Johansson S


Full name : Johansson Susanne

First name : Susanne

Mail : FOI\; Swedish Defence Research Agency\; CBRN Defence and Security\; cementv\; Umea\; 901

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Country : Sweden

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References (15)

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 position of single-base deletions in the VNTR sequence of the carboxyl ester lipase (CEL) gene determines proteotoxicity - Gravdal_2021_J.Biol.Chem_296_100661
Author(s) : Gravdal A , Xiao X , Cnop M , El Jellas K , Johansson S , Njolstad PR , Lowe ME , Johansson BB , Molven A , Fjeld K
Ref : Journal of Biological Chemistry , 296 :100661 , 2021
Abstract : Variable number of tandem repeat (VNTR) sequences in the genome can have functional consequences that contribute to human disease. This is the case for the CEL gene, which is specifically expressed in pancreatic acinar cells and encodes the digestive enzyme carboxyl ester lipase. Rare single-base deletions (DELs) within the first (DEL1) or fourth (DEL4) VNTR segment of CEL cause maturity-onset diabetes of the young, type 8 (MODY8), an inherited disorder characterized by exocrine pancreatic dysfunction and diabetes. Studies on the DEL1 variant have suggested that MODY8 is initiated by CEL protein misfolding and aggregation. However, it is unclear how the position of single-base deletions within the CEL VNTR affects pathogenic properties of the protein. Here, we investigated four naturally occurring CEL variants, arising from single-base deletions in different VNTR segments (DEL1, DEL4, DEL9, and DEL13). When the four variants were expressed in human embryonic kidney 293 cells, only DEL1 and DEL4 led to significantly reduced secretion, increased intracellular aggregation, and increased endoplasmic reticulum stress compared with normal CEL protein. The level of O-glycosylation was affected in all DEL variants. Moreover, all variants had enzymatic activity comparable with that of normal CEL. We conclude that the longest aberrant protein tails, resulting from single-base deletions in the proximal VNTR segments, have highest pathogenic potential, explaining why DEL1 and DEL4 but not DEL9 and DEL13 have been observed in patients with MODY8. These findings further support the view that CEL mutations cause pancreatic disease through protein misfolding and proteotoxicity, leading to endoplasmic reticulum stress and activation of the unfolded protein response.
ESTHER : Gravdal_2021_J.Biol.Chem_296_100661
PubMedSearch : Gravdal_2021_J.Biol.Chem_296_100661
PubMedID: 33862081

Title : Two new mutations in the CEL gene causing diabetes and hereditary pancreatitis: How to correctly identify MODY8 cases - El Jellas_2021_J.Clin.Endocrinol.Metab__
Author(s) : El Jellas K , Dusatkova P , Haldorsen IS , Molnes J , Tjora E , Johansson BB , Fjeld K , Johansson S , Pruhova S , Groop L , Lohr JM , Njolstad PR , Molven A
Ref : J Clinical Endocrinology Metab , : , 2021
Abstract : OBJECTIVE: Maturity-onset diabetes of the young, type 8 (MODY8) is associated with mutations in the CEL gene, which encodes the digestive enzyme carboxyl ester lipase. Several diabetes cases and families have in recent years been attributed to mutations in CEL without any functional or clinical evidence provided. To facilitate correct MODY8 diagnostics, we screened two cohorts of diabetes patients and delineated the phenotype. RESEARCH DESIGN: Young, lean Swedish and Finnish patients with a diagnosis of type 2 diabetes (352 cases, 406 controls) were screened for mutations in the CEL gene. We also screened 58 Czech MODY cases who had tested negative for common MODY genes. For CEL mutation-positive subjects, family history was recorded, and clinical investigations and pancreatic imaging performed. RESULTS: One Swedish and one Czech case with germline mutation in CEL were identified. Clinical and radiological investigations of these two probands and their families revealed dominantly inherited insulin-dependent diabetes, pancreatic exocrine dysfunction and atrophic pancreas with lipomatosis and cysts. Notably, hereditary pancreatitis was the predominant phenotype in one pedigree. Both families carried single-base pair deletions in the proximal part of the CEL variable number of tandem repeat (VNTR) region in exon 11. The mutations are predicted to lead to aberrant protein tails that make the CEL protein susceptible to aggregation. CONCLUSIONS: The diagnosis of MODY8 requires a pancreatic exocrine phenotype and a deletion in the CEL VNTR in addition to dominantly inherited diabetes. CEL screening may be warranted also in families with hereditary pancreatitis of unknown genetic etiology.
ESTHER : El Jellas_2021_J.Clin.Endocrinol.Metab__
PubMedSearch : El Jellas_2021_J.Clin.Endocrinol.Metab__
PubMedID: 34850019
Gene_locus related to this paper: human-CEL

