6.4 A Chronic-Pancreatitis-Associated CTRC Variant...
Mesotrypsinogen（encoded by PRSS3）is the third and last functional trypsinogen isoform（Chen et al.2013b）.PRSS1 and PRSS2 are both located on chromosome 7q35 whereas PRSS3 was translocated to chromosome 9p13 some 15-20 million years ago（Rowen et al.2005）.This translocation liberated PRSS3 from its shared functional or regulatory constraints exerted at the original locus，reflected by the dramatic differences between mesotrypsinogen and the cationic and anionic trypsinogens in terms of their expression levels in the pancreas and their biochemical properties（Nyaruhucha et al.1997；Rinderknecht et al.1984；Szmola et al.2003）.Remarkably，virtually all the unique properties of mesotrypsin may be attributed to an ancestral mutation that replaced a glycine residue at position 198 with an arginine（i.e.，the amino acid position 198 is arginine in mesotrypsinogen but glycine in both cationic and anionic trypsinogens）；the mutation of Arg198 in mesotrypsin back to Gly converted mesotrypsin to a normal trypsin（Szmola et al.2003）.Therefore，p.Glyl98Arg represents part of the evolutionary signature of mesotrypsinogen.(https://www.daowen.com)
A CTRC variant，p.Gly2l4Arg，was identified in a subject with chronic pancreatitis in Slovakia（Szabó et al.2015a）.Biochemical characterization demonstrated that the mutant CTRC had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovineβ-casein or the natural CTRC substrates human cationic trypsinogen and procarboxypeptidase Al.Consequently，the CTRC p.Gly2l4Arg mutation was considered to be analogous to the evolutionary p.Glyl98Arg mutation in human mesotrypsin，which rendered this trypsin isoform resistant to proteinaceous inhibitors and conferred its ability to cleave these inhibitors（Szabó et al.2015a）.This finding nicely illustrates“how the same natural mutation in homologous pancreatic serine proteases can evolve a new physiological role or lead to pathology，determined by the biological context of protease function”（Szabó et al.2015a）.