281 results on '"Froese, D Sean'
Search Results
2. Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
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Linnea K. M. Blomgren, Melanie Huber, Sabrina R. Mackinnon, Céline Bürer, Arnaud Baslé, Wyatt W. Yue, D. Sean Froese, and Thomas J. McCorvie
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Science - Abstract
Abstract 5,10-methylenetetrahydrofolate reductase (MTHFR) commits folate-derived one-carbon units to generate the methyl-donor s-adenosyl-l-methionine (SAM). Eukaryotic MTHFR appends to the well-conserved catalytic domain (CD) a unique regulatory domain (RD) that confers feedback inhibition by SAM. Here we determine the cryo-electron microscopy structures of human MTHFR bound to SAM and its demethylated product s-adenosyl-l-homocysteine (SAH). In the active state, with the RD bound to a single SAH, the CD is flexible and exposes its active site for catalysis. However, in the inhibited state the RD pocket is remodelled, exposing a second SAM-binding site that was previously occluded. Dual-SAM bound MTHFR demonstrates a substantially rearranged inter-domain linker that reorients the CD, inserts a loop into the active site, positions Tyr404 to bind the cofactor FAD, and blocks substrate access. Our data therefore explain the long-distance regulatory mechanism of MTHFR inhibition, underpinned by the transition between dual-SAM and single-SAH binding in response to cellular methylation status.
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- 2024
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3. Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency
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Déborah Mathis, Jasmine Koch, Sophie Koller, Kay Sauter, Christa Flück, Anne-Christine Uldry, Patrick Forny, D. Sean Froese, and Alexander Laemmle
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Malate aspartate shuttle ,Malate dehydrogenase 2 deficiency ,Human induced pluripotent stem cell technology ,hiPSC-derived hepatocytes ,Proteomics ,Metabolic profiling ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Mitochondrial malate dehydrogenase 2 (MDH2) is crucial to cellular energy generation through direct participation in the tricarboxylic acid (TCA) cycle and the malate aspartate shuttle (MAS). Inherited MDH2 deficiency is an ultra-rare metabolic disease caused by bi-allelic pathogenic variants in the MDH2 gene, resulting in early-onset encephalopathy, psychomotor delay, muscular hypotonia and frequent seizures. Currently, there is no cure for this devastating disease. We recently reported symptomatic improvement of a three-year-old girl with MDH2 deficiency following treatment with the triglyceride triheptanoin. Here, we aimed to better characterize this disease and improve our understanding of the potential utility of triheptanoin treatment. Using fibroblasts derived from this patient, we generated induced pluripotent stem cells (hiPSCs) and differentiated them into hepatocytes (hiPSC-Heps). Characterization of patient-derived hiPSCs and hiPSC-Heps revealed significantly reduced MDH2 protein expression. Untargeted proteotyping of hiPSC-Heps revealed global dysregulation of mitochondrial proteins, including upregulation of TCA cycle and fatty acid oxidation enzymes. Metabolomic profiling confirmed TCA cycle and MAS dysregulation, and demonstrated normalization of malate, fumarate and aspartate following treatment with the triheptanoin components glycerol and heptanoate. Taken together, our results provide the first patient-derived hiPSC-Hep-based model of MDH2 deficiency, confirm altered TCA cycle function, and provide further evidence for the implementation of triheptanoin therapy for this ultra-rare disease. Synopsis: This study reveals altered expression of mitochondrial pathways including the tricarboxylic acid cycle and changes in metabolite profiles in malate dehydrogenase 2 deficiency and provides the molecular basis for triheptanoin treatment in this ultra-rare disease.
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- 2024
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4. Real-time detection of enzymatically formed hydrogen sulfide by pathogenic variants of cystathionine beta-synthase using hemoglobin I of Lucina pectinata as a biosensor
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Myszkowska, Joanna, Klotz, Katharina, Leandro, Paula, Kruger, Warren D., Froese, D. Sean, Baumgartner, Matthias R., Spiekerkoetter, Ute, and Hannibal, Luciana
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- 2024
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5. Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency
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Mathis, Déborah, Koch, Jasmine, Koller, Sophie, Sauter, Kay, Flück, Christa, Uldry, Anne-Christine, Forny, Patrick, Froese, D. Sean, and Laemmle, Alexander
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- 2024
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6. Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase
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Sokolovskaya, Olga M, Plessl, Tanja, Bailey, Henry, Mackinnon, Sabrina, Baumgartner, Matthias R, Yue, Wyatt W, Froese, D Sean, and Taga, Michiko E
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Biochemistry and Cell Biology ,Biological Sciences ,Nutrition ,1.1 Normal biological development and functioning ,Underpinning research ,Coenzymes ,Humans ,Kinetics ,Methylmalonyl-CoA Mutase ,Vitamin B 12 ,MMUT ,Vitamin B-12 ,Cobamide ,Methylmalonyl-CoA mutase ,Cobalamin ,Methylmalonic aciduria ,Vitamin B(12) ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
Cobalamin, commonly known as vitamin B12, is an essential micronutrient for humans because of its role as an enzyme cofactor. Cobalamin is one of over a dozen structurally related compounds - cobamides - that are found in certain foods and are produced by microorganisms in the human gut. Very little is known about how different cobamides affect B12-dependent metabolism in human cells. Here, we test in vitro how diverse cobamide cofactors affect the function of methylmalonyl-CoA mutase (MMUT), one of two cobalamin-dependent enzymes in humans. We find that, although cobalamin is the most effective cofactor for MMUT, multiple cobamides support MMUT function with differences in binding affinity (Kd), binding kinetics (kon), and concentration dependence during catalysis (KM, app). Additionally, we find that six disease-associated MMUT variants that cause cobalamin-responsive impairments in enzymatic activity also respond to other cobamides, with the extent of catalytic rescue dependent on the identity of the cobamide. Our studies challenge the exclusive focus on cobalamin in the context of human physiology, indicate that diverse cobamides can support the function of a human enzyme, and suggest future directions that will improve our understanding of the roles of different cobamides in human biology.
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- 2021
7. Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency
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Forny, Patrick, Bonilla, Ximena, Lamparter, David, Shao, Wenguang, Plessl, Tanja, Frei, Caroline, Bingisser, Anna, Goetze, Sandra, van Drogen, Audrey, Harshman, Keith, Pedrioli, Patrick G. A., Howald, Cedric, Poms, Martin, Traversi, Florian, Bürer, Céline, Cherkaoui, Sarah, Morscher, Raphael J., Simmons, Luke, Forny, Merima, Xenarios, Ioannis, Aebersold, Ruedi, Zamboni, Nicola, Rätsch, Gunnar, Dermitzakis, Emmanouil T., Wollscheid, Bernd, Baumgartner, Matthias R., and Froese, D. Sean
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- 2023
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8. Disorders of Cobalamin Cobalamin disorders and Folate Transport Folate disorders and Metabolism
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Fowler, Brian, Froese, D. Sean, Watkins, David, Saudubray, Jean-Marie, editor, Baumgartner, Matthias R., editor, García-Cazorla, Ángeles, editor, and Walter, John, editor
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- 2022
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9. Biotin-Responsive Disorders Biotin-responsive Disorders
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Froese, D. Sean, Baumgartner, Matthias R., Saudubray, Jean-Marie, editor, Baumgartner, Matthias R., editor, García-Cazorla, Ángeles, editor, and Walter, John, editor
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- 2022
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10. Disorders of Cobalamin Metabolism
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Baumgartner, Matthias R., Froese, D. Sean, Blau, Nenad, editor, Dionisi Vici, Carlo, editor, Ferreira, Carlos R., editor, Vianey-Saban, Christine, editor, and van Karnebeek, Clara D. M., editor
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- 2022
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11. Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate
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McCorvie, Thomas J., Loria, Paula M., Tu, Meihua, Han, Seungil, Shrestha, Leela, Froese, D. Sean, Ferreira, Igor M., Berg, Allison P., and Yue, Wyatt W.