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 role of the carboxyl ester lipase (CEL) gene in pancreatic disease - Johansson_2018_Pancreatology_18_12
Author(s) : Johansson BB , Fjeld K , El Jellas K , Gravdal A , Dalva M , Tjora E , Raeder H , Kulkarni RN , Johansson S , Njolstad PR , Molven A
Ref : Pancreatology , 18 :12 , 2018
Abstract : The enzyme carboxyl ester lipase (CEL), also known as bile salt-dependent or -stimulated lipase (BSDL, BSSL), hydrolyzes dietary fat, cholesteryl esters and fat-soluble vitamins in the duodenum. CEL is mainly expressed in pancreatic acinar cells and lactating mammary glands. The human CEL gene resides on chromosome 9q34.3 and contains a variable number of tandem repeats (VNTR) region that encodes a mucin-like protein tail. Although the number of normal repeats does not appear to significantly influence the risk for pancreatic disease, single-base pair deletions in the first VNTR repeat cause a syndrome of endocrine and exocrine dysfunction denoted MODY8. Hallmarks are low fecal elastase levels and pancreatic lipomatosis manifesting before the age of twenty, followed by development of diabetes and pancreatic cysts later in life. The mutant protein forms intracellular and extracellular aggregates, suggesting that MODY8 is a protein misfolding disease. Recently, a recombined allele between CEL and its pseudogene CELP was discovered. This allele (CEL-HYB) encodes a chimeric protein with impaired secretion increasing five-fold the risk for chronic pancreatitis. The CEL gene has proven to be exceptionally polymorphic due to copy number variants of the CEL-CELP locus and alterations involving the VNTR. Genome-wide association studies or deep sequencing cannot easily pick up this wealth of genetic variation. CEL is therefore an attractive candidate gene for further exploration of links to pancreatic disease.
ESTHER : Johansson_2018_Pancreatology_18_12
PubMedSearch : Johansson_2018_Pancreatology_18_12
PubMedID: 29233499
Gene_locus related to this paper: human-CEL

