Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis.

Zsanett Jancsó,Eliwira Kolodziejczyk,Aleksandra Anna Kujko,Grzegorz Oracz,Evette S Radisky,Miklós Sahin-Tóth,Agnieszka Magdalena Rygiel

doi:10.3389/fgene.2019.00046

Zsanett Jancsó, Eliwira Kolodziejczyk + Show 5 more

Open Access

https://doi.org/10.3389/fgene.2019.00046

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Abstract

Mutations in the PRSS1 (serine protease 1) gene encoding human cationic trypsinogen cause hereditary pancreatitis or may be associated with sporadic chronic pancreatitis. The mutations exert their pathogenic effect either by increasing intra-pancreatic trypsinogen activation (trypsin pathway) or by causing proenzyme misfolding and endoplasmic reticulum stress (misfolding pathway). Here we report a novel heterozygous c.568G>A (p.Glu190Lys) variant identified in a case with chronic pancreatitis. The parents of the index patient had no history of pancreatitis but were unavailable for genetic testing. Functional characterization revealed 2.5-fold increased autoactivation of the mutant trypsinogen relative to wild type. Unlike many other clinically relevant PRSS1 mutations, p.Glu190Lys did not alter the chymotrypsin C (CTRC)-dependent degradation of trypsinogen nor did it increase CTRC-mediated processing of the trypsinogen activation peptide. Cellular secretion of the mutant protein was unchanged indicating normal folding behavior. Based on the genetic and functional evidence, we classify the p.Glu190Lys PRSS1 variant as likely pathogenic, which stimulates autoactivation of cationic trypsinogen independently of CTRC.

Highlights

Mutations in the PRSS1 gene encoding human cationic trypsinogen have been found in families with autosomal dominant hereditary pancreatitis and in sporadic cases without a family history (Whitcomb et al, 1996; Németh and Sahin-Tóth, 2014)
Misfolding mutants are more often found in sporadic cases they have been observed in families with hereditary pancreatitis (Németh et al, 2017a)
The parents of the index patient had no history of pancreatitis but were unavailable for genetic testing The p.Glu190Lys variant is not listed in the 1000 genomes, dbSNP, genomic GNomad, ClinVar and HGMD databases

Summary

Introduction

Mutations in the PRSS1 (serine protease 1) gene encoding human cationic trypsinogen have been found in families with autosomal dominant hereditary pancreatitis and in sporadic cases without a family history (Whitcomb et al, 1996; Németh and Sahin-Tóth, 2014). Studies spanning almost two decades revealed that PRSS1 mutations cause pancreatitis via two different mechanisms; the trypsin-dependent and the misfolding dependent pathways (Hegyi and Sahin-Tóth, 2017; Sahin-Tóth, 2017). The majority of clinically relevant mutations exert their effect by increasing intra-pancreatic autoactivation of cationic trypsinogen resulting in elevated levels of harmful trypsin activity (Hegyi and Sahin-Tóth, 2017). Most of these mutations tend to associate with hereditary pancreatitis.

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