ArticleBiochimica et biophysica acta2015
A novel mutation in PNLIP causes pancreatic triglyceride lipase deficiency through protein misfolding.
Article in Biochimica et biophysica acta, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 57 citations in OpenAlex.
- 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
- Novel chymotrypsin C (CTRC) variants from real-world genetic testing of pediatric chronic pancreatitis cases.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 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
- Characterization of novel PNLIP variants in congenital pancreatic lipase deficiency.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2023Article
- Article
- Exocrine Pancreatic Insufficiency in Children - Challenges in Management.Pediatric health, medicine and therapeutics · 2023Review
- Novel p.G250A Mutation Associated with Chronic Pancreatitis Highlights Misfolding-Prone Region in Carboxypeptidase A1 (CPA1).International journal of molecular sciences · 2022Article
- Insights into the architecture of human-induced polygenic selection in Duroc pigs.Journal of animal science and biotechnology · 2022Article
- Misfolding-induced chronic pancreatitis in CPA1 N256K mutant mice is unaffected by global deletion of Ddit3/Chop.Scientific reports · 2022Article
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- Novel homozygous mutation of PNLIP gene in congenital pancreatic lipase deficiency: an extended family study.Therapeutic advances in chronic disease · 2022Article
- Single nucleotide polymorphisms in CEL-HYB1 increase risk for chronic pancreatitis through proteotoxic misfolding.Human mutation · 2020Article
- Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis.The American journal of gastroenterology · 2019Article
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- Article
- Genetic risk in chronic pancreatitis: the misfolding-dependent pathway.Current opinion in gastroenterology · 2017Review
- A Carboxyl Ester Lipase (CEL) Mutant Causes Chronic Pancreatitis by Forming Intracellular Aggregates That Activate Apoptosis.The Journal of biological chemistry · 2016Article
- Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis.American journal of physiology. Gastrointestinal and liver physiology · 2016Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Congenital pancreatic triglyceride lipase (PNLIP) deficiency is a rare disorder with uncertain genetic background as most cases were described before gene sequencing was readily available. Recently, two brothers with PNLIP deficiency were found to carry a homozygous missense mutation, c.662C>T (p.T221M) in the PNLIP gene (J. Lipid Res. 2014. 55:307-312). Molecular modeling suggested the substitution would change the orientation of residues in the catalytic site and disrupt the function of p.T221M PNLIP. To test the effect of the p.T221M mutation on PNLIP function, we expressed wild-type and p.T221M PNLIP in human embryonic kidney (HEK) 293A cells and dexamethasone-differentiated AR42J rat acinar cells. In both cellular models, wild-type PNLIP was secreted into the conditioned medium where it was readily detectable by protein staining, immunoblot or lipase activity assays. In contrast, mutant p.T221M was not secreted into the medium, but it was present in cell lysates where it accumulated in the insoluble fraction. Intracellular retention of mutant p.T221M resulted in endoplasmic reticulum (ER) stress as measured by elevated XBP1 splicing and increased levels of ER chaperones. Our results demonstrate that the presence of methionine at position 221 in the PNLIP protein sequence causes misfolding and aggregation of the p.T221M mutant inside the cell. The consequent loss of enzyme secretion adequately explains the clinical phenotype of PNLIP deficiency reported for homozygous carriers of p.T221M. Furthermore, the ability of mutant p.T221M to induce ER stress suggests that this form of PNLIP deficiency might cause acinar cell damage as well.
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