Title : Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity - Turcot_2018_Nat.Genet_50_26
Author(s) : Turcot V , Lu Y , Highland HM , Schurmann C , Justice AE , Fine RS , Bradfield JP , Esko T , Giri A , Graff M , Guo X , Hendricks AE , Karaderi T , Lempradl A , Locke AE , Mahajan A , Marouli E , Sivapalaratnam S , Young KL , Alfred T , Feitosa MF , Masca NGD , Manning AK , Medina-Gomez C , Mudgal P , Ng MCY , Reiner AP , Vedantam S , Willems SM , Winkler TW , Abecasis G , Aben KK , Alam DS , Alharthi SE , Allison M , Amouyel P , Asselbergs FW , Auer PL , Balkau B , Bang LE , Barroso I , Bastarache L , Benn M , Bergmann S , Bielak LF , Bluher M , Boehnke M , Boeing H , Boerwinkle E , Boger CA , Bork-Jensen J , Bots ML , Bottinger EP , Bowden DW , Brandslund I , Breen G , Brilliant MH , Broer L , Brumat M , Burt AA , Butterworth AS , Campbell PT , Cappellani S , Carey DJ , Catamo E , Caulfield MJ , Chambers JC , Chasman DI , Chen YI , Chowdhury R , Christensen C , Chu AY , Cocca M , Collins FS , Cook JP , Corley J , Corominas Galbany J , Cox AJ , Crosslin DS , Cuellar-Partida G , D'Eustacchio A , Danesh J , Davies G , Bakker PIW , Groot MCH , Mutsert R , Deary IJ , Dedoussis G , Demerath EW , Heijer M , Hollander AI , Ruijter HM , Dennis JG , Denny JC , Angelantonio E , Drenos F , Du M , Dube MP , Dunning AM , Easton DF , Edwards TL , Ellinghaus D , Ellinor PT , Elliott P , Evangelou E , Farmaki AE , Farooqi IS , Faul JD , Fauser S , Feng S , Ferrannini E , Ferrieres J , Florez JC , Ford I , Fornage M , Franco OH , Franke A , Franks PW , Friedrich N , Frikke-Schmidt R , Galesloot TE , Gan W , Gandin I , Gasparini P , Gibson J , Giedraitis V , Gjesing AP , Gordon-Larsen P , Gorski M , Grabe HJ , Grant SFA , Grarup N , Griffiths HL , Grove ML , Gudnason V , Gustafsson S , Haessler J , Hakonarson H , Hammerschlag AR , Hansen T , Harris KM , Harris TB , Hattersley AT , Have CT , Hayward C , He L , Heard-Costa NL , Heath AC , Heid IM , Helgeland O , Hernesniemi J , Hewitt AW , Holmen OL , Hovingh GK , Howson JMM , Hu Y , Huang PL , Huffman JE , Ikram MA , Ingelsson E , Jackson AU , Jansson JH , Jarvik GP , Jensen GB , Jia Y , Johansson S , Jorgensen ME , Jorgensen T , Jukema JW , Kahali B , Kahn RS , Kahonen M , Kamstrup PR , Kanoni S , Kaprio J , Karaleftheri M , Kardia SLR , Karpe F , Kathiresan S , Kee F , Kiemeney LA , Kim E , Kitajima H , Komulainen P , Kooner JS , Kooperberg C , Korhonen T , Kovacs P , Kuivaniemi H , Kutalik Z , Kuulasmaa K , Kuusisto J , Laakso M , Lakka TA , Lamparter D , Lange EM , Lange LA , Langenberg C , Larson EB , Lee NR , Lehtimaki T , Lewis CE , Li H , Li J , Li-Gao R , Lin H , Lin KH , Lin LA , Lin X , Lind L , Lindstrom J , Linneberg A , Liu CT , Liu DJ , Liu Y , Lo KS , Lophatananon A , Lotery AJ , Loukola A , Luan J , Lubitz SA , Lyytikainen LP , Mannisto S , Marenne G , Mazul AL , McCarthy MI , McKean-Cowdin R , Medland SE , Meidtner K , Milani L , Mistry V , Mitchell P , Mohlke KL , Moilanen L , Moitry M , Montgomery GW , Mook-Kanamori DO , Moore C , Mori TA , Morris AD , Morris AP , Muller-Nurasyid M , Munroe PB , Nalls MA , Narisu N , Nelson CP , Neville M , Nielsen SF , Nikus K , Njolstad PR , Nordestgaard BG , Nyholt DR , O'Connel JR , O'Donoghue ML , Olde Loohuis LM , Ophoff RA , Owen KR , Packard CJ , Padmanabhan S , Palmer CNA , Palmer ND , Pasterkamp G , Patel AP , Pattie A , Pedersen O , Peissig PL , Peloso GM , Pennell CE , Perola M , Perry JA , Perry JRB , Pers TH , Person TN , Peters A , Petersen ERB , Peyser PA , Pirie A , Polasek O , Polderman TJ , Puolijoki H , Raitakari OT , Rasheed A , Rauramaa R , Reilly DF , Renstrom F , Rheinberger M , Ridker PM , Rioux JD , Rivas MA , Roberts DJ , Robertson NR , Robino A , Rolandsson O , Rudan I , Ruth KS , Saleheen D , Salomaa V , Samani NJ , Sapkota Y , Sattar N , Schoen RE , Schreiner PJ , Schulze MB , Scott RA , Segura-Lepe MP , Shah SH , Sheu WH , Sim X , Slater AJ , Small KS , Smith AV , Southam L , Spector TD , Speliotes EK , Starr JM , Stefansson K , Steinthorsdottir V , Stirrups KE , Strauch K , Stringham HM , Stumvoll M , Sun L , Surendran P , Swift AJ , Tada H , Tansey KE , Tardif JC , Taylor KD , Teumer A , Thompson DJ , Thorleifsson G , Thorsteinsdottir U , Thuesen BH , Tonjes A , Tromp G , Trompet S , Tsafantakis E , Tuomilehto J , Tybjaerg-Hansen A , Tyrer JP , Uher R , Uitterlinden AG , Uusitupa M , Laan SW , Duijn CM , Leeuwen N , van Setten J , Vanhala M , Varbo A , Varga TV , Varma R , Velez Edwards DR , Vermeulen SH , Veronesi G , Vestergaard H , Vitart V , Vogt TF , Volker U , Vuckovic D , Wagenknecht LE , Walker M , Wallentin L , Wang F , Wang CA , Wang S , Wang Y , Ware EB , Wareham NJ , Warren HR , Waterworth DM , Wessel J , White HD , Willer CJ , Wilson JG , Witte DR , Wood AR , Wu Y , Yaghootkar H , Yao J , Yao P , Yerges-Armstrong LM , Young R , Zeggini E , Zhan X , Zhang W , Zhao JH , Zhao W , Zhou W , Zondervan KT , Rotter JI , Pospisilik JA , Rivadeneira F , Borecki IB , Deloukas P , Frayling TM , Lettre G , North KE , Lindgren CM , Hirschhorn JN , Loos RJF
Ref : Nat Genet , 50 :26 , 2018
Abstract : Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
ESTHER : Turcot_2018_Nat.Genet_50_26
PubMedSearch : Turcot_2018_Nat.Genet_50_26
PubMedID: 29273807