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- 2022
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12. Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria
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Forny, Patrick, Plessl, Tanja, Frei, Caroline, Bürer, Celine, Froese, D. Sean, and Baumgartner, Matthias R.
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- 2022
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13. Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin B12
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Oussalah, Abderrahim, Siblini, Youssef, Hergalant, Sébastien, Chéry, Céline, Rouyer, Pierre, Cavicchi, Catia, Guerrini, Renzo, Morange, Pierre-Emmanuel, Trégouët, David, Pupavac, Mihaela, Watkins, David, Pastinen, Tomi, Chung, Wendy K., Ficicioglu, Can, Feillet, François, Froese, D. Sean, Baumgartner, Matthias R., Benoist, Jean-François, Majewski, Jacek, Morrone, Amelia, Rosenblatt, David S., and Guéant, Jean-Louis
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- 2022
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14. Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia
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Luciani, Alessandro, Denley, Matthew C. S., Govers, Larissa P., Sorrentino, Vincenzo, and Froese, D. Sean
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- 2021
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15. Mitochondrial dysfunction drives a neuronal exhaustion phenotype in methylmalonic aciduria
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Denley, Matthew Christopher Simon, primary, Straub, Monique S, additional, Marcionelli, Giulio, additional, Güra, Miriam A, additional, Penton Ribas, David, additional, Delvendahl, Igor, additional, Poms, Martin, additional, Vekeriotaite, Beata, additional, Conte, Federica, additional, von Meyenn, Ferdinand, additional, Froese, D Sean, additional, and Baumgartner, Matthias R, additional
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- 2024
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16. Absence of MMACHC in peripheral retinal cells does not lead to an ocular phenotype in mice
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Kiessling, Eva, Nötzli, Sarah, Todorova, Vyara, Forny, Merima, Baumgartner, Matthias R., Samardzija, Marijana, Krijt, Jakub, Kožich, Viktor, Grimm, Christian, and Froese, D. Sean
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- 2021
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17. Disorders of Cobalamin and Folate Transport and Metabolism
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Fowler, Brian, primary, Froese, D. Sean, additional, and Watkins, David, additional
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- 2022
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18. Biotin-Responsive Disorders
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Froese, D. Sean, primary and Baumgartner, Matthias R., additional
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- 2022
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19. Decrease of disease‐related metabolites upon fasting in a hemizygous knock‐in mouse model (Mut‐ko/ki) of methylmalonic aciduria
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Marie Lucienne, Déborah Mathis, Nathan Perkins, Ralph Fingerhut, Matthias R. Baumgartner, and D. Sean Froese
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catabolism ,disease amelioration ,fasting ,Methylmalonic aciduria ,methylmalonyl‐CoA mutase ,mouse model ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Genetics ,QH426-470 - Abstract
Abstract Methylmalonyl‐CoA mutase (MMUT) is part of the propionyl‐CoA catabolic pathway, responsible for the breakdown of branched‐chain amino acids, odd‐chain fatty acids and the side‐chain of cholesterol. Patients with deficient activity of MMUT suffer from isolated methylmalonic aciduria (MMAuria), frequently presenting in the newborn period with failure to thrive and metabolic crisis. Even well managed patients remain at risk for metabolic crises, of which one known trigger is acute illness, which may lead to poor feeding and vomiting, putting the patient in a catabolic state. This situation is believed to result in increased breakdown of propionyl‐CoA catabolic pathway precursors, producing massively elevated levels of disease related metabolites, including methylmalonic acid and propionylcarnitine. Here, we used fasting of a hemizygous mouse model (Mut‐ko/ki) of MMUT deficiency to study the role of induced catabolism on metabolite production. Although mice lost weight and displayed markers consistent with a catabolic state, contrary to expectation, we found strongly reduced levels of methylmalonic acid and propionylcarnitine in fasted conditions. Switching Mut‐ko/ki mice from a high‐protein diet to fasted conditions, or from a standard diet to a no‐protein diet, resulted in similar reductions of methylmalonic acid and propionylcarnitine levels. These results suggest, in our mouse model at least, induction of a catabolic state on its own may not be sufficient to trigger elevated metabolite levels.
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- 2021
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20. In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria
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Lucienne, Marie, Aguilar-Pimentel, Juan Antonio, Amarie, Oana V., Becker, Lore, Calzada-Wack, Julia, da Silva-Buttkus, Patricia, Garrett, Lillian, Hölter, Sabine M., Mayer-Kuckuk, Philipp, Rathkolb, Birgit, Rozman, Jan, Spielmann, Nadine, Treise, Irina, Busch, Dirk H., Klopstock, Thomas, Schmidt-Weber, Carsten, Wolf, Eckhard, Wurst, Wolfgang, Forny, Merima, Mathis, Déborah, Fingerhut, Ralph, Froese, D. Sean, Gailus-Durner, Valerie, Fuchs, Helmut, de Angelis, Martin Hrabě, and Baumgartner, Matthias R.
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- 2020
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21. The complex machinery of human cobalamin metabolism
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McCorvie, Thomas J, Ferreira, Douglas, Yue, Wyatt W, Froese, D Sean, University of Zurich, Yue, Wyatt W, and Froese, D Sean
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2716 Genetics (clinical) ,1311 Genetics ,10036 Medical Clinic ,Genetics ,610 Medicine & health ,Genetics (clinical) - Published
- 2023
22. Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency
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Heuberger, Kathrin, Bailey, Henry J., Burda, Patricie, Chaikuad, Apirat, Krysztofinska, Ewelina, Suormala, Terttu, Bürer, Céline, Lutz, Seraina, Fowler, Brian, Froese, D. Sean, Yue, Wyatt W., and Baumgartner, Matthias R.
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- 2019
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23. Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase
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Blomgren, Linnea Klara Maryann, primary, Huber, Melanie, additional, Burer, Celine, additional, Basle, Arnaud, additional, Froese, D. Sean, additional, Yue, Wyatt W., additional, and McCorvie, Thomas J., additional
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- 2023
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24. Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition
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D. Sean Froese, Jolanta Kopec, Elzbieta Rembeza, Gustavo Arruda Bezerra, Anselm Erich Oberholzer, Terttu Suormala, Seraina Lutz, Rod Chalk, Oktawia Borkowska, Matthias R. Baumgartner, and Wyatt W. Yue
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Science - Abstract
The human enzyme MTHFR links the folate and methionine cycles, which are essential for the biosynthesis of nucleotides and proteins. Here, the authors present the crystal structure and biochemical analysis of human MTHFR, providing molecular insights into its function and regulation in higher eukaryotes.
