Janniche Torsvik
University of Bergen
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Publication
Featured researches published by Janniche Torsvik.
Nature Genetics | 2015
Karianne Fjeld; Frank Ulrich Weiss; Denise Lasher; Jonas Rosendahl; Jian-Min Chen; Bente B. Johansson; Holger Kirsten; Claudia Ruffert; Emmanuelle Masson; Solrun J. Steine; Peter Bugert; Miriam Cnop; Robert Grützmann; Julia Mayerle; Joachim Mössner; Monika Ringdal; Hans-Ulrich Schulz; Matthias Sendler; Peter Simon; Paweł Sztromwasser; Janniche Torsvik; Markus Scholz; Erling Tjora; Claude Férec; Heiko Witt; Markus M. Lerch; Pål R. Njølstad; Stefan Johansson
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 × 10−6 by two-tailed Fishers 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 × 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.
Journal of Biological Chemistry | 2011
Bente B. Johansson; Janniche Torsvik; Lise Bjørkhaug; Mette Vesterhus; Anja Ragvin; Erling Tjora; Karianne Fjeld; Dag Hoem; Stefan Johansson; Helge Ræder; Susanne Lindquist; Olle Hernell; Miriam Cnop; Jaakko Saraste; Torgeir Flatmark; Pål R. Njølstad
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.
Human Genetics | 2010
Janniche Torsvik; Stefan Johansson; Anders Johansen; Jakob Ek; Jayne Minton; Helge Ræder; Sian Ellard; Andrew T. Hattersley; Oluf Pedersen; Torben Hansen; Pål R. Njølstad
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.
Pancreatology | 2013
Anja Ragvin; Karianne Fjeld; F. Ulrich Weiss; Janniche Torsvik; Ali Aghdassi; Julia Mayerle; Peter Simon; Pål R. Njølstad; Markus M. Lerch; Stefan Johansson
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.
Embo Molecular Medicine | 2016
Dario Brunetti; Janniche Torsvik; Cristina Dallabona; Pedro Filipe Teixeira; Paweł Sztromwasser; Erika Fernandez-Vizarra; Raffaele Cerutti; Aurelio Reyes; Carmela Preziuso; Giulia d'Amati; Enrico Baruffini; Carlo Viscomi; Ileana Ferrero; Helge Boman; Wenche Telstad; Stefan Johansson; Elzbieta Glaser; Per M. Knappskog; Massimo Zeviani; Laurence A. Bindoff
Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1+/− heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ‐positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration.
Journal of Biological Chemistry | 2014
Janniche Torsvik; Bente B. Johansson; Monica Dalva; Michaël Marie; Karianne Fjeld; Stefan Johansson; Geir Bjørkøy; Jaakko Saraste; Pål R. Njølstad
Background: Mutations in the carboxyl ester lipase (CEL) gene cause a syndrome of pancreatic exocrine and endocrine dysfunction (MODY8). Results: Secreted mutant CEL forms aggregates that line the plasma membrane and are cleared by endocytosis. Conclusion: The mutant and normal CEL protein exhibit different cellular properties both in pancreatic and non-pancreatic cell models. Significance: MODY8 pathogenesis may involve endocytosis of a mutant CEL protein with toxic effect. Maturity-onset diabetes of the young, type 8 (MODY8) is characterized by a syndrome of autosomal dominantly inherited diabetes and exocrine pancreatic dysfunction. It is caused by deletion mutations in the last exon of the carboxyl ester lipase (CEL) gene, resulting in a CEL protein with increased tendency to aggregate. In this study we investigated the intracellular distribution of the wild type (WT) and mutant (MUT) CEL proteins in cellular models. We found that both CEL-WT and CEL-MUT were secreted via the endoplasmic reticulum and Golgi compartments. However, their subcellular distributions differed, as only CEL-MUT was observed as an aggregate at the cell surface and inside large cytoplasmic vacuoles. Many of the vacuoles were identified as components of the endosomal system, and after its secretion, the mutant CEL protein was re-internalized, transported to the lysosomes, and degraded. Internalization of CEL-MUT also led to reduced viability of pancreatic acinar and beta cells. These findings may have implications for the understanding of how the acinar-specific CEL-MUT protein causes both exocrine and endocrine pancreatic disease.
Gene | 2018
Sylvia Varland; Line M. Myklebust; Siri Øfsthus Goksøyr; Nina Glomnes; Janniche Torsvik; Jan Erik Varhaug; Thomas Arnesen
N-terminal acetylation is a highly abundant and important protein modification in eukaryotes catalyzed by N-terminal acetyltransferases (NATs). In humans, six different NATs have been identified (NatA-NatF), each composed of individual subunits and acetylating a distinct set of substrates. Along with most NATs, NatC acts co-translationally at the ribosome. The NatC complex consists of the catalytic subunit Naa30 and the auxiliary subunits Naa35 and Naa38, and can potentially Nt-acetylate cytoplasmic proteins when the initiator methionine is followed by a bulky hydrophobic/amphipathic residue at position 2. Here, we have identified a splice variant of human NAA30, which encodes a truncated protein named Naa30288. The splice variant was abundantly present in thyroid cancer tissues and in several different human cancer cell lines. Surprisingly, Naa30288 localized predominantly to the nucleus, as opposed to annotated Naa30 which has a cytoplasmic localization. Full-length Naa30 acetylated a classical NatC substrate peptide in vitro, whereas no significant NAT activity was detected for Naa30288. Due to the nuclear localization, we also examined acetyltransferase activity towards lysine residues. Neither full-length Naa30 nor Naa30288 displayed any lysine acetyltransferase activity. Overexpression of full-length Naa30 increased cell viability via inhibition of apoptosis. In contrast, Naa30288 did not exert an anti-apoptotic effect. In sum, we identified a novel and widely expressed Naa30 isoform with a potential non-catalytic role in the nucleus.
Gene | 2006
Thomas Arnesen; Dave Anderson; Janniche Torsvik; Helene B. Halseth; Jan Erik Varhaug; Johan R. Lillehaug
Pancreatology | 2017
Monica Dalva; Khadija El Jellas; Solrun J. Steine; Bente B. Johansson; Monika Ringdal; Janniche Torsvik; Heike Immervoll; Dag Hoem; Felix Laemmerhirt; Peter Simon; Markus M. Lerch; Stefan Johansson; Pål R. Njølstad; Frank Ulrich Weiss; Karianne Fjeld
Pancreatology | 2014
Karianne Fjeld; Stefan Johansson; Jonas Rosendahl; Jian-Min Chen; Denise Lasher; Miriam Cnop; Bente B. Johansson; Emmanuelle Masson; Julia Mayerle; Joachim Mössner; Claudia Ruffert; Solrun J. Steine; Erling Tjora; Janniche Torsvik; Claude Férec; F. Ulrich Weiss; Heiko Witt; Markus M. Lerch; Pål R. Njølstad