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

Title : The number of tandem repeats in the carboxyl-ester lipase (CEL) gene as a risk factor in alcoholic and idiopathic chronic pancreatitis - Ragvin_2013_Pancreatology_13_29
Author(s) : Ragvin A , Fjeld K , Weiss FU , Torsvik J , Aghdassi A , Mayerle J , Simon P , Njolstad PR , Lerch MM , Johansson S , Molven A
Ref : Pancreatology , 13 :29 , 2013
Abstract : BACKGROUND/AIMS: The variable number of tandem repeats (VNTR) in the last exon of the carboxyl-ester lipase (CEL) gene has been reported to associate with alcohol-induced chronic pancreatitis (ACP) in a Japanese study. Here, we have investigated the association between the number of CEL VNTR repeats and ACP or idiopathic chronic pancreatitis (ICP) in a cohort of German patients. METHODS: Patients diagnosed with ACP (n = 203) or ICP (n = 64) were genotyped using a screening method consisting of PCR followed by DNA fragment analysis. The allele frequencies of different CEL VNTR lengths were compared to the frequencies in healthy controls (n = 390). RESULTS: We observed no statistical significant associations between CEL VNTR allele frequencies and ACP or ICP. CONCLUSION: This study did not find evidence that supported an association between the common length variations of the CEL VNTR and chronic pancreatitis.
ESTHER : Ragvin_2013_Pancreatology_13_29
PubMedSearch : Ragvin_2013_Pancreatology_13_29
PubMedID: 23395566
Gene_locus related to this paper: human-CEL