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- 2018
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25. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients
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Jean-Louis Guéant, Céline Chéry, Abderrahim Oussalah, Javad Nadaf, David Coelho, Thomas Josse, Justine Flayac, Aurélie Robert, Isabelle Koscinski, Isabelle Gastin, Pierre Filhine-Tresarrieu, Mihaela Pupavac, Alison Brebner, David Watkins, Tomi Pastinen, Alexandre Montpetit, Fadi Hariri, David Tregouët, Benjamin A Raby, Wendy K. Chung, Pierre-Emmanuel Morange, D. Sean Froese, Matthias R. Baumgartner, Jean-François Benoist, Can Ficicioglu, Virginie Marchand, Yuri Motorin, Chrystèle Bonnemains, François Feillet, Jacek Majewski, and David S. Rosenblatt
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Science - Abstract
Inborn errors of vitamin B12 metabolism of the cblC class are caused by mutations in the MMACHC gene. Here, Guéant et al. report epi-cblC, a class of cblC in which patients are compound heterozygous for a genetic mutation and a secondary epimutation at the MMACHC locus.
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- 2018
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26. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria
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Lucienne, Marie, primary, Gerlini, Raffaele, additional, Rathkolb, Birgit, additional, Calzada-Wack, Julia, additional, Forny, Patrick, additional, Wueest, Stephan, additional, Kaech, Andres, additional, Traversi, Florian, additional, Forny, Merima, additional, Bürer, Céline, additional, Aguilar-Pimentel, Antonio, additional, Irmler, Martin, additional, Beckers, Johannes, additional, Sauer, Sven, additional, Kölker, Stefan, additional, Dewulf, Joseph P, additional, Bommer, Guido T, additional, Hoces, Daniel, additional, Gailus-Durner, Valerie, additional, Fuchs, Helmut, additional, Rozman, Jan, additional, Froese, D Sean, additional, Baumgartner, Matthias R, additional, and de Angelis, Martin Hrabě, additional
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- 2023
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27. Cellular and computational models reveal environmental and metabolic interactions in MMUT-type methylmalonic aciduria
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Charlotte Ramon, Florian Traversi, Céline Bürer, D. Sean Froese, and Jörg Stelling
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constraint-based modeling ,Genetics ,rare disease ,methylmalonic aciduria ,CRISPR-Cas9 ,metabolism ,Genetics (clinical) - Abstract
Methylmalonyl-coenzyme A (CoA) mutase (MMUT)-type methylmalonic aciduria is a rare inherited metabolic disease caused by the loss of function of the MMUT enzyme. Patients develop symptoms resembling those of primary mitochondrial disorders, but the underlying causes of mitochondrial dysfunction remain unclear. Here, we examined environmental and genetic interactions in MMUT deficiency using a combination of computational modeling and cellular models to decipher pathways interacting with MMUT. Immortalized fibroblast (hTERT BJ5ta) MMUT-KO (MUTKO) clones displayed a mild mitochondrial impairment in standard glucose-based medium, but they did not to show increased reliance on respiratory metabolism nor reduced growth or viability. Consistently, our modeling predicted MUTKO specific growth phenotypes only for lower extracellular glutamine concentrations. Indeed, two of three MMUT-deficient BJ5ta cell lines showed a reduced viability in glutamine-free medium. Further, growth on 183 different carbon and nitrogen substrates identified increased NADH (nicotinamide adenine dinucleotide) metabolism of BJ5ta and HEK293 MUTKO cells compared with controls on purine- and glutamine-based substrates. With this knowledge, our modeling predicted 13 reactions interacting with MMUT that potentiate an effect on growth, primarily those of secondary oxidation of propionyl-CoA, oxidative phosphorylation and oxygen diffusion. Of these, we validated 3-hydroxyisobutytyl-CoA hydrolase (HIBCH) in the secondary propionyl-CoA oxidation pathway. Altogether, these results suggest compensation for the loss of MMUT function by increasing anaplerosis through glutamine or by diverting flux away from MMUT through the secondary propionyl-CoA oxidation pathway, which may have therapeutic relevance., Journal of Inherited Metabolic Disease, 46 (3), ISSN:1573-2665, ISSN:0141-8955
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- 2023
28. Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: data from the E-HOD registry
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Huemer, Martina, Diodato, Daria, Martinelli, Diego, Olivieri, Giorgia, Blom, Henk, Gleich, Florian, Kölker, Stefan, Kožich, Viktor, Morris, Andrew A., Seifert, Burkhardt, Froese, D. Sean, Baumgartner, Matthias R., Dionisi-Vici, Carlo, the EHOD consortium, Alcalde Martin, C., Baethmann, M., Ballhausen, D., Blasco-Alonso, J., Boy, N., Bueno, M., Burgos Peláez, R., Cerone, R., Chabrol, B., Chapman, K. A., Couce, M. L., Crushell, E., Dalmau Serra, J., Diogo, L., Ficicioglu, C., García Jimenez, M. C., García Silva, M. T., Gaspar, A. M., Gautschi, M., González-Lamuño, D., Gouveia, S., Grünewald, S., Hendriksz, C., Janssen, M. C. H., Jesina, P., Koch, J., Konstantopoulou, V., Lavigne, C., Lund, A. M., Martins, E. G., Meavilla Olivas, S., Mention, K., Mochel, F., Mundy, H., Murphy, E., Paquay, S., Pedrón-Giner, C., Ruiz Gómez, M. A., Santra, S., Schiff, M., Schwartz, I. V., Scholl-Bürgi, S., Servais, A., Skouma, A., Tran, C., Vives Piñera, I., Walter, J., and Weisfeld-Adams, J.
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- 2018
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29. Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate
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Thomas J. McCorvie, Paula M. Loria, Meihua Tu, Seungil Han, Leela Shrestha, D. Sean Froese, Igor M. Ferreira, Allison P. Berg, and Wyatt W. Yue
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Structural Biology ,Molecular Biology - Abstract
Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by allosteric activation of glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0–4.0 Å resolution of phosphorylated human GYS1, in complex with a minimal interacting region of glycogenin, in the inhibited, activated and catalytically competent states. Phosphorylations of specific terminal residues are sensed by different arginine clusters, locking the GYS1 tetramer in an inhibited state via intersubunit interactions. The Glc6P activator promotes conformational change by disrupting these interactions and increases the flexibility of GYS1, such that it is poised to adopt a catalytically competent state when the sugar donor UDP-glucose (UDP-glc) binds. We also identify an inhibited-like conformation that has not transitioned into the activated state, in which the locking interaction of phosphorylation with the arginine cluster impedes subsequent conformational changes due to Glc6P binding. Our results address longstanding questions regarding the mechanism of human GYS1 regulation.
