Misfolding cationic trypsinogen variant p.L104P causes hereditary pancreatitis

We read the recent publication of Schnúr et al. [1] with great interest, in which the authors proposed that a subset of human cationic trypsinogen (PRSS1) variants cause chronic pancreatitis by inducing misfolding and endoplasmic reticulum (ER) stress rather than increased intra-pancreatic trypsin activity.PRSS1 variants that promote premature trypsinogen activation are the strongest known risk factors for chronic pancreatitis; often associated with autosomal dominant hereditary pancreatitis.ER-stress causing PRSS1 variants, on the other hand, have been mostly found in sporadic disease with no family history suggesting these variants might confer lower risk.To refute this notion, here we report a hereditary pancreatitis family of Hungarian origin carrying the heterozygous c.311T>C (p.L104P) PRSS1 variant which was recently demonstrated to induce misfolding and ER stress.[2]The index patient, his mother and first cousin developed recurrent acute or chronic pancreatitis in this family (Figure 1).Sanger sequencing was carried out on genomic DNA of all 12 live family members after informed consent was obtained.All exons of the PRSS1, SPINK1, CTRC and CPA1 genes and exons 4, 10 and 11 of the CFTR gene were sequenced in all affected subjects.In all unaffected family members PRSS1 exon 3 was sequenced.In the unaffected children of the index patient's cousin CTRC exons 2 and 3 were also analyzed.All three affected members were heterozygous for the p.L104P PRSS1 variant.