Misfolding PRSS1 variant p.Ala61Val in a case of suspected intrauterine pancreatitis

Background/objectives: Genetic variants in PRSS1 encoding human cationic trypsinogen are associated with hereditary pancreatitis. The clinically frequent variants exert their pathogenic effect by increasing intrapancreatic trypsin activity, while a distinct subset of variants causes disease via mutation-induced trypsinogen misfolding and endoplasmic reticulum (ER) stress. Here, we report a novel misfolding PRSS1 variant.

Methods: We used next-generation and Sanger sequencing to screen the index patient. We performed structural modeling and analyzed the functional effects of the PRSS1 variant.

Results: A heterozygous c.182C>T (p.Ala61Val) PRSS1 variant was identified in a case of suspected intrauterine pancreatitis with pseudocyst formation. Recombinant p.Ala61Val trypsinogen autoactivated to lower trypsin levels, but activity of p.Ala61Val trypsin was similar to wild type. In cell culture experiments, the variant exhibited reduced secretion and intracellular retention. Cells expressing the p.Ala61Val variant showed signs of ER stress, as judged by elevated mRNA expression of Hspa5 encoding the chaperone BiP, and increased mRNA splicing of the transcription factor XBP1.

Conclusions: Taken together, the observations expand the repertoire of misfolding PRSS1 variants and highlight the need for functional analysis to identify this rare form of genetic etiology.