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- 2022
30. Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency
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Forny, Patrick; https://orcid.org/0000-0003-1877-2976, Bonilla, Ximena; https://orcid.org/0000-0002-4950-6825, Lamparter, David; https://orcid.org/0000-0002-9216-8825, Shao, Wenguang; https://orcid.org/0000-0003-0905-0728, Plessl, Tanja, Frei, Caroline; https://orcid.org/0000-0002-8879-6327, Bingisser, Anna, Goetze, Sandra; https://orcid.org/0000-0001-6880-8020, van Drogen, Audrey, Harshman, Keith, Pedrioli, Patrick G A, Howald, Cédric, Poms, Martin; https://orcid.org/0000-0002-4426-314X, Traversi, Florian, Bürer, Céline, Cherkaoui, Sarah; https://orcid.org/0000-0002-0636-4177, Morscher, Raphael J; https://orcid.org/0000-0003-3378-9266, Simmons, Luke, Forny, Merima, Xenarios, Ioannis; https://orcid.org/0000-0002-3413-6841, Aebersold, Ruedi; https://orcid.org/0000-0002-9576-3267, Zamboni, Nicola; https://orcid.org/0000-0003-1271-1021, Rätsch, Gunnar; https://orcid.org/0000-0001-5486-8532, Dermitzakis, Emmanouil T, Wollscheid, Bernd; https://orcid.org/0000-0002-3923-1610, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Forny, Patrick; https://orcid.org/0000-0003-1877-2976, Bonilla, Ximena; https://orcid.org/0000-0002-4950-6825, Lamparter, David; https://orcid.org/0000-0002-9216-8825, Shao, Wenguang; https://orcid.org/0000-0003-0905-0728, Plessl, Tanja, Frei, Caroline; https://orcid.org/0000-0002-8879-6327, Bingisser, Anna, Goetze, Sandra; https://orcid.org/0000-0001-6880-8020, van Drogen, Audrey, Harshman, Keith, Pedrioli, Patrick G A, Howald, Cédric, Poms, Martin; https://orcid.org/0000-0002-4426-314X, Traversi, Florian, Bürer, Céline, Cherkaoui, Sarah; https://orcid.org/0000-0002-0636-4177, Morscher, Raphael J; https://orcid.org/0000-0003-3378-9266, Simmons, Luke, Forny, Merima, Xenarios, Ioannis; https://orcid.org/0000-0002-3413-6841, Aebersold, Ruedi; https://orcid.org/0000-0002-9576-3267, Zamboni, Nicola; https://orcid.org/0000-0003-1271-1021, Rätsch, Gunnar; https://orcid.org/0000-0001-5486-8532, Dermitzakis, Emmanouil T, Wollscheid, Bernd; https://orcid.org/0000-0002-3923-1610, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, and Froese, D Sean; https://orcid.org/0000-0003-1557-3517
- Abstract
Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.
- Published
- 2023
31. Insights into energy balance dysregulation from a mouse model of methylmalonic aciduria
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Lucienne, Marie, Gerlini, Raffaele, Rathkolb, Birgit, Calzada-Wack, Julia, Forny, Patrick, Wueest, Stephan, Kaech, Andres, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio, Irmler, Martin, Beckers, Johannes, Sauer, Sven, Kölker, Stefan, Dewulf, Joseph P, Bommer, Guido T, Hoces, Daniel, Gailus-Durner, Valerie, Fuchs, Helmut, Rozman, Jan, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R, de Angelis, Martin Hrabě, Lucienne, Marie, Gerlini, Raffaele, Rathkolb, Birgit, Calzada-Wack, Julia, Forny, Patrick, Wueest, Stephan, Kaech, Andres, Traversi, Florian, Forny, Merima, Bürer, Céline, Aguilar-Pimentel, Antonio, Irmler, Martin, Beckers, Johannes, Sauer, Sven, Kölker, Stefan, Dewulf, Joseph P, Bommer, Guido T, Hoces, Daniel, Gailus-Durner, Valerie, Fuchs, Helmut, Rozman, Jan, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Baumgartner, Matthias R, and de Angelis, Martin Hrabě
- Abstract
Inherited disorders of mitochondrial metabolism, including isolated methylmalonic aciduria, present unique challenges to energetic homeostasis by disrupting energy-producing pathways. To better understand global responses to energy shortage, we investigated a hemizygous mouse model of methylmalonyl-CoA mutase (Mmut)–type methylmalonic aciduria. We found Mmut mutant mice to have reduced appetite, energy expenditure and body mass compared with littermate controls, along with a relative reduction in lean mass but increase in fat mass. Brown adipose tissue showed a process of whitening, in line with lower body surface temperature and lesser ability to cope with cold challenge. Mutant mice had dysregulated plasma glucose, delayed glucose clearance and a lesser ability to regulate energy sources when switching from the fed to fasted state, while liver investigations indicated metabolite accumulation and altered expression of peroxisome proliferator–activated receptor and Fgf21-controlled pathways. Together, these shed light on the mechanisms and adaptations behind energy imbalance in methylmalonic aciduria and provide insight into metabolic responses to chronic energy shortage, which may have important implications for disease understanding and patient management.
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- 2023
32. The complex machinery of human cobalamin metabolism
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McCorvie, Thomas J; https://orcid.org/0000-0002-1502-7113, Ferreira, Douglas, Yue, Wyatt W; https://orcid.org/0000-0001-6959-6007, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, McCorvie, Thomas J; https://orcid.org/0000-0002-1502-7113, Ferreira, Douglas, Yue, Wyatt W; https://orcid.org/0000-0001-6959-6007, and Froese, D Sean; https://orcid.org/0000-0003-1557-3517
- Abstract
Vitamin B$_{12}$ (cobalamin, Cbl) is required as a cofactor by two human enzymes, 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) and methylmalonyl-CoA mutase (MMUT). Within the body, a vast array of transporters, enzymes and chaperones are required for the generation and delivery of these cofactor forms. How they perform these functions is dictated by the structure and interactions of the proteins involved, the molecular bases of which are only now being elucidated. In this review, we highlight recent insights into human Cbl metabolism and address open questions in the field by employing a protein structure and interactome based perspective. We discuss how three very similar proteins-haptocorrin, intrinsic factor and transcobalamin-exploit slight structural differences and unique ligand receptor interactions to effect selective Cbl absorption and internalisation. We describe recent advances in the understanding of how endocytosed Cbl is transported across the lysosomal membrane and the implications of the recently solved ABCD4 structure. We detail how MMACHC and MMADHC cooperate to modify and target cytosolic Cbl to the client enzymes MTR and MMUT using ingenious modifications to an ancient nitroreductase fold, and how MTR and MMUT link with their accessory enzymes to sustainably harness the supernucleophilic potential of Cbl. Finally, we provide an outlook on how future studies may combine structural and interactome based approaches and incorporate knowledge of post-translational modifications to bring further insights.
