Ferec C

References (6)

Title : The CEL-HYB1 Hybrid Allele Promotes Digestive Enzyme Misfolding and Pancreatitis in Mice - Mao_2022_Cell.Mol.Gastroenterol.Hepatol__
Author(s) : Mao XT , Zou WB , Cao Y , Wang YC , Deng SJ , Cooper DN , Ferec C , Li ZS , Chen JM , Liao Z
Ref : Cell Mol Gastroenterol Hepatol , : , 2022
Abstract : BACKGROUND & AIMS: A hybrid allele that originated from homologous recombination between CEL and its pseudogene (CELP), CEL-HYB1 increases the risk of chronic pancreatitis (CP). Although suggested to cause digestive enzyme misfolding, definitive in vivo evidence for this postulate has been lacking. METHODS: CRISPR-Cas9 was used to generate humanized mice harboring the CEL-HYB1 allele on a C57BL/6J background. Humanized CEL mice and C57BL/6J mice were used as controls. Pancreata were collected and analyzed by histology, immunohistochemistry, immunoblotting and transcriptomics. Isolated pancreatic acini were cultured in vitro to measure the secretion and aggregation of CEL-HYB1. Mice were given caerulein injections to induce acute pancreatitis (AP) and CP. RESULTS: Pancreata from mice expressing CEL-HYB1 developed pathological features characteristic of focal pancreatitis that included acinar atrophy and vacuolization, inflammatory infiltrates and fibrosis in a time-dependent manner. CEL-HYB1 expression in pancreatic acini led to decreased secretion and increased intracellular aggregation, and triggered endoplasmic reticulum stress compared with CEL. The autophagy levels of pancreata from mice expressing CEL-HYB1 changed at different developmental stages; some aged CEL-HYB1 mice exhibited an accumulation of large autophagic vesicles and impaired autophagy in acinar cells. Administration of caerulein increased the severity of AP/CP in mice expressing CEL-HYB1 compared to control mice, accompanied by higher levels of endoplasmic reticulum stress. CONCLUSIONS: Expression of a humanized form of CEL-HYB1 in mice promotes endoplasmic reticulum stress and pancreatitis through a misfolding-dependent pathway. Impaired autophagy appears to be involved in the pancreatic injury in aged CEL-HYB1 mice. These mice have the potential to be used as a model to identify therapeutic targets for CP.
ESTHER : Mao_2022_Cell.Mol.Gastroenterol.Hepatol__
PubMedSearch : Mao_2022_Cell.Mol.Gastroenterol.Hepatol__
PubMedID: 35398595

Title : Identification and functional characterization of a novel heterozygous missense variant in the LPL associated with recurrent hypertriglyceridemia-induced acute pancreatitis in pregnancy - Shi_2020_Mol.Genet.Genomic.Med__e1048
Author(s) : Shi XL , Yang Q , Pu N , Li XY , Chen WW , Zhou J , Li G , Tong ZH , Ferec C , Cooper DN , Chen JM , Li WQ
Ref : Mol Genet Genomic Med , :e1048 , 2020
Abstract : BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a life-threatening disease for both mother and fetus. To date, only three patients with recurrent hypertriglyceridemia-induced APIP (HTG-APIP) have been reported to carry rare variants in the lipoprotein lipase (LPL) gene, which encodes the key enzyme responsible for triglyceride (TG) metabolism. Coincidently, all three patients harbored LPL variants on both alleles and presented with complete or severe LPL deficiency. METHODS: The entire coding regions and splice junctions of LPL and four other TG metabolism genes (APOC2, APOA5, GPIHBP1, and LMF1) were analyzed by Sanger sequencing in a Han Chinese patient who had experienced two episodes of HTG-APIP. The impact of a novel LPL missense variant on LPL protein expression and activity was analyzed by transient expression in HEK293T cells. RESULTS: A novel heterozygous LPL missense variant, p.His210Leu (c.629A > T), was identified in our patient. This variant did not affect protein synthesis but significantly impaired LPL secretion and completely abolished the enzymatic activity of the mutant protein. CONCLUSION: This report describes the first identification and functional characterization of a heterozygous variant in the LPL that predisposed to recurrent HTG-APIP. Our findings confirm a major genetic contribution to the etiology of individual predisposition to HTG-APIP.
ESTHER : Shi_2020_Mol.Genet.Genomic.Med__e1048
PubMedSearch : Shi_2020_Mol.Genet.Genomic.Med__e1048
PubMedID: 31962008
Gene_locus related to this paper: human-LPL

