Trypsinogen Gene Mutations in Patients with Chronic or Recurrent Acute Pancreatitis

Abstract

Three-point mutations (R117H, N211, A16V) within the cationic trypsinogen gene have been identified in patients with hereditary pancreatitis (HP). A genetic background has also been discussed for idiopathic juvenile chronic pancreatitis (IJCP), which closely mimicks the clinical pattern of HP, and alcoholic chronic pancreatitis because only a small number of heavy drinkers develop pancreatitis. This prompted us to screen 104 patients in our well-defined pancreatitis cohort for the currently known cationic trypsinogen gene mutations. The R117H mutation was detected in seven patients (six patients of two clinically classified HP families, one patient with clinically classified IJCP) and the A16V mutation in one IJCP patient. No cationic trypsinogen gene mutations were found in the remaining 96 patients with chronic and recurrent acute pancreatitis of various etiologies. Our results demonstrate the need for genetic testing to exclude HP, particularly in the presence of an atypical or unknown family history. In addition, cationic trypsinogen gene mutations are no predisposing factor in patients with chronic and recurrent acute pancreatitis of different etiologies.

The Natural History of Alcoholic Chronic Pancreatitis.

“…9) (10). The impact of the ill-defined predisposing factors (environmental and/or genetic) on the long-term course of ACPneeds further investigations (20).…”

“…In fact, 16 patients of our group classified as IJCP have been tested recently for trypsinogen gene mutations and 2 of the youngest patients with onset of disease below the age of 10 ( Fig. 3) tested positive (one for R 117H, one for A 16 V) while the remaing patients were negative (20). Progressive exocrine and endocrine insufficiency are typically observed both in IJCP and ISCP but compared to ACP, pancreatic dysfunction develops with a marked delay in relation to onset of the disease (18,19).Furthermore, recurrent episodes of pancreatitis occur over a prolonged period of time in IJCP in contrast to ACPand ISCP.…”

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

“…Initially, the mutation was reported in 10% of chronic pancreatitis patients without a family history. In subsequent European and North American studies, only a minority of patients with idiopathic chronic pancreatitis carried the PRSS1-A16V mutation [Chen et al, 1999bPfützer and Whitcomb, 1999;Howes et al, 2001Howes et al, , 2004Truninger et al, 2001;Teich et al, 2002]. This discrepancy might be explained by the strict selection of pediatric patients in the initial report, which decreased the effect of environmental risk factors of chronic pancreatitis to a large extent [Witt et al, 1999].…”

Molecular pathology and evolutionary and physiological implications of pancreatitis-associated cationic trypsinogen mutations

“…80% (Bell et al 1998;Creighton et al 2000;Dasouki et al 1998;Elitsur et al 1998;Ferec et al 1999;Gress et al 1998;Howes et al 2001;Nishimori et al 1999;Teich et al 1999;Pandya et al 1997Pandya et al -1998Truninger et al 2001;Weber et al 1999;Whitcomb et al 1996). Several lines of good evidence, particularly that the R122 residue was identified to be the primary autolysis site of human cationic trypsin (Gaboriaud et al 1996), and that histidine is not cleaved by trypsin, lend strong support to the theory that the R122H mutation would disrupt an important "fail-safe" or "self-destruct" defensive mechanism against premature trypsin activation within the pancreas, which could lead to autodigestion of the pancreas itself (Whitcomb et al 1996).…”