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- 2023
33. Mitochondrial disease, mitophagy, and cellular distress in methylmalonic acidemia
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Alessandro Luciani, D. Sean Froese, Vincenzo Sorrentino, Larissa P. Govers, Matthew C. S. Denley, University of Zurich, Luciani, Alessandro, Sorrentino, Vincenzo, and Froese, D Sean
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Mitochondrial Diseases ,Cellular differentiation ,Mitochondrial disease ,2804 Cellular and Molecular Neuroscience ,Methylmalonic acidemia ,610 Medicine & health ,Disease ,Review ,Mitochondrion ,Biology ,Inherited metabolic diseases ,10052 Institute of Physiology ,1307 Cell Biology ,Cellular and Molecular Neuroscience ,Mitophagy ,1312 Molecular Biology ,medicine ,Animals ,Homeostasis ,Humans ,Molecular Biology ,Cell damage ,Amino Acid Metabolism, Inborn Errors ,Pharmacology ,Organelles ,Cell Biology ,medicine.disease ,Mitochondria ,3004 Pharmacology ,Metabolism ,Oxidative stress ,1313 Molecular Medicine ,570 Life sciences ,biology ,Molecular Medicine ,Energy Metabolism ,Neuroscience ,Signal Transduction - Abstract
Mitochondria—the intracellular powerhouse in which nutrients are converted into energy in the form of ATP or heat—are highly dynamic, double-membraned organelles that harness a plethora of cellular functions that sustain energy metabolism and homeostasis. Exciting new discoveries now indicate that the maintenance of this ever changing and functionally pleiotropic organelle is particularly relevant in terminally differentiated cells that are highly dependent on aerobic metabolism. Given the central role in maintaining metabolic and physiological homeostasis, dysregulation of the mitochondrial network might therefore confer a potentially devastating vulnerability to high-energy requiring cell types, contributing to a broad variety of hereditary and acquired diseases. In this Review, we highlight the biological functions of mitochondria-localized enzymes from the perspective of understanding—and potentially reversing—the pathophysiology of inherited disorders affecting the homeostasis of the mitochondrial network and cellular metabolism. Using methylmalonic acidemia as a paradigm of complex mitochondrial dysfunction, we discuss how mitochondrial directed-signaling circuitries govern the homeostasis and physiology of specialized cell types and how these may be disturbed in disease. This Review also provides a critical analysis of affected tissues, potential molecular mechanisms, and novel cellular and animal models of methylmalonic acidemia which are being used to develop new therapeutic options for this disease. These insights might ultimately lead to new therapeutics, not only for methylmalonic acidemia, but also for other currently intractable mitochondrial diseases, potentially transforming our ability to regulate homeostasis and health.
- Published
- 2021
34. The Role of Protein Structural Analysis in the Next Generation Sequencing Era
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Yue, Wyatt W., Froese, D. Sean, Brennan, Paul E., Houk, Kendall N., Series editor, Hunter, Christopher A., Series editor, Krische, Michael J, Series editor, Lehn, Jean-Marie, Series editor, Ley, Steven V., Series editor, Olivucci, Massimo, Series editor, Thiem, Joachim, Series editor, Venturi, Margherita, Series editor, Wong, Chi-Huey, Series editor, Wong, Henry N.C., Series editor, L.S. Tang, Nelson, editor, and Poon, Terence, editor
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- 2014
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35. 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.
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- 2015
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36. Cellular and computational models reveal environmental and metabolic interactions inMMUT‐type methylmalonic aciduria
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Ramon, Charlotte, primary, Traversi, Florian, additional, Bürer, Céline, additional, Froese, D. Sean, additional, and Stelling, Jörg, additional
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- 2022
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37. Functional characterization of missense mutations in severe methylenetetrahydrofolate reductase deficiency using a human expression system
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Burda, Patricie, Suormala, Terttu, Heuberger, Dorothea, Schäfer, Alexandra, Fowler, Brian, Froese, D. Sean, and Baumgartner, Matthias R.
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- 2017
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38. Cellular and computational models reveal environmental and genetic interactions in MMUT-type methylmalonic aciduria
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Charlotte Ramon, Florian Traversi, Céline Bürer, D. Sean Froese, and Jörg Stelling
- Abstract
MMUT-type methylmalonic aciduria is a rare inherited metabolic disease caused by the loss of function of the methylmalonyl-CoA mutase (MMUT) enzyme. Patients develop symptoms resembling those of primary mitochondrial disorders, but the underlying causes of mitochondrial dysfunction remain unclear. Here, we examined environmental and genetic interactions in MMUT deficiency using a combination of computational modeling and cellular models to decipher pathways interacting with MMUT. Immortalized fibroblast (hTERT BJ5ta) MMUT-KO (MUTKO) clones displayed a mild mitochondrial impairment in standard glucose-based medium, but they did not to show increased reliance on respiratory metabolism nor reduced growth or viability. Consistently, our modeling predicted MUTKO specific growth phenotypes only for lower extracellular glutamine concentrations. Indeed, two of three MMUT-deficient BJ5ta cell lines showed a reduced viability in glutamine-free medium. Further, growth on 183 different carbon and nitrogen substrates identified increased NADH (nicotinamide adenine dinucleotide) metabolism of BJ5ta and HEK293 MUTKO cells compared to controls on purine- and glutamine-based substrates. With this knowledge, our modeling predicted 13 reactions interacting with MMUT that potentiate an effect on growth, primarily those of secondary oxidation of propionyl-CoA, oxidative phosphorylation and oxygen diffusion. Of these, we validated 3-hydroxyisobutytyl-CoA hydrolase (HIBCH) in the secondary propionyl-CoA oxidation pathway. Altogether, these results suggest compensation for the loss of MMUT function by increasing anaplerosis through glutamine or by diverting flux away from MMUT through the secondary propionyl-CoA oxidation pathway, which may have therapeutic relevance.1sentence take-home messageBy perturbing metabolic pathways through genetic and environmental interventions in cellular and computational models of MMUT-type methylmalonic aciduria, we identified glutamine and secondary oxidative propionyl-CoA oxidation pathways as being important in the disease.
