320 results on '"Ashikov A"'
Search Results
2. In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis
- Author
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Federica Conte, Angel Ashikov, Rachel Mijdam, Eline G. P. van de Ven, Monique van Scherpenzeel, Raisa Veizaj, Seyed P. Mahalleh-Yousefi, Merel A. Post, Karin Huijben, Daan M. Panneman, Richard J. T. Rodenburg, Nicol C. Voermans, Alejandro Garanto, Werner J. H. Koopman, Hans J. C. T. Wessels, Marek J. Noga, and Dirk J. Lefeber
- Subjects
phosphoglucomutase 1 ,PGM1 deficiency ,PGM1 congenital disorder of glycosylation ,in vitro muscle model ,muscle energy homeostasis ,muscle metabolic plasticity ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.
- Published
- 2023
- Full Text
- View/download PDF
3. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
- Author
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Linders, Peter T. A., Gerretsen, Eveline C. F., Ashikov, Angel, Vals, Mari-Anne, de Boer, Rinse, Revelo, Natalia H., Arts, Richard, Baerenfaenger, Melissa, Zijlstra, Fokje, Huijben, Karin, Raymond, Kimiyo, Muru, Kai, Fjodorova, Olga, Pajusalu, Sander, Õunap, Katrin, ter Beest, Martin, Lefeber, Dirk, and van den Bogaart, Geert
- Published
- 2021
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- View/download PDF
4. A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy
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Walinka vanTol, Angel Ashikov, Eckhard Korsch, Nurulamin Abu Bakar, Michèl A. Willemsen, Christian Thiel, and Dirk J. Lefeber
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congenital disorders of glycosylation ,dolichol‐phosphate‐mannose ,dystroglycanopathy ,MPDU1‐CDG ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract Congenital disorders of glycosylation type I (CDG‐I) are inborn errors of metabolism, generally characterized by multisystem clinical manifestations, including developmental delay, hepatopathy, hypotonia, and skin, skeletal, and neurological abnormalities. Among others, dolichol‐phosphate‐mannose (DPM) is the mannose donor for N‐glycosylation as well as O‐mannosylation. DOLK‐CDG, DPM1‐CDG, DPM2‐CDG, and DPM3‐CDG are defects in the DPM synthesis showing both CDG‐I abnormalities and reduced O‐mannosylation of alpha‐dystroglycan (αDG), which leads to muscular dystrophy‐dystroglycanopathy. Mannose‐phosphate‐dolichol utilization defect 1 (MPDU1) plays a role in the utilization of DPM. Here, we report two MPDU1‐CDG patients without skin involvement, but with massive dilatation of the biliary duct system and dystroglycanopathy characteristics including hypotonia, elevated creatine kinase, dilated cardiomyopathy, buphthalmos, and congenital glaucoma. Biochemical analyses revealed elevated disialotransferrin in serum, and analyses in fibroblasts showed shortened lipid linked oligosaccharides and DPM, and reduced O‐mannosylation of αDG. Thus, MPDU1‐CDG can be added to the list of disorders with overlapping biochemical and clinical abnormalities of CDG‐I and dystroglycanopathy. Synopsis Mannose‐phosphate‐dolichol utilization defect 1 patients can have overlapping biochemical and clinical abnormalities of congenital disorders of glycosylation type I and dystroglycanopathy.
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- 2019
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- View/download PDF
5. In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis
- Author
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Conte, Federica, primary, Ashikov, Angel, additional, Mijdam, Rachel, additional, van de Ven, Eline G. P., additional, van Scherpenzeel, Monique, additional, Veizaj, Raisa, additional, Mahalleh-Yousefi, Seyed P., additional, Post, Merel A., additional, Huijben, Karin, additional, Panneman, Daan M., additional, Rodenburg, Richard J. T., additional, Voermans, Nicol C., additional, Garanto, Alejandro, additional, Koopman, Werner J. H., additional, Wessels, Hans J. C. T., additional, Noga, Marek J., additional, and Lefeber, Dirk J., additional
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- 2023
- Full Text
- View/download PDF
6. In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis.
- Author
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Conte, F., Ashikov, A.M., Mijdam, R., Ven, E.G.P. van de, Scherpenzeel, M. van, Veizaj, R., Mahalleh-Yousefi, S.P., Post, M.A., Huijben, Karin, Panneman, D.M., Rodenburg, R.J.T., Voermans, N.C., Garanto, A., Koopman, W.J.H., Wessels, H.J.C.T., Noga, M.J., Lefeber, D.J., Conte, F., Ashikov, A.M., Mijdam, R., Ven, E.G.P. van de, Scherpenzeel, M. van, Veizaj, R., Mahalleh-Yousefi, S.P., Post, M.A., Huijben, Karin, Panneman, D.M., Rodenburg, R.J.T., Voermans, N.C., Garanto, A., Koopman, W.J.H., Wessels, H.J.C.T., Noga, M.J., and Lefeber, D.J.
- Abstract
Contains fulltext : 292737.pdf (Publisher’s version ) (Open Access), Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on (13)C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.
- Published
- 2023
7. In Vitro Skeletal Muscle Model of PGM1 Deficiency Reveals Altered Energy Homeostasis
- Author
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Conte, Federica, Ashikov, Angel, Mijdam, Rachel, van de Ven, Eline G.P., van Scherpenzeel, Monique, Veizaj, Raisa, Mahalleh-Yousefi, Seyed P., Post, Merel A., Huijben, Karin, Panneman, Daan M., Rodenburg, Richard J.T., Voermans, Nicol C., Garanto, Alejandro, Koopman, Werner J.H., Wessels, Hans J.C.T., Noga, Marek J., Lefeber, Dirk J., Conte, Federica, Ashikov, Angel, Mijdam, Rachel, van de Ven, Eline G.P., van Scherpenzeel, Monique, Veizaj, Raisa, Mahalleh-Yousefi, Seyed P., Post, Merel A., Huijben, Karin, Panneman, Daan M., Rodenburg, Richard J.T., Voermans, Nicol C., Garanto, Alejandro, Koopman, Werner J.H., Wessels, Hans J.C.T., Noga, Marek J., and Lefeber, Dirk J.
- Abstract
Phosphoglucomutase 1 (PGM1) is a key enzyme for the regulation of energy metabolism from glycogen and glycolysis, as it catalyzes the interconversion of glucose 1-phosphate and glucose 6-phosphate. PGM1 deficiency is an autosomal recessive disorder characterized by a highly heterogenous clinical spectrum, including hypoglycemia, cleft palate, liver dysfunction, growth delay, exercise intolerance, and dilated cardiomyopathy. Abnormal protein glycosylation has been observed in this disease. Oral supplementation with D-galactose efficiently restores protein glycosylation by replenishing the lacking pool of UDP-galactose, and rescues some symptoms, such as hypoglycemia, hepatopathy, and growth delay. However, D-galactose effects on skeletal muscle and heart symptoms remain unclear. In this study, we established an in vitro muscle model for PGM1 deficiency to investigate the role of PGM1 and the effect of D-galactose on nucleotide sugars and energy metabolism. Genome-editing of C2C12 myoblasts via CRISPR/Cas9 resulted in Pgm1 (mouse homologue of human PGM1, according to updated nomenclature) knockout clones, which showed impaired maturation to myotubes. No difference was found for steady-state levels of nucleotide sugars, while dynamic flux analysis based on 13C6-galactose suggested a block in the use of galactose for energy production in knockout myoblasts. Subsequent analyses revealed a lower basal respiration and mitochondrial ATP production capacity in the knockout myoblasts and myotubes, which were not restored by D-galactose. In conclusion, an in vitro mouse muscle cell model has been established to study the muscle-specific metabolic mechanisms in PGM1 deficiency, which suggested that galactose was unable to restore the reduced energy production capacity.