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 : Protease-Sensitive Pancreatic Lipase Variants Are Associated With Early Onset Chronic Pancreatitis - Lasher_2019_Am.J.Gastroenterol_114_974
Author(s) : Lasher D , Szabo A , Masamune A , Chen JM , Xiao X , Whitcomb DC , Barmada MM , Ewers M , Ruffert C , Paliwal S , Issarapu P , Bhaskar S , Mani KR , Chandak GR , Laumen H , Masson E , Kume K , Hamada S , Nakano E , Seltsam K , Bugert P , Muller T , Groneberg DA , Shimosegawa T , Rosendahl J , Ferec C , Lowe ME , Witt H , Sahin-Toth M
Ref : Am J Gastroenterol , 114 :974 , 2019
Abstract : OBJECTIVES: Premature activation of the digestive protease trypsin within the pancreatic parenchyma is a critical factor in the pathogenesis of pancreatitis. Alterations in genes that affect intrapancreatic trypsin activity are associated with chronic pancreatitis (CP). Recently, carboxyl ester lipase emerged as a trypsin-independent risk gene. Here, we evaluated pancreatic lipase (PNLIP) as a potential novel susceptibility gene for CP. METHODS: We analyzed all 13 PNLIP exons in 429 nonalcoholic patients with CP and 600 control subjects from Germany, in 632 patients and 957 controls from France, and in 223 patients and 1,070 controls from Japan by DNA sequencing. Additionally, we analyzed selected exons in further 545 patients with CP and 1,849 controls originating from Germany, United States, and India. We assessed the cellular secretion, lipase activity, and proteolytic stability of recombinant PNLIP variants. RESULTS: In the German discovery cohort, 8/429 (1.9%) patients and 2/600 (0.3%) controls carried a PNLIP missense variant (P = 0.02, odds ratio [OR] = 5.7, 95% confidence interval [CI] = 1.1-38.9). Variants detected in patients were prone to proteolytic degradation by trypsin and chymotrypsin. In the French replication cohort, protease-sensitive variants were also enriched in patients with early-onset CP (5/632 [0.8%]) vs controls (1/957 [0.1%]) (P = 0.04, OR = 7.6, 95% CI = 0.9-172.9). In contrast, we detected no protease-sensitive variants in the non-European populations. In the combined European data, protease-sensitive variants were found in 13/1,163 cases (1.1%) and in 3/3,000 controls (0.1%) (OR = 11.3, 95% CI = 3.0-49.9, P < 0.0001). CONCLUSIONS: Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP.
ESTHER : Lasher_2019_Am.J.Gastroenterol_114_974
PubMedSearch : Lasher_2019_Am.J.Gastroenterol_114_974
PubMedID: 30789418
Gene_locus related to this paper: human-PNLIP

Title : No Association Between CEL-HYB Hybrid Allele and Chronic Pancreatitis in Asian Populations - Zou_2016_Gastroenterology_150_1558
Author(s) : Zou WB , Boulling A , Masamune A , Issarapu P , Masson E , Wu H , Sun XT , Hu LH , Zhou DZ , He L , Fichou Y , Nakano E , Hamada S , Kakuta Y , Kume K , Isayama H , Paliwal S , Mani KR , Bhaskar S , Cooper DN , Ferec C , Shimosegawa T , Chandak GR , Chen JM , Li ZS , Liao Z
Ref : Gastroenterology , 150 :1558 , 2016
Abstract : A hybrid allele between the carboxyl ester lipase gene (CEL) and its pseudogene, CELP (called CEL-HYB), generated by nonallelic homologous recombination between CEL intron 10 and CELP intron 10', was found to increase susceptibility to chronic pancreatitis in a case-control study of patients of European ancestry. We attempted to replicate this finding in 3 independent cohorts from China, Japan, and India, but failed to detect the CEL-HYB allele in any of these populations. The CEL-HYB allele might therefore be an ethnic-specific risk factor for chronic pancreatitis. An alternative hybrid allele (CEL-HYB2) was identified in all 3 Asian populations (1.7% combined carrier frequency), but was not associated with chronic pancreatitis.
ESTHER : Zou_2016_Gastroenterology_150_1558
PubMedSearch : Zou_2016_Gastroenterology_150_1558
PubMedID: 26946345

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