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- 2022
39. HIF1 and DROSHA are involved in MMACHC repression in hypoxia
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Kiessling, Eva, primary, Peters, Florian, additional, Ebner, Lynn J.A., additional, Merolla, Luca, additional, Samardzija, Marijana, additional, Baumgartner, Matthias R., additional, Grimm, Christian, additional, and Froese, D. Sean, additional
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- 2022
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40. Cellular and computational models reveal environmental and genetic interactions in MMUT-type methylmalonic aciduria
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Ramon, Charlotte, primary, Traversi, Florian, additional, Bürer, Céline, additional, Froese, D. Sean, additional, and Stelling, Jörg, additional
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- 2022
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41. Spectrum and characterization of bi-allelic variants in MMAB causing cblB-type methylmalonic aciduria
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Tanja Plessl, Céline Bürer, Caroline Frei, D. Sean Froese, Patrick Forny, Matthias R. Baumgartner, University of Zurich, Froese, D Sean, and Baumgartner, Matthias R
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2716 Genetics (clinical) ,610 Medicine & health ,Cobalamin ,Cofactor ,03 medical and health sciences ,chemistry.chemical_compound ,Adenosine Triphosphate ,0302 clinical medicine ,Mutase ,1311 Genetics ,Genetics ,medicine ,Humans ,Missense mutation ,Proto-Oncogene Proteins c-cbl ,Allele ,Amino Acid Metabolism, Inborn Errors ,Alleles ,Genetics (clinical) ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,0303 health sciences ,Alkyl and Aryl Transferases ,biology ,Hydroxocobalamin ,Molecular biology ,Vitamin B 12 ,chemistry ,Methylmalonic aciduria ,10036 Medical Clinic ,Mutation ,biology.protein ,CBLB ,Propionates ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Pathogenic variants in MMAB cause cblB-type methylmalonic aciduria, an autosomal-recessive disorder of propionate metabolism. MMAB encodes ATP:cobalamin adenosyltransferase, using ATP and cob(I)alamin to create 5’-deoxyadenosylcobalamin (AdoCbl), the cofactor of methylmalonyl-CoA mutase (MMUT). We identified bi-allelic disease-causing variants in MMAB in 97 individuals with cblB-type methylmalonic aciduria, including 33 different and 16 novel variants. Missense changes accounted for the most frequent pathogenic alleles (p.(Arg186Trp), N = 57; p.(Arg191Trp), N = 19); while c.700C > T (p.(Arg234*)) was the most frequently identified truncating variant (N = 14). In fibroblasts from 76 affected individuals, the ratio of propionate incorporation in the presence and absence of hydroxocobalamin (PI ratio) was associated to clinical cobalamin responsiveness and later disease onset. We found p.(Arg234*) to be associated with cobalamin responsiveness in vitro, and clinically with later onset; p.(Arg186Trp) and p.(Arg191Trp) showed no clear cobalamin responsiveness and early onset. Mapping these and novel variants onto the MMAB structure revealed their potential to affect ATP and AdoCbl binding. Follow-up biochemical characterization of recombinant MMAB identified its three active sites to be equivalent for ATP binding, determined by fluorescence spectroscopy (Kd = 21 µM) and isothermal calorimetry (Kd = 14 µM), but function as two non-equivalent AdoCbl binding sites (Kd1 = 0.55 μM; Kd2 = 8.4 μM). Ejection of AdoCbl was activated by ATP (Ka = 24 µM), which was sensitized by the presence of MMUT (Ka = 13 µM). This study expands the landscape of pathogenic MMAB variants, provides association of in vitro and clinical responsiveness, and facilitates insight into MMAB function, enabling better disease understanding.
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- 2022
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42. Shifting landscapes of human MTHFR missense-variant effects
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Céline Bürer, Viktor Kozich, D. Sean Froese, Jochen Weile, Song Sun, Marinella Gebbia, Nishka Kishore, Robert L. Nussbaum, Iosifina Fotiadou, David Watkins, Alexander Holenstein, Ranim Maaieh, Roujia Li, Michael Garton, Rima Rozen, Linnea Blomgren, Shan Yang, Frederick P. Roth, Yingzhou Wu, Marta Verby, and Julia Kitaygorodsky
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Genotype ,Methylenetetrahydrofolate reductase deficiency ,Folate Metabolism ,DNA Mutational Analysis ,Mutation, Missense ,Homocystinuria ,Saccharomyces cerevisiae ,folate ,Article ,homocystinuria ,03 medical and health sciences ,0302 clinical medicine ,deep mutational scanning ,Dietary folate ,Genetics ,medicine ,Humans ,Missense mutation ,variant effect mapping ,Methylenetetrahydrofolate Reductase (NADPH2) ,Genetics (clinical) ,Gene Library ,030304 developmental biology ,mthfr ,0303 health sciences ,biology ,clinical variant interpretation ,cystathionine beta synthase ,medicine.disease ,Diploidy ,methylenetetrahydrofolate reductase ,Cystathionine beta synthase ,Phenotype ,molecular dynamics ,digestive system diseases ,Amino Acid Substitution ,Methylenetetrahydrofolate reductase ,gene- environment interaction ,biology.protein ,030217 neurology & neurosurgery - Abstract
Summary Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.
- Published
- 2021
43. Cellular and computational models reveal environmental and metabolic interactions in MMUT‐type methylmalonic aciduria.
- Author
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Ramon, Charlotte, Traversi, Florian, Bürer, Céline, Froese, D. Sean, and Stelling, Jörg
- Abstract
Methylmalonyl‐coenzyme A (CoA) mutase (MMUT)‐type methylmalonic aciduria is a rare inherited metabolic disease caused by the loss of function of the MMUT enzyme. Patients develop symptoms resembling those of primary mitochondrial disorders, but the underlying causes of mitochondrial dysfunction remain unclear. Here, we examined environmental and genetic interactions in MMUT deficiency using a combination of computational modeling and cellular models to decipher pathways interacting with MMUT. Immortalized fibroblast (hTERT BJ5ta) MMUT‐KO (MUTKO) clones displayed a mild mitochondrial impairment in standard glucose‐based medium, but they did not to show increased reliance on respiratory metabolism nor reduced growth or viability. Consistently, our modeling predicted MUTKO specific growth phenotypes only for lower extracellular glutamine concentrations. Indeed, two of three MMUT‐deficient BJ5ta cell lines showed a reduced viability in glutamine‐free medium. Further, growth on 183 different carbon and nitrogen substrates identified increased NADH (nicotinamide adenine dinucleotide) metabolism of BJ5ta and HEK293 MUTKO cells compared with controls on purine‐ and glutamine‐based substrates. With this knowledge, our modeling predicted 13 reactions interacting with MMUT that potentiate an effect on growth, primarily those of secondary oxidation of propionyl‐CoA, oxidative phosphorylation and oxygen diffusion. Of these, we validated 3‐hydroxyisobutytyl‐CoA hydrolase (HIBCH) in the secondary propionyl‐CoA oxidation pathway. Altogether, these results suggest compensation for the loss of MMUT function by increasing anaplerosis through glutamine or by diverting flux away from MMUT through the secondary propionyl‐CoA oxidation pathway, which may have therapeutic relevance. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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44. Clinical pattern, mutations and in vitro residual activity in 33 patients with severe 5, 10 methylenetetrahydrofolate reductase (MTHFR) deficiency