- Published
- 2023
8. GDP-Fucose Transporter 1 (SLC35C1)
- Author
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Bakker, Hans, Ashikov, Angel, Routier, Francoise H., Gerardy-Schahn, Rita, Taniguchi, Naoyuki, editor, Honke, Koichi, editor, Fukuda, Minoru, editor, Narimatsu, Hisashi, editor, Yamaguchi, Yoshiki, editor, and Angata, Takashi, editor
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- 2014
- Full Text
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9. UDP-Xylose and UDP-N-Acetylglucosamine Transporter (SLC35B4)
- Author
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Bakker, Hans, Ashikov, Angel, Taniguchi, Naoyuki, editor, Honke, Koichi, editor, Fukuda, Minoru, editor, Narimatsu, Hisashi, editor, Yamaguchi, Yoshiki, editor, and Angata, Takashi, editor
- Published
- 2014
- Full Text
- View/download PDF
10. Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation
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Riemersma, Moniek, Froese, D. Sean, van Tol, Walinka, Engelke, Udo F., Kopec, Jolanta, van Scherpenzeel, Monique, Ashikov, Angel, Krojer, Tobias, von Delft, Frank, Tessari, Marco, Buczkowska, Anna, Swiezewska, Ewa, Jae, Lucas T., Brummelkamp, Thijn R., Manya, Hiroshi, Endo, Tamao, van Bokhoven, Hans, Yue, Wyatt W., and Lefeber, Dirk J.
- Published
- 2015
- Full Text
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11. ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation
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Eric J. R. Jansen, Sharita Timal, Margret Ryan, Angel Ashikov, Monique van Scherpenzeel, Laurie A. Graham, Hanna Mandel, Alexander Hoischen, Theodore C. Iancu, Kimiyo Raymond, Gerry Steenbergen, Christian Gilissen, Karin Huijben, Nick H. M. van Bakel, Yusuke Maeda, Richard J. Rodenburg, Maciej Adamowicz, Ellen Crushell, Hans Koenen, Darius Adams, Julia Vodopiutz, Susanne Greber-Platzer, Thomas Müller, Gregor Dueckers, Eva Morava, Jolanta Sykut-Cegielska, Gerard J. M. Martens, Ron A. Wevers, Tim Niehues, Martijn A. Huynen, Joris A. Veltman, Tom H. Stevens, and Dirk J. Lefeber
- Subjects
Science - Abstract
Here, Dirk Lefeber and colleagues identify functional mutations in ATP6AP1 encoding Ac45. The authors show that Ac45 is the functional ortholog of yeast V-ATPase assembly factor Voa1 and provide evidence for tissue-specific Ac45 processing, associated with the clinical phenotype of immunodeficiency, hepatopathy, and neurocognitive abnormalities.
- Published
- 2016
- Full Text
- View/download PDF
12. Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1
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Nurulamin Abu Bakar, Angel Ashikov, Jaime Moritz Brum, Roel Smeets, Marjan Kersten, Karin Huijben, Wee Teik Keng, Carlos Eduardo Speck‐Martins, Daniel Rocha de Carvalho, Isabela Maria Pinto Oliveira de Rizzo, Walquiria Domingues de Mello, Rebecca Heiner‐Fokkema, Kathleen Gorman, Stephanie Grunewald, Helen Michelakakis, Marina Moraitou, Diego Martinelli, Monique van Scherpenzeel, Mirian Janssen, Lonneke de Boer, Lambertus P. van den Heuvel, Christian Thiel, Dirk J. Lefeber, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
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Glycosylation ,congenital disorders of glycosylation (CDG) ,Oligosaccharides ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,multi-omics ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,N-Acetylglucosaminyltransferases ,TETRASACCHARIDE ,Mannosyltransferases ,TRANSFERRIN ,glycomics ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Congenital Disorders of Glycosylation ,Polysaccharides ,Genetics ,Humans ,CDG type 1 (CDG-I) ,smMIPs ,diagnostics by mass spectrometry ,Mannose ,Genetics (clinical) - Abstract
Contains fulltext : 282651.pdf (Publisher’s version ) (Open Access) Congenital disorders of glycosylation type 1 (CDG-I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with nonspecific neurological symptoms. The biochemical hallmark of CDG-I is a partial absence of complete N-glycans on transferrin. However, recent findings of a diagnostic N-tetrasaccharide for ALG1-CDG and increased high-mannose N-glycans for a few other CDG suggested the potential of glycan structural analysis for CDG-I gene discovery. We analyzed the relative abundance of total plasma N-glycans by high resolution quadrupole time-of-flight mass spectrometry in a large cohort of 111 CDG-I patients with known (n = 75) or unsolved (n = 36) genetic cause. We designed single-molecule molecular inversion probes (smMIPs) for sequencing of CDG-I candidate genes on the basis of specific N-glycan signatures. Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG. Moreover, group-specific high-mannose N-glycan signatures were found in ALG3-, ALG9-, ALG11-, ALG12-, RFT1-, SRD5A3-, DOLK-, DPM1-, DPM3-, MPDU1-, ALG13-CDG, and hereditary fructose intolerance. Further differential analysis revealed high-mannose profiles, characteristic for ALG12- and ALG9-CDG. Prediction of candidate genes by glycomics profiling in 36 patients with thus far unsolved CDG-I and subsequent smMIPs sequencing led to a yield of solved cases of 78% (28/36). Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG-I patient cohorts.
- Published
- 2022
13. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings
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Rita Barone, Filippo Vairo, Bobby G. Ng, Jaak Jaeken, Gert Matthijs, James Pitt, Thierry Dupré, Lyndon Gallacher, Liesbeth Keldermans, Helen Michelakakis, Marina Ventouratou, Susan M. White, Sze Chern Lim, Melissa Baerenfaenger, Mirian C. H. Janssen, Angel Ashikov, Karin Huijben, Sandrine Vuillaumier-Barrot, Diana Ballhausen, Daisy Rymen, Agustí Rodríguez-Palmero, Blai Morales-Romero, Antonia Ribes, Peter Witters, Heidi Peters, Erika Souche, Eva Morava, Agata Fiumara, Pascale de Lonlay, Matthew P. Wilson, Dirk Lefeber, Wasantha Ranatunga, Alejandro Garanto, Hudson H. Freeze, Christian Thiel, BioAnalytical Chemistry, and AIMMS
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Male ,Mutant ,congenital disorders of glycosylation ,chemistry.chemical_compound ,0302 clinical medicine ,Catalytic Domain ,Missense mutation ,Musculoskeletal Diseases ,Genetics (clinical) ,Genes, Dominant ,chemistry.chemical_classification ,Genetics ,0303 health sciences ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Middle Aged ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Pedigree ,Oligosaccharyltransferase complex ,Child, Preschool ,glycosylation ,Female ,Adult ,Heterozygote ,Glycosylation ,Adolescent ,Protein subunit ,Biology ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,oligosaccharyltransferase complex ,medicine ,Humans ,dominant inheritance ,Amino Acid Sequence ,030304 developmental biology ,Sequence Homology, Amino Acid ,Oligosaccharyltransferase ,Membrane Proteins ,medicine.disease ,chemistry ,Hexosyltransferases ,Nervous System Diseases ,Glycoprotein ,Congenital disorder of glycosylation ,030217 neurology & neurosurgery - Abstract
Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:11 pages:2130-2144 ispartof: location:United States status: published
- Published
- 2021
14. Arabidopsis ROCK1 transports UDP-GlcNAc/UDP-GalNAc and regulates ER protein quality control and cytokinin activity
- Author
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Niemann, Michael C. E., Bartrina, Isabel, Ashikov, Angel, Weber, Henriette, Novák, Ondřej, Spíchal, Lukáš, Strnad, Miroslav, Strasser, Richard, Bakker, Hans, Schmülling, Thomas, and Werner, Tomáš
- Published
- 2015
15. Structure and function of nucleotide sugar transporters: Current progress
- Author
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Barbara Hadley, Andrea Maggioni, Angel Ashikov, Christopher J. Day, Thomas Haselhorst, and Joe Tiralongo
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Nucleotide sugar transporters ,CMP-sialic acid transporter ,Golgi apparatus ,Endoplasmic reticulum ,STD NMR spectroscopy ,Biotechnology ,TP248.13-248.65 - Abstract
The proteomes of eukaryotes, bacteria and archaea are highly diverse due, in part, to the complex post-translational modification of protein glycosylation. The diversity of glycosylation in eukaryotes is reliant on nucleotide sugar transporters to translocate specific nucleotide sugars that are synthesised in the cytosol and nucleus, into the endoplasmic reticulum and Golgi apparatus where glycosylation reactions occur. Thirty years of research utilising multidisciplinary approaches has contributed to our current understanding of NST function and structure. In this review, the structure and function, with reference to various disease states, of several NSTs including the UDP-galactose, UDP-N-acetylglucosamine, UDP-N-acetylgalactosamine, GDP-fucose, UDP-N-acetylglucosamine/UDP-glucose/GDP-mannose and CMP-sialic acid transporters will be described. Little is known regarding the exact structure of NSTs due to difficulties associated with crystallising membrane proteins. To date, no three-dimensional structure of any NST has been elucidated. What is known is based on computer predictions, mutagenesis experiments, epitope-tagging studies, in-vitro assays and phylogenetic analysis. In this regard the best-characterised NST to date is the CMP-sialic acid transporter (CST). Therefore in this review we will provide the current state-of-play with respect to the structure–function relationship of the (CST). In particular we have summarised work performed by a number groups detailing the affect of various mutations on CST transport activity, efficiency, and substrate specificity.
