Steine SJ

References (6)

Title : 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 - Brekke_2024_Hum.Mol.Genet__
Author(s) : Brekke RS , Gravdal A , El Jellas K , Curry GE , Lin J , Wilhelm SJ , Steine SJ , Mas E , Johansson S , Lowe ME , Johansson BB , Xiao X , Fjeld K , Molven A
Ref : Hum Mol Genet , : , 2024
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.
ESTHER : Brekke_2024_Hum.Mol.Genet__
PubMedSearch : Brekke_2024_Hum.Mol.Genet__
PubMedID: 38483348

Title : The genetic risk factor CEL-HYB1 causes proteotoxicity and chronic pancreatitis in mice - Fjeld_2022_Pancreatology__
Author(s) : Fjeld K , Gravdal A , Brekke RS , Alam J , Wilhelm SJ , El Jellas K , Pettersen HN , Lin J , Solheim MH , Steine SJ , Johansson BB , Njlstad PR , Verbeke CS , Xiao X , Lowe ME , Molven A
Ref : Pancreatology , : , 2022
Abstract : Title "Biosensors for the Detection of Enzymes Based on Aggregation-Induced Emission" Journal "Biosensors (Basel)" Volume "12" Page "" "" Medline "36354464" Abstract "Gao_2022_Biosensors.(Basel)_12_" LongText "Gao_2022_Biosensors.(Basel)_12_" Enzymes play a critical role in most complex biochemical processes. Some of them can be regarded as biomarkers for disease diagnosis. Taking advantage of aggregation-induced emission (AIE)-based biosensors, a series of fluorogens with AIE characteristics (AIEgens) have been designed and synthesized for the detection and imaging of enzymes. In this work, we summarized the advances in AIEgens-based probes and sensing platforms for the fluorescent detection of enzymes, including proteases, phosphatases, glycosidases, cholinesterases, telomerase and others. The AIEgens involve organic dyes and metal nanoclusters. This work provides valuable references for the design of novel AIE-based sensing platforms.
ESTHER : Fjeld_2022_Pancreatology__
PubMedSearch : Fjeld_2022_Pancreatology__
PubMedID: 36379850

Title : Characterization of CEL-DUP2: Complete duplication of the carboxyl ester lipase gene is unlikely to influence risk of chronic pancreatitis - Fjeld_2020_Pancreatology__
Author(s) : Fjeld K , Masson E , Lin JH , Michl P , Stokowy T , Gravdal A , El Jellas K , Steine SJ , Hoem D , Johansson BB , Dalva M , Ruffert C , Zou WB , Li ZS , Njolstad PR , Chen JM , Liao Z , Johansson S , Rosendahl J , Ferec C , Molven A
Ref : Pancreatology , : , 2020
Abstract : BACKGROUND/OBJECTIVES: Carboxyl ester lipase is a pancreatic enzyme encoded by CEL, an extremely polymorphic human gene. Pathogenic variants of CEL either increases the risk for chronic pancreatitis (CP) or cause MODY8, a syndrome of pancreatic exocrine and endocrine dysfunction. Here, we aimed to characterize a novel duplication allele of CEL (CEL-DUP2) and to investigate whether it associates with CP or pancreatic cancer. METHODS: The structure of CEL-DUP2 was determined by a combination of Sanger sequencing, DNA fragment analysis, multiplex ligation-dependent probe amplification and whole-genome sequencing. We developed assays for screening of CEL-DUP2 and analyzed cohorts of idiopathic CP, alcoholic CP and pancreatic cancer. CEL protein expression was analyzed by immunohistochemistry. RESULTS: CEL-DUP2 consists of an extra copy of the complete CEL gene. The allele has probably arisen from non-allelic, homologous recombination involving the adjacent pseudogene of CEL. We found no association between CEL-DUP2 carrier frequency and CP in cohorts from France (cases/controls: 2.5%/2.4%; P = 1.0), China (10.3%/8.1%; P = 0.08) or Germany (1.6%/2.3%; P = 0.62). Similarly, no association with disease was observed in alcohol-induced pancreatitis (Germany: 3.2%/2.3%; P = 0.51) or pancreatic cancer (Norway; 2.5%/3.2%; P = 0.77). Notably, the carrier frequency of CEL-DUP2 was more than three-fold higher in Chinese compared with Europeans. CEL protein expression was similar in tissues from CEL-DUP2 carriers and controls. CONCLUSIONS: Our results support the contention that the number of CEL alleles does not influence the risk of pancreatic exocrine disease. Rather, the pathogenic CEL variants identified so far involve exon 11 sequence changes that substantially alter the protein's tail region.
ESTHER : Fjeld_2020_Pancreatology__
PubMedSearch : Fjeld_2020_Pancreatology__
PubMedID: 32007358

