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http://purl.uniprot.org/citations/33079780http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/33079780http://www.w3.org/2000/01/rdf-schema#comment"

Objectives

The hybrid allele of the carboxyl ester lipase gene (CEL-HYB1) is a genetic risk factor for chronic pancreatitis (CP) although the mechanism promoting disease development is largely unknown. Here, we aimed to clinically describe subjects carrying the CEL-HYB1 allele and to elucidate why the protein product is pathogenic by analyzing pancreatic secretions and cellular models.

Methods

Norwegian cases (n = 154) diagnosed with recurrent acute pancreatitis or CP were subjected to genetic screening by a CEL-HYB1-specific PCR assay followed by Sanger sequencing. For investigation of CEL-HYB1 protein secretion, duodenal juice samples from cases and controls were analyzed by western blotting. HEK293cells were transfected with constructs expressing CEL-HYB1 or the normal CEL protein (CEL-WT) and analyzed by qPCR, cell fractionation and western blotting.

Results

Two CEL-HYB1-positive families were identified. In both pedigrees, CEL-HYB1 did not fully co-segregate with disease. One proband had recurrent acute pancreatitis and was an active smoker. Her mother was a CEL-HYB1 carrier who had suffered from several attacks of acute pancreatitis until she stopped smoking. The other proband was diagnosed with CP and pancreas divisum. Her CEL-HYB1-positive parent was symptom-free but exhibited pancreatic imaging changes. When analyzing the CEL protein in duodenal juice, CEL-WT was readily detectable but no band corresponding to the risk variant was seen. In CEL-HYB1-transfected cells, we observed impaired protein secretion, protein aggregation and endoplasmic reticulum stress.

Conclusion

Our data suggest that CEL-HYB1, in combination with well-known pancreatitis risk factors, causes disease through the misfolding-dependent pathway of genetic CP risk."xsd:string
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http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Cnop M."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Fjeld K."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Johansson B.B."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Molven A."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Tjora E."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Engjom T."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Gravdal A."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/author"Dimcevski G.G."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/name"Eur J Gastroenterol Hepatol"xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/pages"839-843"xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/title"Protein misfolding in combination with other risk factors in CEL-HYB1-mediated chronic pancreatitis."xsd:string
http://purl.uniprot.org/citations/33079780http://purl.uniprot.org/core/volume"33"xsd:string
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