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- 2014
- Full Text
- View/download PDF
16. Dynamic tracing of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
- Author
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Scherpenzeel, M. van, Conte, F., Büll, C., Ashikov, A.M., Hermans, E., Willems, A.P., Tol, W. van, Kragt, E., Noga, M.J., Moret, E.E., Heise, Torben, Langereis, J.D., Rossing, E., Zimmermann, M., Rubio-Gozalbo, M.E., Jonge, M.I. de, Adema, G.J., Zamboni, N., Boltje, T.J., Lefeber, D.J., Scherpenzeel, M. van, Conte, F., Büll, C., Ashikov, A.M., Hermans, E., Willems, A.P., Tol, W. van, Kragt, E., Noga, M.J., Moret, E.E., Heise, Torben, Langereis, J.D., Rossing, E., Zimmermann, M., Rubio-Gozalbo, M.E., Jonge, M.I. de, Adema, G.J., Zamboni, N., Boltje, T.J., and Lefeber, D.J.
- Abstract
Contains fulltext : 248778.pdf (Publisher’s version ) (Open Access)
- Published
- 2022
17. Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1
- Author
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AbuBakar, N. Bin, Ashikov, A.M., Brum, J.M., Smeets, R.J.P., Kersten, Marjan, Huijben, Karin, Keng, W.T., Speck-Martins, C.E., Carvalho, D.R., Rizzo, I. de, Mello, W.D. de, Heiner-Fokkema, R., Gorman, K., Grunewald, S., Michelakakis, H., Moraitou, M., Martinelli, D., Scherpenzeel, M. van, Janssen, M.C.H., Boer, L. de, Heuvel, L.P.W.J. van den, Thiel, C, Lefeber, D.J., AbuBakar, N. Bin, Ashikov, A.M., Brum, J.M., Smeets, R.J.P., Kersten, Marjan, Huijben, Karin, Keng, W.T., Speck-Martins, C.E., Carvalho, D.R., Rizzo, I. de, Mello, W.D. de, Heiner-Fokkema, R., Gorman, K., Grunewald, S., Michelakakis, H., Moraitou, M., Martinelli, D., Scherpenzeel, M. van, Janssen, M.C.H., Boer, L. de, Heuvel, L.P.W.J. van den, Thiel, C, and Lefeber, D.J.
- Abstract
Contains fulltext : 282651.pdf (Publisher’s version ) (Open Access), Congenital disorders of glycosylation type 1 (CDG-I) comprise a group of 27 genetic defects with heterogeneous multisystem phenotype, mostly presenting with nonspecific neurological symptoms. The biochemical hallmark of CDG-I is a partial absence of complete N-glycans on transferrin. However, recent findings of a diagnostic N-tetrasaccharide for ALG1-CDG and increased high-mannose N-glycans for a few other CDG suggested the potential of glycan structural analysis for CDG-I gene discovery. We analyzed the relative abundance of total plasma N-glycans by high resolution quadrupole time-of-flight mass spectrometry in a large cohort of 111 CDG-I patients with known (n = 75) or unsolved (n = 36) genetic cause. We designed single-molecule molecular inversion probes (smMIPs) for sequencing of CDG-I candidate genes on the basis of specific N-glycan signatures. Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG. Moreover, group-specific high-mannose N-glycan signatures were found in ALG3-, ALG9-, ALG11-, ALG12-, RFT1-, SRD5A3-, DOLK-, DPM1-, DPM3-, MPDU1-, ALG13-CDG, and hereditary fructose intolerance. Further differential analysis revealed high-mannose profiles, characteristic for ALG12- and ALG9-CDG. Prediction of candidate genes by glycomics profiling in 36 patients with thus far unsolved CDG-I and subsequent smMIPs sequencing led to a yield of solved cases of 78% (28/36). Combined plasma glycomics profiling and targeted smMIPs sequencing of candidate genes is a powerful approach to identify causative mutations in CDG-I patient cohorts.
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- 2022
18. Dynamic tracing of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
- Author
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Afd Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Scherpenzeel, Monique, Conte, Federica, Büll, Christian, Ashikov, Angel, Hermans, Esther, Willems, Anke, Tol, Walinka, Kragt, Else, Noga, Marek, Moret, Ed E, Heise, Torben, Langereis, Jeroen D, Rossing, Emiel, Zimmermann, Michael, Rubio-Gozalbo, M Estela, de Jonge, Marien I, Adema, Gosse J, Zamboni, Nicola, Boltje, Thomas, Lefeber, Dirk J, Afd Chemical Biology and Drug Discovery, Chemical Biology and Drug Discovery, Scherpenzeel, Monique, Conte, Federica, Büll, Christian, Ashikov, Angel, Hermans, Esther, Willems, Anke, Tol, Walinka, Kragt, Else, Noga, Marek, Moret, Ed E, Heise, Torben, Langereis, Jeroen D, Rossing, Emiel, Zimmermann, Michael, Rubio-Gozalbo, M Estela, de Jonge, Marien I, Adema, Gosse J, Zamboni, Nicola, Boltje, Thomas, and Lefeber, Dirk J
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- 2022
19. Effects of a human recombinant alkaline phosphatase during impaired mitochondrial function in human renal proximal tubule epithelial cells
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Peters, Esther, Schirris, Tom, van Asbeck, Alexander H, Gerretsen, Jelle, Eymael, Jennifer, Ashikov, Angel, Adjobo-Hermans, Merel J.W., Russel, Frans, Pickkers, Peter, and Masereeuw, Rosalinde
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- 2017
- Full Text
- View/download PDF
20. Cryptococcus neoformans UGT1 encodes a UDP-Galactose/UDP-GalNAc transporter
- Author
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Li, Lucy X, Ashikov, Angel, Liu, Hong, Griffith, Cara L, Bakker, Hans, and Doering, Tamara L
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- 2017
- Full Text
- View/download PDF
21. Synergistic use of glycomics and single‐molecule molecular inversion probes for identification of congenital disorders of glycosylation type‐1
- Author
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Abu Bakar, Nurulamin, primary, Ashikov, Angel, additional, Brum, Jaime Moritz, additional, Smeets, Roel, additional, Kersten, Marjan, additional, Huijben, Karin, additional, Keng, Wee Teik, additional, Speck‐Martins, Carlos Eduardo, additional, de Carvalho, Daniel Rocha, additional, de Rizzo, Isabela Maria Pinto Oliveira, additional, de Mello, Walquiria Domingues, additional, Heiner‐Fokkema, Rebecca, additional, Gorman, Kathleen, additional, Grunewald, Stephanie, additional, Michelakakis, Helen, additional, Moraitou, Marina, additional, Martinelli, Diego, additional, van Scherpenzeel, Monique, additional, Janssen, Mirian, additional, de Boer, Lonneke, additional, van den Heuvel, Lambertus P., additional, Thiel, Christian, additional, and Lefeber, Dirk J., additional
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- 2022
- Full Text
- View/download PDF
22. Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease
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Elzbieta Czarnowska, Magda Cannata Serio, Pavel Pichurin, Sharita Timal, Jos C. Jansen, Hannu Kalimo, Adriaan G. Holleboom, Can Ficicioglu, Margret Ryan, Johan W. Jonker, Richard J. Rodenburg, Linda Hasadsri, Angel Ashikov, Christian Gilissen, Miao He, W. Alfredo Ríos-Ocampo, Matias Simons, Lars E. Larsen, Dirk Lefeber, Berge A. Minassian, Alessandra Rugierri, Joris A. Veltman, Tom H. Stevens, Gwenn Le Meur, Eva Morava, Piotr Socha, Kimiyo Raymond, Laurie A. Graham, Vascular Medicine, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Faculteit Medische Wetenschappen/UMCG, Medicum, Department of Pathology, University of Helsinki, and HUS Helsinki and Uusimaa Hospital District
- Subjects
Male ,0301 basic medicine ,Biopsy ,DNA Mutational Analysis ,chemistry.chemical_compound ,Steatohepatitis/Metabolic Liver Disease ,Congenital Disorders of Glycosylation ,0302 clinical medicine ,Lipid droplet ,Nonalcoholic fatty liver disease ,Cells, Cultured ,Chemistry ,Liver Diseases ,CHOLESTEROL ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Pedigree ,3. Good health ,Cell biology ,DEFICIENCY ,Liver ,030211 gastroenterology & hepatology ,Original Article ,Erratum ,ENZYMES ,Adult ,Vacuolar Proton-Translocating ATPases ,X-LINKED MYOPATHY ,Primary Cell Culture ,Mutation, Missense ,ENDOPLASMIC-RETICULUM ,Abnormal protein glycosylation ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Autophagy ,medicine ,Humans ,VACUOLAR MEMBRANE ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Hepatology ,Cholesterol ,Endoplasmic reticulum ,Original Articles ,Fibroblasts ,medicine.disease ,TRANSPORT ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Unfolded protein response ,Steatosis ,Congenital disorder of glycosylation ,GOLGI HOMEOSTASIS - Abstract
Background and Aims Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy.Approach and Results Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways.Conclusions Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease.
