ArticleAmerican journal of physiology. Gastrointestinal and liver physiology2016
Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis.
Article in American journal of physiology. Gastrointestinal and liver physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 29 citations in OpenAlex.
- Trypsinogen (PRSS1 and PRSS2) gene dosage correlates with pancreatitis risk across genetic and transgenic studies: a systematic review and re-analysis.Human genetics · 2022Pooled it
- Loss of the ER-cargo protein CLN8 increases severity of acute pancreatitis and upregulates ER-stress and ER-phagy.Molecular biomedicine · 2026Article
- Chymotrypsin B2 (CTRB2) Deletion Variant Induces Endoplasmic Reticulum Stress but does not Increase Risk for Chronic Pancreatitis.Pancreas · 2025Article
- The Challenge of Type 3c Diabetes: From Accurate Diagnosis to Effective Treatment.JCEM case reports · 2025Article
- The 12-Year Experience of the Hungarian Pancreatic Study Group.Journal of clinical medicine · 2025Review
- Misfolding PRSS1 variant p.Ala61Val in a case of suspected intrauterine pancreatitis.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2025Article
- Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1).International journal of molecular sciences · 2022Article
- Expanding ACMG variant classification guidelines into a general framework.Human genomics · 2022Article
- Misfolding-induced chronic pancreatitis in CPA1 N256K mutant mice is unaffected by global deletion of Ddit3/Chop.Scientific reports · 2022Article
- ATF6 regulates the development of chronic pancreatitis by inducing p53-mediated apoptosis.Cell death & disease · 2019Article
- Recent Insights Into the Pathogenic Mechanism of Pancreatitis: Role of Acinar Cell Organelle Disorders.Pancreas · 2019Review
- HumanGut · 2019Article
- Novel PathogenicFrontiers in genetics · 2019Article
- Chronic pancreatitis: an update on genetic risk factors.Current opinion in gastroenterology · 2018Review
- Genetic risk in chronic pancreatitis: the misfolding-dependent pathway.Current opinion in gastroenterology · 2017Review
- Article
- Genetic Risk in Chronic Pancreatitis: The Trypsin-Dependent Pathway.Digestive diseases and sciences · 2017Review
- New insights into the pathways initiating and driving pancreatitis.Current opinion in gastroenterology · 2016Article
- Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2.The Journal of biological chemistry · 2016Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Mutations in the PRSS1 gene encoding human cationic trypsinogen are associated with hereditary and sporadic chronic pancreatitis. High-penetrance PRSS1 mutations found in hereditary pancreatitis alter activation and/or degradation of cationic trypsinogen, thereby promoting intrapancreatic trypsinogen activation. In contrast, a number of rare PRSS1 variants identified in subjects with sporadic chronic pancreatitis cause misfolding and endoplasmic reticulum (ER) stress. Mutation p.L104P is unique among natural PRSS1 variants, since it affects the substrate binding site of trypsin. The aim of the present study was to establish the clinical significance of variant p.L104P through functional analysis. We found that p.L104P trypsin exhibited decreased activity on peptide and protein substrates; however, autoactivation was slightly accelerated. Remarkably, binding of the physiological trypsin inhibitor serine protease inhibitor Kazal type 1 (SPINK1) was decreased by 70-fold. In the presence of the trypsinogen-degrading enzyme chymotrypsin C, mutant p.L104P autoactivated to higher trypsin levels than wild-type trypsinogen. This apparent resistance to degradation was due to slower cleavage at Arg(122) rather than Leu(81) Finally, secretion of mutant p.L104P from transfected cells was markedly reduced due to intracellular retention and aggregation with concomitant elevation of ER stress markers. We conclude that PRSS1 variant p.L104P exhibits a variety of phenotypic changes that can increase risk for chronic pancreatitis. Mutation-induced misfolding and associated ER stress are the dominant effects that support a direct pathogenic role in chronic pancreatitis.
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Registered trials
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