Title : The hybrid allele 1 of carboxyl-ester lipase (CEL-HYB1) in Polish pediatric patients with chronic pancreatitis - Oracz_2019_Pancreatology_19_531
Author(s) : Oracz G , Kujko AA , Fjeld K , Wertheim-Tysarowska K , Adamus-Bialek W , Steine SJ , Koziel D , Gluszek S , Molven A , Rygiel AM
Ref : Pancreatology , 19 :531 , 2019
Abstract : OBJECTIVES: It has previously been reported in a European case-control study with patients from Germany and France that CEL-HYB1, a hybrid allele of the carboxyl ester lipase (CEL) gene and its pseudogene CELP, increases susceptibility to chronic pancreatitis (CP). Here, we aimed to replicate this finding in Polish pediatric patients with CP. METHOD: The distribution of the CEL-HYB1 allele in a CP pediatric cohort (n = 147, median age at CP onset 7.6 years) with no history of alcohol/smoking abuse was compared with ethnically matched healthy controls (n = 500, median age 46 years). Screening was performed using long-range PCR followed by agarose gel-electrophoresis. RESULTS: We observed no significant difference in the carrier frequency of the CEL-HYB1 allele between CP patients (7/147, 4.8%) and controls (12/500, 2.4%; P = 0.16). CONCLUSIONS: This study found no statistically significant association between CEL-HYB1 and chronic pancreatitis in a cohort of Polish pediatric CP patients.
ESTHER : Oracz_2019_Pancreatology_19_531
PubMedSearch : Oracz_2019_Pancreatology_19_531
PubMedID: 31036489

Title : Copy number variants and VNTR length polymorphisms of the carboxyl-ester lipase (CEL) gene as risk factors in pancreatic cancer - Dalva_2017_Pancreatology_17_83
Author(s) : Dalva M , El Jellas K , Steine SJ , Johansson BB , Ringdal M , Torsvik J , Immervoll H , Hoem D , Laemmerhirt F , Simon P , Lerch MM , Johansson S , Njolstad PR , Weiss FU , Fjeld K , Molven A
Ref : Pancreatology , 17 :83 , 2017
Abstract : BACKGROUND/OBJECTIVES: We have recently described copy number variants (CNVs) of the human carboxyl-ester lipase (CEL) gene, including a recombined deletion allele (CEL-HYB) that is a genetic risk factor for chronic pancreatitis. Associations with pancreatic disease have also been reported for the variable number of tandem repeat (VNTR) region located in CEL exon 11. Here, we examined if CEL CNVs and VNTR length polymorphisms affect the risk for developing pancreatic cancer. METHODS: CEL CNVs and VNTR were genotyped in a German family with non-alcoholic chronic pancreatitis and pancreatic cancer, in 265 German and 197 Norwegian patients diagnosed with pancreatic adenocarcinoma, and in 882 controls. CNV screening was performed using PCR assays followed by agarose gel electrophoresis whereas VNTR lengths were determined by DNA fragment analysis. RESULTS: The investigated family was CEL-HYB-positive. However, an association of CEL-HYB or a duplication CEL allele with pancreatic cancer was not seen in our two patient cohorts. The frequency of the 23-repeat VNTR allele was borderline significant in Norwegian cases compared to controls (1.2% vs. 0.3%; P = 0.05). For all other VNTR lengths, no statistically significant difference in frequency was observed. Moreover, no association with pancreatic cancer was detected when CEL VNTR lengths were pooled into groups of short, normal or long alleles. CONCLUSIONS: We could not demonstrate an association between CEL CNVs and pancreatic cancer. An association is also unlikely for CEL VNTR lengths, although analyses in larger materials are necessary to completely exclude an effect of rare VNTR alleles.
ESTHER : Dalva_2017_Pancreatology_17_83
PubMedSearch : Dalva_2017_Pancreatology_17_83
PubMedID: 27773618
Gene_locus related to this paper: human-CEL

Title : A recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis - Fjeld_2015_Nat.Genet_47_518
Author(s) : Fjeld K , Weiss FU , Lasher D , Rosendahl J , Chen JM , Johansson BB , Kirsten H , Ruffert C , Masson E , Steine SJ , Bugert P , Cnop M , Grutzmann R , Mayerle J , Mossner J , Ringdal M , Schulz HU , Sendler M , Simon P , Sztromwasser P , Torsvik J , Scholz M , Tjora E , Ferec C , Witt H , Lerch MM , Njolstad PR , Johansson S , Molven A
Ref : Nat Genet , 47 :518 , 2015
Abstract : Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1-46.9; P = 1.3 x 10(-6) by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2-8.5; P = 1.2 x 10(-11); formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.
ESTHER : Fjeld_2015_Nat.Genet_47_518
PubMedSearch : Fjeld_2015_Nat.Genet_47_518
PubMedID: 25774637