Title : Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease - Johansson_2011_J.Biol.Chem_286_34593
Author(s) : Johansson BB , Torsvik J , Bjorkhaug L , Vesterhus M , Ragvin A , Tjora E , Fjeld K , Hoem D , Johansson S , Raeder H , Lindquist S , Hernell O , Cnop M , Saraste J , Flatmark T , Molven A , Njolstad PR
Ref : Journal of Biological Chemistry , 286 :34593 , 2011
Abstract : CEL-maturity onset diabetes of the young (MODY), diabetes with pancreatic lipomatosis and exocrine dysfunction, is due to dominant frameshift mutations in the acinar cell carboxyl ester lipase gene (CEL). As Cel knock-out mice do not express the phenotype and the mutant protein has an altered and intrinsically disordered tandem repeat domain, we hypothesized that the disease mechanism might involve a negative effect of the mutant protein. In silico analysis showed that the pI of the tandem repeat was markedly increased from pH 3.3 in wild-type (WT) to 11.8 in mutant (MUT) human CEL. By stably overexpressing CEL-WT and CEL-MUT in HEK293 cells, we found similar glycosylation, ubiquitination, constitutive secretion, and quality control of the two proteins. The CEL-MUT protein demonstrated, however, a high propensity to form aggregates found intracellularly and extracellularly. Different physicochemical properties of the intrinsically disordered tandem repeat domains of WT and MUT proteins may contribute to different short and long range interactions with the globular core domain and other macromolecules, including cell membranes. Thus, we propose that CEL-MODY is a protein misfolding disease caused by a negative gain-of-function effect of the mutant proteins in pancreatic tissues.
ESTHER : Johansson_2011_J.Biol.Chem_286_34593
PubMedSearch : Johansson_2011_J.Biol.Chem_286_34593
PubMedID: 21784842
Gene_locus related to this paper: human-CEL

Title : Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes - Torsvik_2010_Hum.Genet_127_55
Author(s) : Torsvik J , Johansson S , Johansen A , Ek J , Minton J , Raeder H , Ellard S , Hattersley A , Pedersen O , Hansen T , Molven A , Njolstad PR
Ref : Hum Genet , 127 :55 , 2010
Abstract : We have previously shown that heterozygous single-base deletions in the carboxyl-ester lipase (CEL) gene cause exocrine and endocrine pancreatic dysfunction in two multigenerational families. These deletions were found in the first and fourth repeats of a variable number of tandem repeats (VNTR), which has proven challenging to sequence due to high GC-content and considerable length variation. We have therefore developed a screening method consisting of a multiplex PCR followed by fragment analysis. The method detected putative disease-causing insertions and deletions in the proximal repeats of the VNTR, and determined the VNTR-length of each allele. When blindly testing 56 members of the two families with known single-base deletions in the CEL VNTR, the method correctly assessed the mutation carriers. Screening of 241 probands from suspected maturity-onset diabetes of the young (MODY) families negative for mutations in known MODY genes (95 individuals from Denmark and 146 individuals from UK) revealed no deletions in the proximal repeats of the CEL VNTR. However, we found one Danish patient with a short, novel CEL allele containing only three VNTR repeats (normal range 7-23 in healthy controls). This allele co-segregated with diabetes or impaired glucose tolerance in the patient's family as six of seven mutation carriers were affected. We also identified individuals who had three copies of a complete CEL VNTR. In conclusion, the CEL gene is highly polymorphic, but mutations in CEL are likely to be a rare cause of monogenic diabetes.
ESTHER : Torsvik_2010_Hum.Genet_127_55
PubMedSearch : Torsvik_2010_Hum.Genet_127_55
PubMedID: 19760265
Gene_locus related to this paper: human-CEL

Title : Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism - Fiskerstrand_2010_Am.J.Hum.Genet_87_410
Author(s) : Fiskerstrand T , H'Mida-Ben Brahim D , Johansson S , M'Zahem A , Haukanes BI , Drouot N , Zimmermann J , Cole AJ , Vedeler C , Bredrup C , Assoum M , Tazir M , Klockgether T , Hamri A , Steen VM , Boman H , Bindoff LA , Koenig M , Knappskog PM
Ref : American Journal of Human Genetics , 87 :410 , 2010
Abstract : Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a neurodegenerative disease marked by early-onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems, including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyze 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behavior, and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects.
ESTHER : Fiskerstrand_2010_Am.J.Hum.Genet_87_410
PubMedSearch : Fiskerstrand_2010_Am.J.Hum.Genet_87_410
PubMedID: 20797687
Gene_locus related to this paper: human-ABHD12