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- 2020
23. Dynamic tracing of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
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Monique van Scherpenzeel, Federica Conte, Christian Büll, Angel Ashikov, Esther Hermans, Anke Willems, Walinka van Tol, Else Kragt, Marek Noga, Ed E Moret, Torben Heise, Jeroen D Langereis, Emiel Rossing, Michael Zimmermann, M Estela Rubio-Gozalbo, Marien I de Jonge, Gosse J Adema, Nicola Zamboni, Thomas Boltje, Dirk J Lefeber, Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), and RS: GROW - R4 - Reproductive and Perinatal Medicine
- Subjects
glycosylation ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,INHIBITION ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Synthetic Organic Chemistry ,synthetic sugar analog ,Biochemistry ,130 000 Cognitive Neurology & Memory ,sugar metabolism ,BIOSYNTHESIS ,fluoro sialic acid ,metabolic oligosaccharide engineering ,SIALIC-ACID ,Glucosamine ,IDENTIFICATION ,MUTATIONS ,SIALYLATION ,Fluoro sialic acid ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,MASS-SPECTROMETRY ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,carbohydrates (lipids) ,TARGET ,Cytidine Monophosphate N-Acetylneuraminic Acid ,Carbohydrate Metabolism ,Sugars ,NUCLEOTIDE SUGARS ,Chromatography, Liquid - Abstract
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact cellular metabolism over time are mostly lacking. We combined ion-pair UHPLC-QqQ mass spectrometry using tributyl- and triethylamine buffers for sensitive analysis of sugar metabolites in cells and organisms and identified low abundant nucleotide sugars, such as UDP-arabinose in human cell lines and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Furthermore, MOE revealed that propargyloxycarbonyl (Poc) labeled ManNPoc was metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, time-course analysis of the effect of antitumor compound 3Fax-NeuNAc by incubation of B16-F10 melanoma cells with N-acetyl-D-[UL-13C6]glucosamine revealed full depletion of endogenous ManNAc 6-phosphate and CMP-NeuNAc within 24 hour. Thus, dynamic tracing of sugar metabolic pathways provides a general approach to reveal time-dependent insights into the metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects., Glycobiology, 32 (3), ISSN:0959-6658
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- 2022
24. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings
- Author
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Wilson, Matthew P., primary, Garanto, Alejandro, additional, Pinto e Vairo, Filippo, additional, Ng, Bobby G., additional, Ranatunga, Wasantha K., additional, Ventouratou, Marina, additional, Baerenfaenger, Melissa, additional, Huijben, Karin, additional, Thiel, Christian, additional, Ashikov, Angel, additional, Keldermans, Liesbeth, additional, Souche, Erika, additional, Vuillaumier-Barrot, Sandrine, additional, Dupré, Thierry, additional, Michelakakis, Helen, additional, Fiumara, Agata, additional, Pitt, James, additional, White, Susan M., additional, Lim, Sze Chern, additional, Gallacher, Lyndon, additional, Peters, Heidi, additional, Rymen, Daisy, additional, Witters, Peter, additional, Ribes, Antonia, additional, Morales-Romero, Blai, additional, Rodríguez-Palmero, Agustí, additional, Ballhausen, Diana, additional, de Lonlay, Pascale, additional, Barone, Rita, additional, Janssen, Mirian C.H., additional, Jaeken, Jaak, additional, Freeze, Hudson H., additional, Matthijs, Gert, additional, Morava, Eva, additional, and Lefeber, Dirk J., additional
- Published
- 2021
- Full Text
- View/download PDF
25. Dynamic tracing of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
- Author
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van Scherpenzeel, Monique, primary, Conte, Federica, additional, Büll, Christian, additional, Ashikov, Angel, additional, Hermans, Esther, additional, Willems, Anke, additional, van Tol, Walinka, additional, Kragt, Else, additional, Noga, Marek, additional, Moret, Ed E, additional, Heise, Torben, additional, Langereis, Jeroen D, additional, Rossing, Emiel, additional, Zimmermann, Michael, additional, Rubio-Gozalbo, M Estela, additional, de Jonge, Marien I, additional, Adema, Gosse J, additional, Zamboni, Nicola, additional, Boltje, Thomas, additional, and Lefeber, Dirk J, additional
- Published
- 2021
- Full Text
- View/download PDF
26. Disease mutations in CMP-sialic acid transporter SLC35A1 result in abnormal α-dystroglycan O-mannosylation, independent from sialic acid
- Author
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Riemersma, Moniek, Sandrock, Julia, Boltje, Thomas J., Büll, Christian, Heise, Torben, Ashikov, Angel, Adema, Gosse J., van Bokhoven, Hans, and Lefeber, Dirk J.
- Published
- 2015
- Full Text
- View/download PDF
27. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
- Author
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Olga Fjodorova, Natalia H. Revelo, Eveline C F Gerretsen, Richard Arts, Kimiyo Raymond, Fokje Zijlstra, Martin ter Beest, Karin Huijben, Rinse de Boer, Angel Ashikov, Katrin Õunap, Mari-Anne Vals, Kai Muru, Geert van den Bogaart, Melissa Baerenfaenger, Peter T. A. Linders, Dirk Lefeber, Sander Pajusalu, Molecular Cell Biology, and Molecular Immunology
- Subjects
Gene isoform ,Glycosylation ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Science ,Amino Acid Motifs ,Glycobiology ,Golgi Apparatus ,General Physics and Astronomy ,STX5 ,Article ,General Biochemistry, Genetics and Molecular Biology ,Congenital Abnormalities ,Abnormal glycosylation ,03 medical and health sciences ,chemistry.chemical_compound ,symbols.namesake ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Golgi ,medicine ,Humans ,Protein Isoforms ,Secretory pathway ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Methionine ,Qa-SNARE Proteins ,Chemistry ,General Chemistry ,Fibroblasts ,Golgi apparatus ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,medicine.disease ,3. Good health ,Cell biology ,Protein Transport ,Mechanisms of disease ,Protein Biosynthesis ,Mutation ,symbols ,Congenital disorder of glycosylation ,030217 neurology & neurosurgery - Abstract
The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking., Mutations in genes critical for proper intra-Golgi transport can cause human syndromes due to defects in glycosylation of proteins. Here, the authors identify a human variant of Syntaxin-5 that causes fatal multisystem disease and mislocalization of glycosyltransferases due to altered Golgi transport.
- Published
- 2021
28. Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings
- Author
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Wilson, M., Garanto, A., Vairo, F., Ng, Bobby G., Ranatunga, Wasantha K., Ventouratou, Marina, Barenfanger, M., Huijben, Karin, Ashikov, A.M., Janssen, M.C.H., Morava, E., Lefeber, D.J., Wilson, M., Garanto, A., Vairo, F., Ng, Bobby G., Ranatunga, Wasantha K., Ventouratou, Marina, Barenfanger, M., Huijben, Karin, Ashikov, A.M., Janssen, M.C.H., Morava, E., and Lefeber, D.J.
