R116C Mutation of Cationic Trypsinogen in a Turkish Family with Recurrent Pancreatitis Illustrates Genetic Microheterogeneity of Hereditary Pancreatitis

Abstract

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC→CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.

Human cationic trypsinogen (PRSS1) variants and chronic pancreatitis

“…These two heterozygous mutations are found in ϳ90% of hereditary pancreatitis families worldwide, with p.R122H accounting for ϳ65% and p.N29I for ϳ25% of the cases. In the remaining 10% of the cases, PRSS1 mutations p.A16V, p.D21A, p.D22G, p.K23R, p.K23_I24insIDK, p.N29T, p.V39A, p.R116C, and p.R122C were identified, always in the heterozygous state (2,12,22,28,40,48,55,57,65,67). Mutations p.D21A, p.D22G, p.K23R, p.K23_I24insIDK, and p.V39A were found only in a single family each.…”

“…Screening of various patient populations with sporadic idiopathic chronic pancreatitis has led to the identification of a large number of rare missense variants (4,7,14,23,30,35,42,55,58). The clinical significance of such variants has been unclear because their low frequency did not allow statistical determination of genetic association with pancreatitis.…”

Genetics of endocrine and exocrine diseases of the pancreas

“…Figure 1 and Suppl. should result in a fully active, two-chain trypsin [55,67], whereas cleavage after Lys194 causes inactivation [92,101]. Ctrc caused a small shift of the T7 trypsinogen band, suggesting cleavage of the activation peptide ( Figure 10B, right panel).…”

“…These two heterozygous mutations are found in ϳ90% of hereditary pancreatitis families worldwide, with p.R122H accounting for ϳ65% and p.N29I for ϳ25% of the cases. In the remaining 10% of the cases, PRSS1 mutations p.A16V, p.D21A, p.D22G, p.K23R, p.K23_I24insIDK, p.N29T, p.V39A, p.R116C, and p.R122C were identified, always in the heterozygous state (2,12,22,28,40,48,55,57,65,67). Mutations p.D21A, p.D22G, p.K23R, p.K23_I24insIDK, and p.V39A were found only in a single family each.…”

“…Screening of various patient populations with sporadic idiopathic chronic pancreatitis has led to the identification of a large number of rare missense variants (4,7,14,23,30,35,42,55,58). The clinical significance of such variants has been unclear because their low frequency did not allow statistical determination of genetic association with pancreatitis.…”