ArticleThe Journal of biological chemistry
Defective binding of SPINK1 variants is an uncommon mechanism for impaired trypsin inhibition in chronic pancreatitis.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.
- Scale and Scope of Gene-Alcohol Interactions in Chronic Pancreatitis: A Systematic Review.Genes · 2021Pooled it
- Age-associated outcomes of ERCP in pediatric chronic pancreatitis.Pediatric research · 2026Article
- SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity, and classificatory challenges.American journal of human genetics · 2025Article
- Minigenes enhance heterologous expression and prevent aberrant splicing of mouse Spink1.Scientific reports · 2025Article
- Genetics and clinical implications of SPINK1 in the pancreatitis continuum and pancreatic cancer.Human genomics · 2025Review
- Study of a panel of genetic mutations in fibrocalcific pancreatic diabetes (FCPD): SPINK1 (N34S) mutation unlikely to be relevant.Scientific reports · 2024Article
- Article
- Acute pancreatitis following asparaginase treatment in pediatric acute lymphoblastic leukemia with a heterozygousFrontiers in pediatrics · 2024Article
- Article
- Expanding ACMG variant classification guidelines into a general framework.Human genomics · 2022Article
- Structural and Biophysical Insights into SPINK1 Bound to Human Cationic Trypsin.International journal of molecular sciences · 2022Article
- Structural Basis of the Pancreatitis-Associated Autoproteolytic Failsafe Mechanism in Human Anionic Trypsin.Journal of inflammation research · 2022Article
- The research progress of anti-inflammatory and anti-fibrosis treatment of chronic pancreatitis.Frontiers in oncology · 2022Review
- Stimuli-responsive polypeptide nanogels for trypsin inhibition.Beilstein journal of nanotechnology · 2022Article
- Article
- Review
- Functional Roles of SPINK1 in Cancers.International journal of molecular sciences · 2021Review
- A Hypothesized Mechanism for Chronic Pancreatitis Caused by the N34S Mutation of Serine Protease Inhibitor Kazal-Type 1 Based on Conformational Studies.Journal of inflammation research · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
The serine protease inhibitor Kazal type 1 (SPINK1) protects the pancreas from intrapancreatic trypsin activation that can lead to pancreatitis. Loss-of-function genetic variants of SPINK1 increase the risk for chronic pancreatitis, often by diminishing inhibitor expression or secretion. Variants that are secreted normally have been presumed to be pathogenic because of defective trypsin inhibition, but evidence has been lacking. Here, we report quantitative studies on the inhibition of human trypsins by wildtype SPINK1 and seven secreted missense variants. We found that tyrosine sulfation of human trypsins weakens binding of SPINK1 because of altered interactions with Tyr43 in the SPINK1 reactive loop. Using authentic sulfated human trypsins, we provide conclusive evidence that SPINK1 variants N34S, N37S, R65Q, and Q68R have unimpaired inhibitory activity, whereas variant P55S exhibits a small and clinically insignificant binding defect. In contrast, rare variants K41N and I42M that affect the reactive-site peptide bond of SPINK1 decrease inhibitor binding by 20,000- to 30,000-fold and three- to sevenfold, respectively. Taken together, the observations indicate that defective trypsin inhibition by SPINK1 variants is an uncommon mechanism in chronic pancreatitis. The results also strengthen the notion that a decline in inhibitor levels explains pancreatitis risk associated with the large majority of SPINK1 variants.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.