- Abstract
Item does not contain fulltext
- Published
- 2021
29. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
- Author
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Linders, P.T.A., Gerretsen, E.C.F., Ashikov, A.M., Vals, M.A., Boer, R.J. de, Revelo, N.H., Arts, Richard, Baerenfaenger, J.M., Huijben, Karin, Zijlstra, F.S., Beest, M.B.A. ter, Lefeber, D.J., Bogaart, G. van den, Linders, P.T.A., Gerretsen, E.C.F., Ashikov, A.M., Vals, M.A., Boer, R.J. de, Revelo, N.H., Arts, Richard, Baerenfaenger, J.M., Huijben, Karin, Zijlstra, F.S., Beest, M.B.A. ter, Lefeber, D.J., and Bogaart, G. van den
- Abstract
Contains fulltext : 239969.pdf (Publisher’s version ) (Open Access)
- Published
- 2021
30. A CMP-sialic acid transporter cloned from Arabidopsis thaliana
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Bakker, Hans, Routier, Françoise, Ashikov, Angel, Neumann, Detlef, Bosch, Dirk, and Gerardy-Schahn, Rita
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- 2008
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31. A syndrome with congenital neutropenia and mutations in G6PC3
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Boztug, Kaan, Appaswamy, Giridharan, Ashikov, Angel, Schaffer, Alejandro A., Salzer, Ulrich, Diestelhorst, Jana, Germeshausen, Manuela, Brandes, Gudrun, Lee-Gossler, Jacqueline, Noyan, Fatih, Gatzke, Anna-Katherina, Minkov, Milen, Greil, Johann, Kratz, Christian, Petropoulou, Theoni, Pellier, Isabelle, Bellanne-Chantelot, Christine, Rezaei, Nima, Monkemoller, Kirsten, Irani-Hakimeh, Noha, Bakker, Hans, Gerardy-Schahn, Rita, Zeidler, Cornelia, Grimbacher, Bodo, Welte, Karl, and Klein, Christoph
- Subjects
Neutropenia -- Diagnosis ,Neutropenia -- Causes of ,Neutropenia -- Risk factors ,Neutropenia -- Genetic aspects ,Gene mutations -- Research ,Gene mutations -- Physiological aspects - Abstract
A study was conducted to investigate the main features and causes of severe congenital neutropenia. Results indicated that defective function of glucose-6-phosphate, catalytic subunit 3, due to mutations in its encoding gene G6PC3, is indicative of the syndrome.
- Published
- 2009
32. Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis
- Author
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Edvardson, Simon, Ashikov, Angel, Jalas, Chaim, Sturiale, Luisa, Shaag, Avraham, Fedick, Anastasia, Treff, Nathan R, Garozzo, Domenico, Gerardy-Schahn, Rita, and Elpeleg, Orly
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- 2013
- Full Text
- View/download PDF
33. Supplement to: A syndrome with congenital neutropenia and mutations in G6PC3.
- Author
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Boztug, K, Appaswamy, G, and Ashikov, A
- Published
- 2009
34. Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
- Author
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van Scherpenzeel, Monique, Conte, Federica, Büll, Christian, Ashikov, Angel, Hermans, Esther, Willems, Anke, van Tol, Walinka, Kragt, Else, Moret, Ed E., Heise, Torben, Langereis, Jeroen D., Rossing, Emiel, Zimmermann, Michael, Rubio-Gozalbo, M. Estela, de Jonge, Marien I., Adema, Gosse J., Zamboni, Nicola, Boltje, Thomas, and Lefeber, Dirk J.
- Subjects
Synthetic sugar analog ,carbohydrates (lipids) ,Glycosylation ,Metabolism ,Metabolic oligosaccharide engineering ,Sialic acid - Abstract
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact metabolism in the cell and over time are mostly lacking. We developed sensitive ion-pair UHPLC-QqQ mass spectrometry methodology for analysis of sugar metabolites in organisms and in model cells and identified novel low abundant nucleotide sugars in human cells, such as ADP-glucose and UDP-arabinose, and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Dynamic tracing of propargyloxycarbonyl (Poc) labeled analogs, commonly used for MOE, revealed that ManNPoc is metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, combined treatment of B16-F10 melanoma cells with antitumor compound 3Fax-NeuNAc and 13C-labeled GlcNAc revealed that endogenous CMP-NeuNAc levels started to decrease before a subsequent decrease of ManNAc 6-phosphate was observed. This implicates 3Fax-NeuNAc first acts as a substrate for cytosolic CMP-sialic acid synthetase and subsequently its product CMP-3Fax-NeuNAc functions as a feed-back inhibitor for UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase. Thus, dynamic analysis of sugar metabolites provides key insights into the time-dependent metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects., bioRxiv
- Published
- 2020
35. Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
- Author
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Gosse J. Adema, Michael B. Zimmermann, Esther Hermans, Emiel Rossing, Thomas J. Boltje, Estela M. Rubio-Gozalbo, Anke P. Willems, Else Kragt, Angel Ashikov, Marien I. de Jonge, Monique van Scherpenzeel, Nicola Zamboni, Torben Heise, Walinka van Tol, Ed E. Moret, Dirk Lefeber, Christian Büll, Jeroen D. Langereis, and Federica Conte
- Subjects
carbohydrates (lipids) ,chemistry.chemical_classification ,chemistry.chemical_compound ,Cytosol ,Biosynthesis ,chemistry ,Biochemistry ,Glycoconjugate ,Rational design ,Metabolism ,Oligosaccharide ,Sugar ,Nucleotide sugar - Abstract
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact metabolism in the cell and over time are mostly lacking. We developed sensitive ion-pair UHPLC-QqQ mass spectrometry methodology for analysis of sugar metabolites in organisms and in model cells and identified novel low abundant nucleotide sugars in human cells, such as ADP-glucose and UDP-arabinose, and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Dynamic tracing of propargyloxycarbonyl (Poc) labeled analogs, commonly used for MOE, revealed that ManNPoc is metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, combined treatment of B16-F10 melanoma cells with antitumor compound 3Fax-NeuNAc and 13C-labeled GlcNAc revealed that endogenous CMP-NeuNAc levels started to decrease before a subsequent decrease of ManNAc 6-phosphate was observed. This implicates 3Fax-NeuNAc first acts as a substrate for cytosolic CMP-sialic acid synthetase and subsequently its product CMP-3Fax-NeuNAc functions as a feed-back inhibitor for UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase. Thus, dynamic analysis of sugar metabolites provides key insights into the time-dependent metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects.
- Published
- 2020
36. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
- Author
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Geert van den Bogaart, Karin Huijben, Katrin Õunap, Olga Fjodorova, Eveline C F Gerretsen, Natalia H. Revelo, Fokje Zijlstra, Richard Arts, Mari-Anne Vals, Kimiyo Raymond, Dirk Lefeber, Angel Ashikov, Sander Pajusalu, Peter T. A. Linders, Kai Muru, Martin ter Beest, and Melissa Baerenfaenger
- Subjects
Gene isoform ,Methionine ,Glycosylation ,Chemistry ,Golgi apparatus ,STX5 ,medicine.disease ,Cell biology ,Abnormal glycosylation ,symbols.namesake ,chemistry.chemical_compound ,symbols ,medicine ,Missense mutation ,Congenital disorder of glycosylation - Abstract
The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, theSTX5mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.
- Published
- 2020
37. Mutations in the V-ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease
- Author
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Cannata Serio, Magda, Graham, Laurie A., Ashikov, A.M., Larsen, Lars Elmann, Raymond, Kimiyo, Timal-Stevenson, S., Gilissen, C.F., Rodenburg, R.J., Veltman, J.A., Simons, Matias, Lefeber, D.J., Cannata Serio, Magda, Graham, Laurie A., Ashikov, A.M., Larsen, Lars Elmann, Raymond, Kimiyo, Timal-Stevenson, S., Gilissen, C.F., Rodenburg, R.J., Veltman, J.A., Simons, Matias, and Lefeber, D.J.