Title : Pancreatic exocrine dysfunction in maturity-onset diabetes of the young type 3 - Vesterhus_2008_Diabetes.Care_31_306
Author(s) : Vesterhus M , Raeder H , Johansson S , Molven A , Njolstad PR
Ref : Diabetes Care , 31 :306 , 2008
Abstract : OBJECTIVE: Exocrine pancreas dysfunction is seen in 10-30% of patients with type 1 and 2 diabetes. We have recently identified a syndrome of diabetes and exocrine pancreas dysfunction attributable to mutations in the carboxyl ester lipase (CEL) gene. We wanted to investigate the prevalence of pancreatic exocrine dysfunction in patients with maturity-onset diabetes of the young type 3 (MODY3). RESEARCH DESIGN AND
METHODS: All 119 patients with MODY3 in the Norwegian MODY Registry were invited to participate, and 70 (60.5%) responded, among whom 63 were adults. Control groups included 140 subjects with type 1 diabetes and 78 nondiabetic control subjects. Pancreatic dysfunction was defined by fecal elastase deficiency. Fecal fat excretion was measured in 25 patients with fecal elastase deficiency. CEL was investigated for sequence changes.
RESULTS: We found a prevalence of fecal elastase deficiency of 12.7% in adult patients with MODY3, compared with 18.6% in patients with type 1 diabetes and 3.8% in nondiabetic control subjects. The six patients with MODY3 with fecal elastase deficiency available for analysis all had increased fecal fat excretion. Fecal elastase decreased with age. Controlled for age, patients with MODY3 still had decreased fecal elastase compared with control subjects. Twelve of 70 patients (17%) had single-base insertions in CEL exon 11. Two of these had fecal elastase deficiency.
CONCLUSIONS: The prevalence of pancreatic exocrine dysfunction was 12.7% in a cohort of 63 adult patients with MODY3, similar to the prevalence among type 1 diabetic patients. Fecal fat excretion was increased in all patients with MODY3 with fecal elastase deficiency who were investigated, underscoring the potential clinical importance of the exocrine dysfunction.
ESTHER : Vesterhus_2008_Diabetes.Care_31_306
PubMedSearch : Vesterhus_2008_Diabetes.Care_31_306
PubMedID: 17989309
Gene_locus related to this paper: human-CEL

Title : Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. - Raeder_2006_Nat.Genet_38_54
Author(s) : Raeder H , Johansson S , Holm PI , Haldorsen IS , Mas E , Sbarra V , Nermoen I , Eide SA , Grevle L , Bjorkhaug L , Sagen JV , Aksnes L , Svik O , Lombardo D , Molven A , Njolstad PR
Ref : Nat Genet , 38 :54 , 2006
Abstract : Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (VNTR)-containing exon 11 of the carboxyl ester lipase (CEL) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL protein were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a group of 182 unrelated subjects with diabetes (odds ratio 4.2 (1.6, 11.5)). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells.
ESTHER : Raeder_2006_Nat.Genet_38_54
PubMedSearch : Raeder_2006_Nat.Genet_38_54
PubMedID: 16369531
Gene_locus related to this paper: human-CEL

Title : Action potentials of cultured human oat cells: whole-cell measurements with the patch-clamp technique - Johansson_1989_Acta.Physiol.Scand_135_573
Author(s) : Johansson S , Rydqvist B , Swerup C , Heilbronn E , Arhem P
Ref : Acta Physiologica Scandinavica , 135 :573 , 1989
Abstract : Oat cells (of the small cell carcinoma of the lung) have been reported to generate calcium action potentials. The calcium channels have further been suggested to play a crucial role in the relation between oat cell carcinoma and the often associated myasthenic syndrome. We have examined cultured human oat cells (U-1690) under voltage-clamp conditions, using the patch-clamp technique. We found, contrary to previous reports, that the action potential was caused by sodium and potassium currents. No calcium current was detected under these conditions, which indicates that calcium channels, if present, are very rare. The findings restrict, but do not rule out, the hypothesis that calcium plays a key role in the carcinoma/myasthenic syndrome relation.
ESTHER : Johansson_1989_Acta.Physiol.Scand_135_573
PubMedSearch : Johansson_1989_Acta.Physiol.Scand_135_573
PubMedID: 2544079