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

Frontiers in Genetics
Zsanett JancsóMiklós Sahin-Tóth

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.

References

Mar 1, 2006·The Journal of Biological Chemistry·Zsófia Nemoda, Miklós Sahin-Tóth
Jun 27, 2007·Proceedings of the National Academy of Sciences of the United States of America·Richárd Szmola, Miklós Sahin-Tóth
Dec 14, 2007·The Journal of Biological Chemistry·Moh'd A SalamehEvette S Radisky
Dec 3, 2010·Methods in Molecular Biology·Orsolya KirályMiklós Sahin-Tóth
Apr 28, 2012·The Journal of Biological Chemistry·András Szabó, Miklós Sahin-Tóth
Jan 25, 2014·American Journal of Physiology. Gastrointestinal and Liver Physiology·Balázs Csaba Németh, Miklós Sahin-Tóth
Dec 30, 2014·BMC Biotechnology·Karin BuettnerThole Zuchner
Jan 30, 2016·American Journal of Physiology. Gastrointestinal and Liver Physiology·Anita BalázsMiklós Sahin-Tóth
Dec 25, 2016·Gut·Balázs Csaba NémethPéter Hegyi
May 26, 2017·Digestive Diseases and Sciences·Eszter Hegyi, Miklós Sahin-Tóth
Jun 27, 2017·Current Opinion in Gastroenterology·Miklós Sahin-Tóth

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Citations

Dec 2, 2020·Clinics and Research in Hepatology and Gastroenterology·Emmanuelle GirodonThierry Bienvenu
Jul 6, 2021·Journal of Pediatric Gastroenterology and Nutrition·Chinenye R DikeAliye Uc

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Methods Mentioned

BETA
PCR
genotyping

Software Mentioned

MutationTaster
SIFT
Bluues
PyMOL
PolyPhen

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