- Abstract
Contains fulltext : 230139.pdf (Publisher’s version ) (Open Access)
- Published
- 2020
38. Discovery of the sugar supply pathways for the O-mannosylation of dystroglycan. On the road for treating muscular dystrophy-dystroglycanopathy
- Author
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Willemsen, M.A.A.P., Lefeber, D.J., Ashikov, A.M., Alsady, M., Tol, W. van, Willemsen, M.A.A.P., Lefeber, D.J., Ashikov, A.M., Alsady, M., and Tol, W. van
- Abstract
Radboud University, 24 januari 2020, Promotores : Willemsen, M.A.A.P., Lefeber, D.J. Co-promotores : Ashikov, A.M., Alsady, M., Contains fulltext : 213932.pdf (publisher's version ) (Open Access)
- Published
- 2020
39. Integrating glycomics and genomics uncovers SLC10A7 as essential factor for bone mineralization by regulating post-Golgi protein transport and glycosylation
- Author
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Angel, Ashikov, Nurulamin, Abu Bakar, Xiao-Yan, Wen, Marco, Niemeijer, Glentino, Rodrigues Pinto Osorio, Koroboshka, Brand-Arzamendi, Linda, Hasadsri, Hana, Hansikova, Kimiyo, Raymond, Dorothée, Vicogne, Nina, Ondruskova, Marleen E H, Simon, Rolph, Pfundt, Sharita, Timal, Roel, Beumers, Christophe, Biot, Roel, Smeets, Marjan, Kersten, Karin, Huijben, Peter T A, Linders, Geert, van den Bogaart, Sacha A F T, van Hijum, Richard, Rodenburg, Lambertus P, van den Heuvel, Francjan, van Spronsen, Tomas, Honzik, Francois, Foulquier, Monique, van Scherpenzeel, Dirk J, Lefeber, Wamelink, Mirjam, Brunner, Han, Mundy, Helen, Michelakakis, Helen, van Hasselt, Peter, van de Kamp, Jiddeke, Martinelli, Diego, Morkrid, Lars, Brocke Holmefjord, Katja, Hertecant, Jozef, Alfadhel, Majid, Carpenter, Kevin, Te Water Naude, Johann, Center for Liver, Digestive and Metabolic Diseases (CLDM), Department of Medicine & Physiology , University of Toronto, First Faculty of Medicine, Charles University [Prague] (CU), Université Lille Nord de France (COMUE), University Medical Center [Utrecht], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Unité de Catalyse et Chimie du Solide - UMR 8181 (UCCS), Centrale Lille Institut (CLIL)-Université d'Artois (UA)-Centrale Lille-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Lille, Paediatrics, Beatrix Children's Hospital/University Medical Center Groningen, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Charles University [Prague], Unité de Catalyse et de Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Ecole Centrale de Lille-Ecole Nationale Supérieure de Chimie de Lille (ENSCL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, NCA - Brain mechanisms in health and disease, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Université d'Artois (UA)-Centrale Lille-Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,0301 basic medicine ,N-GLYCAN ,HOMEOSTASIS ,Glycosylation ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,[SDV]Life Sciences [q-bio] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Golgi Apparatus ,Compound heterozygosity ,DISEASE ,Cohort Studies ,Congenital Disorders of Glycosylation ,Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase ,Missense mutation ,Genetics(clinical) ,Exome ,Glycomics ,Zebrafish ,ComputingMilieux_MISCELLANEOUS ,Cells, Cultured ,Genetics (clinical) ,Genetics & Heredity ,chemistry.chemical_classification ,SEVERE INTELLECTUAL DISABILITY ,Symporters ,biology ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Genomics ,General Medicine ,DEFECTS ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,Pedigree ,Cell biology ,Transport protein ,DEFICIENCY ,Protein Transport ,Phenotype ,symbols ,Female ,ENAMEL ,Life Sciences & Biomedicine ,Adult ,Biochemistry & Molecular Biology ,DISORDERS ,Organic Anion Transporters, Sodium-Dependent ,PHENOTYPES ,DIAGNOSIS ,TRANSFERRIN ,Young Adult ,03 medical and health sciences ,symbols.namesake ,All institutes and research themes of the Radboud University Medical Center ,Calcification, Physiologic ,Genetics ,Animals ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,BIOSYNTHESIS ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,Bone Diseases, Developmental ,Science & Technology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,MUTATIONS ,Infant ,Heterozygote advantage ,Fibroblasts ,Golgi apparatus ,biology.organism_classification ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,chemistry ,Mutation ,Glycoprotein - Abstract
Genomics methodologies have significantly improved elucidation of Mendelian disorders. The combination with high-throughput functional-omics technologies potentiates the identification and confirmation of causative genetic variants, especially in singleton families of recessive inheritance. In a cohort of 99 individuals with abnormal Golgi glycosylation, 47 of which being unsolved, glycomics profiling was performed of total plasma glycoproteins. Combination with whole-exome sequencing in 31 cases revealed a known genetic defect in 15 individuals. To identify additional genetic factors, hierarchical clustering of the plasma glycomics data was done, which indicated a subgroup of four patients that shared a unique glycomics signature of hybrid type N-glycans. In two siblings, compound heterozygous mutations were found in SLC10A7, a gene of unknown function in human. These included a missense mutation that disrupted transmembrane domain 4 and a mutation in a splice acceptor site resulting in skipping of exon 9. The two other individuals showed a complete loss of SLC10A7 mRNA. The patients' phenotype consisted of amelogenesis imperfecta, skeletal dysplasia, and decreased bone mineral density compatible with osteoporosis. The patients' phenotype was mirrored in SLC10A7 deficient zebrafish. Furthermore, alizarin red staining of calcium deposits in zebrafish morphants showed a strong reduction in bone mineralization. Cell biology studies in fibroblasts of affected individuals showed intracellular mislocalization of glycoproteins and a defect in post-Golgi transport of glycoproteins to the cell membrane. In contrast to yeast, human SLC10A7 localized to the Golgi. Our combined data indicate an important role for SLC10A7 in bone mineralization and transport of glycoproteins to the extracellular matrix. ispartof: HUMAN MOLECULAR GENETICS vol:27 issue:17 pages:3029-3045 ispartof: location:England status: published
- Published
- 2018
40. In Vitro Assays of Orphan Glycosyltransferases and Their Application to Identify Notch Xylosyltransferases
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Sethi, Maya K., primary, Buettner, Falk F. R., additional, Ashikov, Angel, additional, and Bakker, Hans, additional
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- 2013
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41. Electric Transport Properties of a Model Nanojunction “Graphene–Fullerene C60–Graphene”
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Sergeyev, D., primary, Ashikov, N., additional, and Zhanturina, N., additional
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- 2020
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42. Mutations in the V‐ATPase Assembly Factor VMA21 Cause a Congenital Disorder of Glycosylation With Autophagic Liver Disease
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Cannata Serio, Magda, primary, Graham, Laurie A., additional, Ashikov, Angel, additional, Larsen, Lars Elmann, additional, Raymond, Kimiyo, additional, Timal, Sharita, additional, Le Meur, Gwenn, additional, Ryan, Margret, additional, Czarnowska, Elzbieta, additional, Jansen, Jos C., additional, He, Miao, additional, Ficicioglu, Can, additional, Pichurin, Pavel, additional, Hasadsri, Linda, additional, Minassian, Berge, additional, Rugierri, Alessandra, additional, Kalimo, Hannu, additional, Ríos‐Ocampo, W. Alfredo, additional, Gilissen, Christian, additional, Rodenburg, Richard, additional, Jonker, Johan W., additional, Holleboom, Adriaan G., additional, Morava, Eva, additional, Veltman, Joris A., additional, Socha, Piotr, additional, Stevens, Tom H., additional, Simons, Matias, additional, and Lefeber, Dirk J., additional
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- 2020
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43. LARGE2 generates the same xylose- and glucuronic acid-containing glycan structures as LARGE
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Ashikov, Angel, Buettner, Falk FR, Tiemann, Birgit, Gerardy-Schahn, Rita, and Bakker, Hans
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- 2013
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44. Dynamic tracing of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs.
