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Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis
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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375306/ https://www.ncbi.nlm.nih.gov/pubmed/30792736 http://dx.doi.org/10.3389/fgene.2019.00046 |
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author | Jancsó, Zsanett Oracz, Grzegorz Kujko, Aleksandra Anna Kolodziejczyk, Eliwira Radisky, Evette S. Rygiel, Agnieszka Magdalena Sahin-Tóth, Miklós |
author_facet | Jancsó, Zsanett Oracz, Grzegorz Kujko, Aleksandra Anna Kolodziejczyk, Eliwira Radisky, Evette S. Rygiel, Agnieszka Magdalena Sahin-Tóth, Miklós |
author_sort | Jancsó, Zsanett |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6375306 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63753062019-02-21 Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis Jancsó, Zsanett Oracz, Grzegorz Kujko, Aleksandra Anna Kolodziejczyk, Eliwira Radisky, Evette S. Rygiel, Agnieszka Magdalena Sahin-Tóth, Miklós Front Genet Genetics 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. Frontiers Media S.A. 2019-02-06 /pmc/articles/PMC6375306/ /pubmed/30792736 http://dx.doi.org/10.3389/fgene.2019.00046 Text en Copyright © 2019 Jancsó, Oracz, Kujko, Kolodziejczyk, Radisky, Rygiel and Sahin-Tóth. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Jancsó, Zsanett Oracz, Grzegorz Kujko, Aleksandra Anna Kolodziejczyk, Eliwira Radisky, Evette S. Rygiel, Agnieszka Magdalena Sahin-Tóth, Miklós Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis |
title | Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis |
title_full | Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis |
title_fullStr | Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis |
title_full_unstemmed | Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis |
title_short | Novel Pathogenic PRSS1 Variant p.Glu190Lys in a Case of Chronic Pancreatitis |
title_sort | novel pathogenic prss1 variant p.glu190lys in a case of chronic pancreatitis |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375306/ https://www.ncbi.nlm.nih.gov/pubmed/30792736 http://dx.doi.org/10.3389/fgene.2019.00046 |
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