MUTATIONS IN THE CATIONIC TRYPSINOGEN GENE ARE ASSOCIATED WITH RECURRENT ACUTE AND CHRONIC-PANCREATITIS

Background & Aims: We recently identified a single R117H mutation in t he cationic trypsinogen gene in several kindreds with an inherited for m of acute and chronic pancreatitis (HP1), providing strong evidence t hat trypsin plays a central role in premature zymogen activation and p ancreatitis, However, not all families studied have this mutation, The aim of this study was to determine the disease-causing mutation in ki ndreds with hereditary pancreatitis that lack the previously identifie d mutation. Methods: Clinical features of the HP1 kindreds were compar ed with those of the new kindreds (HP2), and genetic linkage analysis, screening for mutations through DNA sequencing, and screening an unaf fected population were performed. Results: The onset of symptoms was d elayed and hospitalizations were fewer in HP2 compared with HP1(P < 0. 05). Linkage of the disease gene to chromosome 7q35 was established (l ogarithm of the odds, 3.73), Mutational screening identified a single A to T mutation resulting in an asparagine to isoleucine transition mu tation at position 21 (N21I) in cationic trypsinogen. The mutation was absent in 94 unrelated individuals, representing 188 unique chromosom es. Conclusions: The identification of a second mutation in the cation ic trypsinogen gene (HP2) suggests a dominant role of trypsin in prema ture protease activation-mediated forms of acute pancreatitis. The pat hogenesis of hereditary pancreatitis also suggests that chronic pancre atitis may result from recurrent acute pancreatitis.