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Scherpenzeel, Monique van, Conte, Federica, Büll, Christian, Ashikov, Angel, Hermans, Esther, Willems, Anke, Tol, Walinka van, Kragt, Else, Noga, Marek, Moret, Ed E, Heise, Torben, Langereis, Jeroen D, Rossing, Emiel, Zimmermann, Michael, Rubio-Gozalbo, M Estela, Jonge, Marien I de, Adema, Gosse J, Zamboni, Nicola, Boltje, Thomas, and Lefeber, Dirk J
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TANDEM mass spectrometry ,GLYCOCONJUGATES ,SUGARS ,SUGAR ,SIALIC acids - Abstract
Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact cellular metabolism over time are mostly lacking. We combined ion-pair ultrahigh performance liquid chromatography–triple quadrupole mass spectrometry mass spectrometry using tributyl- and triethylamine buffers for sensitive analysis of sugar metabolites in cells and organisms and identified low abundant nucleotide sugars, such as UDP-arabinose in human cell lines and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Furthermore, MOE revealed that propargyloxycarbonyl (Poc)-labeled ManNPoc was metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, time-course analysis of the effect of antitumor compound 3F
ax -NeuNAc by incubation of B16-F10 melanoma cells with N -acetyl-D-[UL-13 C6]glucosamine revealed full depletion of endogenous ManNAc 6-phosphate and CMP-NeuNAc within 24 h. Thus, dynamic tracing of sugar metabolic pathways provides a general approach to reveal time-dependent insights into the metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects. [ABSTRACT FROM AUTHOR]- Published
- 2022
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45. Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs
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van Scherpenzeel, Monique, primary, Conte, Federica, additional, Büll, Christian, additional, Ashikov, Angel, additional, Hermans, Esther, additional, Willems, Anke, additional, van Tol, Walinka, additional, Kragt, Else, additional, Moret, Ed E., additional, Heise, Torben, additional, Langereis, Jeroen D., additional, Rossing, Emiel, additional, Zimmermann, Michael, additional, Rubio-Gozalbo, M. Estela, additional, de Jonge, Marien I., additional, Adema, Gosse J., additional, Zamboni, Nicola, additional, Boltje, Thomas, additional, and Lefeber, Dirk J., additional
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- 2020
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46. Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5
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Linders, Peter T.A., primary, Gerretsen, Eveline C.F., additional, Ashikov, Angel, additional, Vals, Mari-Anne, additional, de Boer, Rinse, additional, Revelo, Natalia H., additional, Arts, Richard, additional, Baerenfaenger, Melissa, additional, Zijlstra, Fokje, additional, Huijben, Karin, additional, Raymond, Kimiyo, additional, Muru, Kai, additional, Fjodorova, Olga, additional, Pajusalu, Sander, additional, Õunap, Katrin, additional, Beest, Martin ter, additional, Lefeber, Dirk, additional, and van den Bogaart, Geert, additional
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- 2020
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47. Fetal bovine serum impacts the observed N‐glycosylation defects in TMEM165 KO HEK cells
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Climer, Leslie, Morelle, Willy, De Bettignies, Geoffroy, Krzewinski Recchi, Marie-Ange, Lupashin, Vladimir, Medina-Cano, Daniel, Ucuncu, Ekin, Nguyen, Lam Son, Nicouleau, Michael, Lipecka, Joanna, Bizot, Jean-Charles, Thiel, Christian, Lefort, Nathalie, Faivre-Sarrailh, Catherine, Colleaux, Laurence, Guerrera, Ida Chiara, Cantagrel, Vincent, Lebredonchel, Elodie, Garat, Anne, Legrand, Dominique, Decool, Valérie, Klein, André, Ouzzine, Mohamed, Gasnier, Bruno, Potelle, Sven, Groux‐Degroote, Sophie, Cogez, Virginie, Noel, Maxence, Portier, Lucie, Solórzano, Carlos, Dall'Olio, Fabio, Steenackers, Agata, Mortuaire, Marlène, Gonzalez‐Pisfil, Mariano, Henry, Mélanie, Heliot, Laurent, Harduin-Lepers, Anne, Berthe, Audrey, Zaffino, Marie, Muller, claire, Houdou, Marine, Schulz, Céline, Bost, Frédéric, De Fay, Elia, Mazerbourg, Sabine, Flament, Stéphane, Mouajjah, Dounia, Ashikov, Angel, Abu Bakar, Nurulamin, Wen, Xiao-Yan, Niemeijer, Marco, Rodrigues Pinto Osorio, Glentino, Brand-Arzamendi, Koroboshka, Hasadsri, Linda, Hansikova, Hana, Raymond, Kimiyo, Ondruskova, Nina, Simon, Marleen, Pfundt, Rolph, Timal, Sharita, Beumers, Roel, Smeets, Roel, Kersten, Marjan, Huijben, Karin, Linders, Peter, van den Bogaart, Geert, van Hijum, Sacha, Rodenburg, Richard, van den Heuvel, Lambertus, Van Spronsen, Francjan, Honzik, Tomas, van Scherpenzeel, Monique, Lefeber, Dirk, Mirjam, Wamelink, Han, Brunner, Helen, Mundy, Helen, Michelakakis, Peter, van Hasselt, Jiddeke, van de Kamp, Diego, Martinelli, Lars, Morkrid, Katja, Brocke Holmefjord, Jozef, Hertecant, Majid, Alfadhel, Kevin, Carpenter, Johann, te Water Naude, Delos, Maxime, Hellec, Charles, Fifre, Alexandre, Carpentier, Mathieu, Papy-Garcia, Dulce, Allain, Fabrice, Denys, Agnés, Gilormini, Pierre André, Lion, Cédric, Vicogne, Dorothée, Guerardel, Yann, Biot, Christophe, Witters, Peter, Breckpot, Jeroen, Preston, Graem, Morava, Eva, Rujano, Maria, Cannata Serio, Magda, Panasyuk, Ganna, Reunert, Janine, Hauser, Virginie, Park, Julien, Freisinger, Peter, Guida, Maria Clara, Maier, Esther, Wada, Yoshinao, Jäger, Stefanie, Krogan, Nevan, Kretz, Oliver, Nobre, Susana, Garcia, Paula, Quelhas, Dulce, Bird, Thomas, Raskind, Wendy, Schwake, Michael, Duvet, Sandrine, Marquardt, Thorsten, Simons, Matias, Blommaert, Eline, Péanne, Romain, Cherepanova, Natalia, Rymen, Daisy, Staels, Frederik, Jaeken, Jaak, Race, Valérie, Keldermans, Liesbeth, Souche, Erika, Corveleyn, Anniek, Sparkes, Rebecca, Bhattacharya, Kaustuv, Devalck, Christine, Schrijvers, Rik, Foulquier, Francois, Gilmore, Reid, Matthijs, Gert, Université Lille Nord de France (COMUE), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Variabilité génétique des défenses de l'organisme face à son environnement chimique, PRES Université Lille Nord de France-Université de Lille, Droit et Santé, ANR-15-CE14-0001,SOLV_CDG,Décryptage des patients CDG (Congenital Disorders of Glyvosylation) déficients en TMEM165 - de la compréhension des mécanismes moléculaires à une thérapie(2015), ANR-15-RAR3-0004,EURO-CDG-2,A European research network directed towards improving diagnosis and treatment of inborn glycosylation disorders.(2015), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], Baylor University, University of Arkansas for Medical Sciences [UAMS], Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Key-Obs, JRC Institute for Energy and Transport (IET), European Commission - Joint Research Centre [Petten], Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Impact de l'environnement chimique sur la santé humaine (IMPECS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Biologie cellulaire et moléculaire de la sécrétion (BCMS), Centre National de la Recherche Scientifique (CNRS), Departamento de Bioquímica, Instituto Nacional de Enfermedades Respiratorias, Department of Experimental, Diagnostic and Specialty Medicine (DIMES) (DIMES), Università di Bologna [Bologna] (UNIBO), Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Biophotonique Cellulaire Fonctionelle, Institut de Recherche Interdisciplinaire, Institut de Recherche Interdisciplinaire [Villeneuve d'Ascq] (IRI), Université de Lille, Sciences et Technologies-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine & Physiology , University of Toronto, First Faculty of Medicine, Charles University [Prague], University Medical Center [Utrecht], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Paediatrics, Beatrix Children's Hospital/University Medical Center Groningen, Université Toulouse 1 Capitole (UT1), Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Chimie Moléculaire et Formulation (EA 4478), Université de Lille, Sciences et Technologies, Unité de Catalyse et de Chimie du Solide - UMR 8181 (UCCS), Université d'Artois (UA)-Ecole Centrale de Lille-Ecole Nationale Supérieure de Chimie de Lille (ENSCL)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, University Children's Hospital, Centre de recherche Croissance et signalisation (UMR_S 845), Reutlingen University, Department of General Pediatrics, Münster University Children Hospital, Molecular Diagnostics, Center for Human Genetics, Gasthuisberg, Katholieke Universiteit Leuven and Flanders Interuniversity Institute for Biotechnology 4, Leuven, Belgium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Human Genetics, and Laboratory of clinical immunology
