary or idiopathic chronic pancreatitis. These alterations increased the copy number of PRSS1 as well as PRSS2, which encodes anionic trypsinogen. Second, we characterized a hybrid trypsinogen gene, in which exons 1 and 2 were derived from PRSS2 and exons 3 to 5 from PRSS1. Interestingly, this hybrid gene had two independent gain-of-function effects: increased trypsinogen gene copy number and it contained the p.N29I pancreatitis-causing missense mutation. Lastly, we identified two loss-of-function copy number mutations (deletions) in the SPINK1 gene, which encodes pancreatic secretory trypsin inhibitor (PSTI). Particularly, in one family with chronic pancreatitis, deletion of the complete SPINK1 gene was co-inherited with a CFTR missense mutation (p.L997F), revealing another layer of complexity between CNV and SNS interactions in the determination of a given disease phenotype. These findings represent a further demonstration of how studies of CNVs have altered the landscape of genetic research in the past few years and offer a fresh glimpse into the exciting realm of human CNVs.