{"doi":"10.1093/hmg/ddae034","title":"Common single-base insertions in the VNTR of the carboxyl ester lipase (<i>CEL</i>) gene are benign and also likely to arise somatically in the exocrine pancreas","abstract":"The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in a control material of 416 subjects (0.075). We performed functional testing in HEK293T cells of a set of CEL-INS variants, in which the insertion site varied from the first to the 12th VNTR repeat. Lipase activity showed little difference among the variants. However, CEL-INS variants with insertions occurring in the most proximal repeats led to protein aggregation and endoplasmic reticulum stress, which upregulated the unfolded protein response. Moreover, by using a CEL-INS-specific antibody, we observed patchy signals in pancreatic tissue from humans without any CEL-INS variant in the germline. Similar pancreatic staining was seen in knock-in mice expressing the most common human CEL VNTR with 16 repeats. CEL-INS proteins may therefore be constantly produced from somatic events in the normal pancreatic parenchyma. This observation along with the high population frequency of CEL-INS alleles strongly suggests that these variants are benign, with a possible exception for insertions in VNTR repeats 1-4.","journal":"Human Molecular Genetics","year":2024,"id":467527,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9561,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":721480,"name":"Anny Gravdal","orcid":null,"position":1,"is_corresponding":false},{"id":720905,"name":"Khadija El Jellas","orcid":"0000-0003-4473-1422","position":2,"is_corresponding":false},{"id":1175621,"name":"Grace Curry","orcid":"0000-0001-7132-2099","position":3,"is_corresponding":false},{"id":902545,"name":"Lin Jianguo","orcid":null,"position":4,"is_corresponding":false},{"id":294781,"name":"Steven J Wilhelm","orcid":"0000-0002-0521-7730","position":5,"is_corresponding":false},{"id":902546,"name":"Solrun J. Steine","orcid":null,"position":6,"is_corresponding":false},{"id":1300229,"name":"Eric Mas","orcid":"0000-0002-8925-9195","position":7,"is_corresponding":false},{"id":241485,"name":"Stefan Johansson","orcid":"0000-0002-2298-7008","position":8,"is_corresponding":false},{"id":368884,"name":"Mark E. Lowe","orcid":"0000-0002-5116-3841","position":9,"is_corresponding":false},{"id":720906,"name":"Bente B. Johansson","orcid":"0000-0001-8893-1915","position":10,"is_corresponding":false},{"id":720904,"name":"Xunjun Xiao","orcid":"0000-0001-5930-4664","position":11,"is_corresponding":false},{"id":720907,"name":"Karianne Fjeld","orcid":"0000-0003-0441-1475","position":12,"is_corresponding":false},{"id":240406,"name":"Anders Molven","orcid":"0000-0003-1847-3079","position":13,"is_corresponding":false},{"id":902106,"name":"Ranveig Seim Brekke","orcid":"0000-0003-4824-9190","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:05:15.025255Z","pmid":"38483348","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}