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Huemer, Martina, Mulder-Bleile, Regina, Burda, Patricie, Froese, D. Sean, Suormala, Terttu, Zeev, Bruria Ben, Chinnery, Patrick F., Dionisi-Vici, Carlo, Dobbelaere, Dries, Gökcay, Gülden, Demirkol, Mübeccel, Häberle, Johannes, Lossos, Alexander, Mengel, Eugen, Morris, Andrew A., Niezen-Koning, Klary E., Plecko, Barbara, Parini, Rossella, Rokicki, Dariusz, Schiff, Manuel, Schimmel, Mareike, Sewell, Adrian C., Sperl, Wolfgang, Spiekerkoetter, Ute, Steinmann, Beat, Taddeucci, Grazia, Trejo-Gabriel-Galán, Jose M., Trefz, Friedrich, Tsuji, Megumi, Vilaseca, María Antònia, von Kleist-Retzow, Jürgen-Christoph, Walker, Valerie, Zeman, Jiri, Baumgartner, Matthias R., and Fowler, Brian
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- 2016
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45. Clinical and structural insights into potential dominant negative triggers of proximal urea cycle disorders
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Carmen Diez-Fernandez, Corinne Gemperle, Véronique Rüfenacht, D. Sean Froese, Ljubica Caldovic, Matthias Lauber, Johannes Häberle, Georgios Makris, University of Zurich, and Häberle, Johannes
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Male ,0301 basic medicine ,Heterozygote ,1303 Biochemistry ,Amino-Acid N-Acetyltransferase ,Carbamoyl-Phosphate Synthase (Ammonia) ,Mutation, Missense ,Dominant negative ,610 Medicine & health ,Biology ,Biochemistry ,Genetic analysis ,law.invention ,03 medical and health sciences ,Protein Domains ,law ,medicine ,Humans ,Missense mutation ,Urea Cycle Disorders, Inborn ,Gene ,Ornithine Carbamoyltransferase ,Genes, Dominant ,Genetic testing ,Genetics ,chemistry.chemical_classification ,030102 biochemistry & molecular biology ,medicine.diagnostic_test ,Homozygote ,General Medicine ,030104 developmental biology ,Enzyme ,Amino Acid Substitution ,chemistry ,10036 Medical Clinic ,Urea cycle ,Recombinant DNA ,Female - Abstract
Despite biochemical and genetic testing being the golden standards for identification of proximal urea cycle disorders (UCDs), genotype-phenotype correlations are often unclear. Co-occurring partial defects affecting more than one gene have not been demonstrated so far in proximal UCDs. Here, we analyzed the mutational spectrum of 557 suspected proximal UCD individuals. We probed oligomerizing forms of NAGS, CPS1 and OTC, and evaluated the surface exposure of residues mutated in heterozygously affected individuals. BN-PAGE and gel-filtration chromatography were employed to discover protein-protein interactions within recombinant enzymes. From a total of 281 confirmed patients, only 15 were identified as “heterozygous-only” candidates (i.e. single defective allele). Within these cases, the only missense variants to potentially qualify as dominant negative triggers were CPS1 p.Gly401Arg and NAGS p.Thr181Ala and p.Tyr512Cys, as assessed by residue oligomerization capacity and surface exposure. However, all three candidates seem to participate in critical intramolecular functions, thus, unlikely to facilitate protein-protein interactions. This interpretation is further supported by BN-PAGE and gel-filtration analyses revealing no multiprotein proximal urea cycle complex formation. Collectively, genetic analysis, structural considerations and in vitro experiments point against a prominent role of dominant negative effects in human proximal UCDs.
- Published
- 2021
46. Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin B12
- Author
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Abderrahim Oussalah, Youssef Siblini, Sébastien Hergalant, Céline Chéry, Pierre Rouyer, Catia Cavicchi, Renzo Guerrini, Pierre-Emmanuel Morange, David Trégouët, Mihaela Pupavac, David Watkins, Tomi Pastinen, Wendy K. Chung, Can Ficicioglu, François Feillet, D. Sean Froese, Matthias R. Baumgartner, Jean-François Benoist, Jacek Majewski, Amelia Morrone, David S. Rosenblatt, Jean-Louis Guéant, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Biochimie – Biologie moléculaire et Nutrition [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de référence des maladies héréditaires du métabolisme (MaMEA Nancy-Brabois), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], Università degli Studi di Firenze = University of Florence (UniFI), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Columbia University Medical Center (CUMC), Columbia University [New York], Perelman School of Medicine, University of Pennsylvania, Children’s Hospital of Philadelphia (CHOP ), University Children’s Hospital Zurich, Universität Zürich [Zürich] = University of Zurich (UZH), Hôpital Robert Debré, McGill University Health Center [Montreal] (MUHC), Service d'Hépato-gastro-entérologie [CHRU Nancy], ANR-15-IDEX-0004,LUE,Isite LUE(2015), Hergalant, Sébastien, and ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID
- Subjects
[MATH.MATH-PR] Mathematics [math]/Probability [math.PR] ,[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,[SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN] ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Methylmalonic aciduria and homocystinuria ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,TESK2 ,[MATH.MATH-PR]Mathematics [math]/Probability [math.PR] ,Promoter hypermethylation ,Secondary epimutation ,[SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN] ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,cblC type ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,Molecular Biology ,Genetics (clinical) ,MMACHC ,[INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM] ,Developmental Biology ,Epi-cblC - Abstract
Background epi-cblC is a recently discovered inherited disorder of intracellular vitamin B12 metabolism associating hematological, neurological, and cardiometabolic outcomes. It is produced by an epimutation at the promoter common to CCDC163P and MMACHC, which results from an aberrant antisense transcription due to splicing mutations in the antisense PRDX1 gene neighboring MMACHC. We studied whether the aberrant transcription produced a second epimutation by encompassing the CpG island of the TESK2 gene neighboring CCDC163P. Methods We unraveled the methylome architecture of the CCDC163P–MMACHC CpG island (CpG:33) and the TESK2 CpG island (CpG:51) of 17 epi-cblC cases. We performed an integrative analysis of the DNA methylome profiling, transcriptome reconstruction of RNA-sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-Seq) of histone H3, and transcription expression of MMACHC and TESK2. Results The PRDX1 splice mutations and activation of numerous cryptic splice sites produced antisense readthrough transcripts encompassing the bidirectional MMACHC/CCDC163P promoter and the TESK2 promoter, resulting in the silencing of both the MMACHC and TESK2 genes through the deposition of SETD2-dependent H3K36me3 marks and the generation of epimutations in the CpG islands of the two promoters. Conclusions The antisense readthrough transcription of the mutated PRDX1 produces an epigenetic silencing of MMACHC and TESK2. We propose using the term 'epi-digenism' to define this epigenetic disorder that affects two genes. Epi-cblC is an entity that differs from cblC. Indeed, the PRDX1 and TESK2 altered expressions are observed in epi-cblC but not in cblC, suggesting further evaluating the potential consequences on cancer risk and spermatogenesis.
