ArticleHuman mutation2020
Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding.
Article in Human mutation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 24 citations in OpenAlex.
- Scale and Scope of Gene-Alcohol Interactions in Chronic Pancreatitis: A Systematic Review.Genes · 2021Pooled it
- Characterization of a PNLIP variant identified in Amish pediatric patients with congenital pancreatic lipase deficiency.Journal of lipid research · 2025Article
- Chymotrypsin B2 (CTRB2) Deletion Variant Induces Endoplasmic Reticulum Stress but does not Increase Risk for Chronic Pancreatitis.Pancreas · 2025Article
- 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
- Carboxyl ester lipase hybrid 1 (CEL-HYB1) haplotypes confer varying risk for chronic pancreatitis.Scientific reports · 2024Article
- Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2024Article
- Common single-base insertions in the VNTR of the carboxyl ester lipase (CEL) gene are benign and also likely to arise somatically in the exocrine pancreas.Human molecular genetics · 2024Article
- Characterization of novel PNLIP variants in congenital pancreatic lipase deficiency.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2023Article
- Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1).International journal of molecular sciences · 2022Article
- The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2022Article
- Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2022Article
- Misfolding-induced chronic pancreatitis in CPA1 N256K mutant mice is unaffected by global deletion of Ddit3/Chop.Scientific reports · 2022Article
- The CEL-HYB1 Hybrid Allele Promotes Digestive Enzyme Misfolding and Pancreatitis in Mice.Cellular and molecular gastroenterology and hepatology · 2022Article
- Review
- The position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity.The Journal of biological chemistryArticle
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Genetic variants contribute to the risk of chronic pancreatitis (CP) in adults and children. The risk variant CEL-HYB1, a recombinant hybrid allele of CEL and its neighboring pseudogene (CELP), encodes a pathogenic variant of the pancreatic digestive enzyme carboxyl ester lipase (CEL). We previously identified combinations of two non-synonymous SNPs, c.1463T>C (p. Ile488Thr) and c.1643C>T (p. Thr548Ile), in the break point region of CEL-HYB1. Herein, we tested whether these missense variants alter CP risk and their impact on functional properties of the CEL-HYB1 protein. Examination of CEL-HYB1 haplotypes in European patients and controls revealed that the combinationThr488-Ile548 was present only in cases (p ≤ .001). The lipase activity of purified recombinant CEL-HYB1 variants showed normal or near normal activity. CEL-HYB variants expressed in HEK293T cells all had decreased secretion compared with CEL, formed intracellular protein aggregates, and triggered endoplasmic reticulum stress. Thus, we propose that the presence of missense variants in CEL-HYB increases the pathogenicity of CEL-HYB1 through misfolding and gain-of-function proteotoxicity. Interestingly, Thr488-Ile548 and Thr488-Thr548 were equally pathogenic in the functional assays even though only the Thr488-Ile548 haplotype was significantly enriched in cases. The explanation for the mismatch between genetic and functional data requires further investigation.
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