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Glycosylation ,Protein family ,[SDV]Life Sciences [q-bio] ,Golgi Apparatus ,FBS ,manganese level ,N‐glycosylation defects ,TMEM165 ,Article ,Antiporters ,Glycomics ,03 medical and health sciences ,chemistry.chemical_compound ,symbols.namesake ,Congenital Disorders of Glycosylation ,0302 clinical medicine ,N-linked glycosylation ,Genetics ,Humans ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Cation Transport Proteins ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Manganese ,0303 health sciences ,Ion Transport ,HEK 293 cells ,Serum Albumin, Bovine ,Golgi apparatus ,Embryonic stem cell ,Cell biology ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,carbohydrates (lipids) ,HEK293 Cells ,chemistry ,symbols ,Calcium ,030217 neurology & neurosurgery ,Fetal bovine serum - Abstract
TMEM165 is involved in a rare genetic human disease named TMEM165‐CDG (congenital disorders of glycosylation). It is Golgi localized, highly conserved through evolution and belongs to the uncharacterized protein family 0016 (UPF0016). The use of isogenic TMEM165 KO HEK cells was crucial in deciphering the function of TMEM165 in Golgi manganese homeostasis. Manganese is a major cofactor of many glycosylation enzymes. Severe Golgi glycosylation defects are observed in TMEM165 Knock Out Human Embryonic Kidney (KO HEK) cells and are rescued by exogenous manganese supplementation. Intriguingly, we demonstrate in this study that the observed Golgi glycosylation defect mainly depends on fetal bovine serum, particularly its manganese level. Our results also demonstrate that iron and/or galactose can modulate the observed glycosylation defects in TMEM165 KO HEK cells. While isogenic cultured cells are widely used to study the impact of gene defects on proteins' glycosylation patterns, these results emphasize the importance of the use of validated fetal bovine serum in glycomics studies. 43;2
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- 2019
48. Activity of N-acylneuraminate-9-phosphatase (NANP) is not essential for de novo sialic acid biosynthesis
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Lingbo Sun, Weihua Tian, Zhang Yang, Esther Hermans, Anke P. Willems, Dirk Lefeber, Monique van Scherpenzeel, Angel Ashikov, Morten Alder Schulz, and Henrik Clausen
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Glycan ,Glycosylation ,Phosphatase ,Biophysics ,CHO Cells ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,Glycolipid ,All institutes and research themes of the Radboud University Medical Center ,Cricetulus ,Biosynthesis ,Animals ,Humans ,Molecular Biology ,Erythropoietin ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,030302 biochemistry & molecular biology ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Sialic acid synthase ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,N-Acetylneuraminic Acid ,Phosphoric Monoester Hydrolases ,Sialic acid ,carbohydrates (lipids) ,Enzyme ,chemistry ,Gene Knockdown Techniques ,biology.protein - Abstract
Background Sialylation of glycoproteins and glycolipids is important for biological processes such as cellular communication, cell migration and protein function. Biosynthesis of CMP-sialic acid, the essential substrate, comprises five enzymatic steps, involving ManNAc and sialic acid and their phosphorylated forms as intermediates. Genetic diseases in this pathway result in different and tissue-restricted phenotypes, which is poorly understood. Methods and results We aimed to study the mechanisms of sialic acid metabolism in knockouts (KO) of the sialic acid pathway in two independent cell lines. Sialylation of cell surface glycans was reduced by KO of GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase), NANS (sialic acid synthase) and CMAS (N-acylneuraminate cytidylyltransferase) genes, but was largely unaffected in NANP (N-acylneuraminate-9-phosphatase) KO, as studied by MAA and PNA lectin binding. NANP is the third enzyme in sialic acid biosynthesis and dephosphorylates sialic acid 9-phosphate to free sialic acid. LC-MS analysis of sialic acid metabolites showed that CMP-sialic acid was dramatically reduced in GNE and NANS KO cells and undetectable in CMAS KO. In agreement with normal cell surface sialylation, CMP-sialic acid levels in NANP KO were comparable to WT cells, even though sialic acid 9-phosphate, the substrate of NANP accumulated. Metabolic flux analysis with 13C6-labelled ManNAc showed a lower, but significant conversion of ManNAc into sialic acid. Conclusions Our data provide evidence that NANP activity is not essential for de novo sialic acid production and point towards an alternative phosphatase activity, bypassing NANP. General significance This report contributes to a better understanding of sialic acid biosynthesis in humans.
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- 2019
49. Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy
- Author
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Moniek Riemersma, Dirk Lefeber, Erik-Jan Kamsteeg, Else Kragt, Nicol C. Voermans, Michèl A.A.P. Willemsen, Monique van Scherpenzeel, Ellen van Beusekom, Esther Hermans, Jeroen R Vermeulen, Maartje Pennings, Mohammad Alsady, Walinka van Tol, Angel Ashikov, Giorgio Tasca, Hans van Bokhoven, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and Pediatric surgery
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0301 basic medicine ,Male ,Glycosylation ,D-RIBOSE ,Ribose ,Clinical Biochemistry ,Pharmacology ,POSTTRANSLATIONAL MODIFICATION ,THERAPY ,Mass Spectrometry ,Muscular Dystrophies ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,ISPD ,Medicine ,Muscular dystrophy ,Dystroglycans ,Cytidine diphosphate ,Nucleoside Diphosphate Sugars ,Middle Aged ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Nucleotidyltransferases ,medicine.anatomical_structure ,Female ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Drug Monitoring ,GLYCOPROTEIN COMPLEX ,ALPHA-DYSTROGLYCAN ,FKRP ,Mice, Transgenic ,METABOLISM ,Ribitol ,complex mixtures ,03 medical and health sciences ,Animals ,Humans ,Disorders of movement Radboud Institute for Molecular Life Sciences [Radboudumc 3] ,Myopathy ,Muscle, Skeletal ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,MUTATIONS ,Biochemistry (medical) ,Skeletal muscle ,medicine.disease ,Fukutin ,carbohydrates (lipids) ,030104 developmental biology ,HEK293 Cells ,chemistry ,Dietary Supplements ,Mutation ,DEFECTIVE GLYCOSYLATION ,business ,030217 neurology & neurosurgery ,Ex vivo ,Chromatography, Liquid - Abstract
BACKGROUND Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment development, and treatment monitoring, sensitive detection of CDP-ribitol is required. METHODS An LC-MS method was optimized for CDP-ribitol in human and mice cells and tissues. RESULTS CDP-ribitol, the product of CRPPA, was detected in all major human and mouse tissues. Moreover, CDP-ribitol concentrations were reduced in fibroblasts and skeletal muscle biopsies from patients with CRPPA myopathy, showing that CDP-ribitol could serve as a diagnostic marker to identify patients with CRPPA with severe Walker–Warburg syndrome and mild limb-girdle muscular dystrophy (LGMD) phenotypes. A screen for potentially therapeutic monosaccharides revealed that ribose, in addition to ribitol, restored CDP-ribitol concentrations and the associated O-glycosylation defect of α-dystroglycan. As the effect occurred in a mutation-dependent manner, we established a CDP-ribitol blood test to facilitate diagnosis and predict individualized treatment response. Ex vivo incubation of blood cells with ribose or ribitol restored CDP-ribitol concentrations in a patient with CRPPA LGMD. CONCLUSIONS Sensitive detection of CDP-ribitol with LC-MS allows fast diagnosis of patients with severe and mild CRPPA myopathy. Ribose offers a readily testable dietary therapy for CRPPA myopathy, with possible applicability for patients with FKRP and FKTN myopathy. Evaluation of CDP-ribitol in blood is a promising tool for the evaluation and monitoring of dietary therapies for CRPPA myopathy in a patient-specific manner.
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- 2019
50. Functional expression of the CMP-sialic acid transporter in Escherichia coli and its identification as a simple mobile carrier
- Author
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Tiralongo, Joe, Ashikov, Angel, Routier, Françoise, Eckhardt, Matthias, Bakker, Hans, Gerardy-Schahn, Rita, and von Itzstein, Mark
- Published
- 2006
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