- Published
- 2022
47. Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency
- Author
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Forny, Patrick; https://orcid.org/0000-0003-1877-2976, Bonilla, Ximena; https://orcid.org/0000-0002-4950-6825, Lamparter, David; https://orcid.org/0000-0002-9216-8825, Shao, Wenguang; https://orcid.org/0000-0003-0905-0728, Plessl, Tanja, Frei, Caroline, Bingisser, Anna, Goetze, Sandra; https://orcid.org/0000-0001-6880-8020, van Drogen, Audrey, Harshman, Keith, Pedrioli, Patrick G A, Howald, Cédric, Poms, Martin; https://orcid.org/0000-0002-4426-314X, Traversi, Florian, Cherkaoui, Sarah; https://orcid.org/0000-0002-0636-4177, Morscher, Raphael J; https://orcid.org/0000-0003-3378-9266, Simmons, Luke, Forny, Merima, Xenarios, Ioannis; https://orcid.org/0000-0002-3413-6841, Aebersold, Ruedi; https://orcid.org/0000-0002-9576-3267, Zamboni, Nicola; https://orcid.org/0000-0003-1271-1021, Raetsch, Gunnar; https://orcid.org/0000-0001-5486-8532, Dermitzakis, Emmanouil; https://orcid.org/0000-0002-9302-6490, Wollscheid, Bernd; https://orcid.org/0000-0002-3923-1610, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Forny, Patrick; https://orcid.org/0000-0003-1877-2976, Bonilla, Ximena; https://orcid.org/0000-0002-4950-6825, Lamparter, David; https://orcid.org/0000-0002-9216-8825, Shao, Wenguang; https://orcid.org/0000-0003-0905-0728, Plessl, Tanja, Frei, Caroline, Bingisser, Anna, Goetze, Sandra; https://orcid.org/0000-0001-6880-8020, van Drogen, Audrey, Harshman, Keith, Pedrioli, Patrick G A, Howald, Cédric, Poms, Martin; https://orcid.org/0000-0002-4426-314X, Traversi, Florian, Cherkaoui, Sarah; https://orcid.org/0000-0002-0636-4177, Morscher, Raphael J; https://orcid.org/0000-0003-3378-9266, Simmons, Luke, Forny, Merima, Xenarios, Ioannis; https://orcid.org/0000-0002-3413-6841, Aebersold, Ruedi; https://orcid.org/0000-0002-9576-3267, Zamboni, Nicola; https://orcid.org/0000-0003-1271-1021, Raetsch, Gunnar; https://orcid.org/0000-0001-5486-8532, Dermitzakis, Emmanouil; https://orcid.org/0000-0002-9302-6490, Wollscheid, Bernd; https://orcid.org/0000-0002-3923-1610, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, and Froese, D Sean; https://orcid.org/0000-0003-1557-3517
- Abstract
Multi-layered omics approaches can help define relationships between genetic factors, biochemical processes and phenotypes thus extending research of inherited diseases beyond identifying their monogenic cause 1. We implemented a multi-layered omics approach for the inherited metabolic disorder methylmalonic aciduria (MMA). We performed whole genome sequencing, transcriptomic sequencing, and mass spectrometry-based proteotyping from matched primary fibroblast samples of 230 individuals (210 affected, 20 controls) and related the molecular data to 105 phenotypic features. Integrative analysis identified a molecular diagnosis for 84% (177/210) of affected individuals, the majority (148) of whom had pathogenic variants in methylmalonyl-CoA mutase (MMUT). Untargeted analysis of all three omics layers revealed dysregulation of the TCA cycle and surrounding metabolic pathways, a finding that was further corroborated by multi-organ metabolomics of a hemizygous Mmut mouse model. Integration of phenotypic disease severity indicated downregulation of oxoglutarate dehydrogenase and upregulation of glutamate dehydrogenase, two proteins involved in glutamine anaplerosis of the TCA cycle. The relevance of disturbances in this pathway was supported by metabolomics and isotope tracing studies which showed decreased glutamine-derived anaplerosis in MMA. We further identified MMUT to physically interact with both, oxoglutarate dehydrogenase complex components and glutamate dehydrogenase providing evidence for a multi-protein metabolon that orchestrates TCA cycle anaplerosis. This study emphasizes the utility of a multi-modal omics approach to investigate metabolic diseases and highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA. Take home message Combination of integrative multi-omics technologies with clinical and biochemical features leads to an increased diagnostic rate compared to genome sequencing alone and identifies anaplerotic rewiring as a t
- Published
- 2022
48. HIF1 and DROSHA are involved in MMACHC repression in hypoxia
- Author
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Kiessling, Eva, Peters, Florian; https://orcid.org/0000-0002-8529-2326, Ebner, Lynn J A; https://orcid.org/0000-0002-9665-9197, Merolla, Luca, Samardzija, Marijana; https://orcid.org/0000-0003-0991-4653, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Grimm, Christian; https://orcid.org/0000-0001-9318-4352, Froese, D Sean; https://orcid.org/0000-0003-1557-3517, Kiessling, Eva, Peters, Florian; https://orcid.org/0000-0002-8529-2326, Ebner, Lynn J A; https://orcid.org/0000-0002-9665-9197, Merolla, Luca, Samardzija, Marijana; https://orcid.org/0000-0003-0991-4653, Baumgartner, Matthias R; https://orcid.org/0000-0002-9270-0826, Grimm, Christian; https://orcid.org/0000-0001-9318-4352, and Froese, D Sean; https://orcid.org/0000-0003-1557-3517
- Abstract
The MMACHC gene encodes for an enzyme involved in intracellular vitamin B12 metabolism, and autosomal recessive defects in MMACHC represent the most common disorder of intracellular vitamin B12 metabolism. Recent studies have identified increased levels of reactive oxygen species in cells and tissues with MMACHC dysfunction, suggesting a role for oxidative stress in disease. To investigate the link between oxidative stress and MMACHC, we exposed mice as well as human and mouse cells to hypoxia, and found significant repression of MMACHC in all investigated tissues (retina, eyecup, liver, kidney) and cell lines (HeLa, ARPE-19, human and mouse fibroblasts, 661W). Furthermore, in HeLa cells, we found transcriptional repression already at 5% oxygen, which was stable during prolonged hypoxia up to 5 days, and a return of MMACHC transcripts to normal levels only 24 h after reoxygenation. This hypoxia-induced downregulation of MMACHC was not due to altered function of the known MMACHC controlling transcription factor complex HCFC1/THAP11/ZNF143. Using in vitro RNA interference against hypoxia-induced transcription factors (HIF1A, HIF2A and REST) as well as the microRNA transcription machinery (DROSHA), we observed release of hypoxia-dependent downregulation of MMACHC expression by HIF1A and DROSHA knockdowns, whose combined effect was additive. Together, these results strongly indicate that MMACHC is a hypoxia-regulated gene whose downregulation appears to be partially mediated through both hypoxia-induced transcription factor and microRNA machinery. These findings suggest that oxidative stress could impair vitamin B12 metabolism by repression of MMACHC in healthy as well as in diseased individuals.
- Published
- 2022
49. INTEGRATED MULTI-OMIC ANALYSIS OF A RARE INBORN ERROR OF METABOLISM
- Author
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Forny, Patrick, primary, Bonilla, Ximena, additional, Lamparter, David, additional, Shao, Wenguang, additional, Plessl, Tanja, additional, Frei, Caroline, additional, Bingisser, Anna, additional, Goetze, Sandra, additional, van Drogen, Audrey, additional, Harshman, Keith, additional, Pedrioli, Patrick, additional, Traversi, Florian, additional, Xenarios, Ioannis, additional, Aebersold, Ruedi, additional, Zamboni, Nicola, additional, Rätsch, Gunnar, additional, Dermitzakis, Emmanouil, additional, Wollscheid, Bernd, additional, Froese, D. Sean, additional, and Baumgartner, Matthias R., additional
- Published
- 2022
- Full Text
- View/download PDF
50. Conformational plasticity of glycogenin and its maltosaccharide substrate during glycogen biogenesis
- Author
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Chaikuad, Apirat, Froese, D. Sean, Berridge, Georgina, von Delft, Frank, Oppermann, Udo, and Yue, Wyatt W.
- Published
- 2011
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