ClinVar

Teich et al. (2006) reported that the 346C-T transition in exon 3 of the PRSS1 gene, resulting in an arg116-to-cys (R116C) substitution, had been identified by 4 independent groups in Turkish, German, and Thai families with hereditary pancreatitis (167800) and in 2 unrelated French patients with pancreatitis.

In an 11-year-old German girl with hereditary pancreatitis, originally reported by Teich et al. (2002), Kereszturi et al. (2009) showed that trypsinogen misfolding is the likely disease mechanism. The R116C substitution occurs in a surface loop that is highly sensitive to autolytic cleavage. In vitro functional expression studies showed that the R116C mutation resulted in misfolding of the protein, but residual amounts of properly folded protein showed normal activation, catalytic properties, and degradation. Expression of the mutant protein in HEK 293T cells showed decreased secretion compared to wildtype, suggesting that the unpaired cysteine residue at codon 116 interferes with proper protein folding, resulting in the mutant protein being retained inside the cell. Biochemical evidence indicated activation of the unfolded protein response, although there was no evidence of increased caspase-3 (CASP3; 600636) activity. The R116C mutation was also found in the girl's 57-year-old affected maternal grandfather and her 38-year-old unaffected mother, indicating incomplete penetrance.