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The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in health and disease

English title The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in health and disease
Applicant Baumgartner Matthias
Number 175779
Funding scheme Project funding
Research institution Universitäts-Kinderspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Metabolic Disorders
Start/End 01.01.2018 - 31.12.2022
Approved amount 700'000.00
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All Disciplines (4)

Discipline
Metabolic Disorders
Molecular Biology
Biochemistry
Paediatrics

Keywords (9)

vitamin B12 / cobalamin ; intracellular cobalamin metabolism; methylmalonic acid; inborn error of metabolism ; neurological disease; protein complex formation and interaction; induced pluripotent stem cells / iPSC; vascular disease; homocysteine

Lay Summary (German)

Lead
Vitamin B12 (Cobalamin) ist ein wasserlösliches Vitamin, das über die Nahrung aufgenommen wird und als Kofaktor für die Funktion von 2 Enzymen im Stoffwechsel von Aminosäuren unerlässlich ist. Dazu wird Vitamin B12 in der Zelle mithilfe von mehreren Proteinen in Adenosylcobalamin und Methylcobalamin umgewandelt, seine biologisch aktiven Kofaktor-Formen. Fehlen diese aufgrund einer zu geringen Aufnahme von Vitamin B12 über die Nahrung oder aufgrund eines genetischen Defekts in der Umwandlung, führt dies zu schwerwiegenden Krankheiten, die bereits beim Neugeborenen oder während der Kindheit zum Tod führen können. Je nach Art des Defekts häufen sich Methylmalonsäure und/oder Homocystein in Blut und Urin an, weshalb man die Krankheiten auch mit Methylmalonazidurie (MMA) und Homocystinurie bezeichnet.
Lay summary

Unser übergeordnetes Ziel ist, das Verständnis über die Funktionen und Interaktionen der Proteine, die zur Umwandlung von Vitamin B12 in der Zelle notwendig sind, zu vertiefen. Zu diesem Zweck werden wir i) die molekularen Mechanismen und Interaktionen des Cobalamin-Stoffwechsels determinieren und  ii) die Krankheitsmechanismen der Hirnschädigung bei MMA in einem neuronalen Zellmodell untersuchen. Schliesslich werden wir  iii) neue therapeutische Interventionen bei MMA wie z.B. Therapie mit Antioxidantien evaluieren. 

Unsere wissenschaftlichen Erkenntnisse werden einen Einblick in die bisher nicht gänzlich verstandene zelluläre und molekulare Biologie des intrazellulären Cobalamin-Stoffwechsels geben, zu einem besseren Verständnis der Hirnschädigung bei der MMA beitragen und die Grundlagen für Entwicklung von besseren Therapien führen.

Direct link to Lay Summary Last update: 23.11.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
Luciani Alessandro, Schumann Anke, Berquez Marine, Chen Zhiyong, Nieri Daniela, Failli Mario, Debaix Huguette, Festa Beatrice Paola, Tokonami Natsuko, Raimondi Andrea, Cremonesi Alessio, Carrella Diego, Forny Patrick, Kölker Stefan, Diomedi Camassei Francesca, Diaz Francisca, Moraes Carlos T., Di Bernardo Diego, Baumgartner Matthias R., Devuyst Olivier (2020), Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency, in Nature Communications, 11(1), 970-970.
Health‐related quality of life in paediatric patients with intoxication‐type inborn errors of metabolism: Analysis of an international data set
Bösch Florin, Landolt Markus A., Baumgartner Matthias R., Zeltner Nina, Kölker Stefan, Gleich Florian, Burlina Alberto, Cazzorla Chiara, Packman Wendy, V. D. Schwartz Ida, Neto Eduardo, Ribeiro Márcia G., Martinelli Diego, Olivieri Giorgia, Huemer Martina (2020), Health‐related quality of life in paediatric patients with intoxication‐type inborn errors of metabolism: Analysis of an international data set, in Journal of Inherited Metabolic Disease, jimd.12301-jimd.12301.
Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut
Hörster Friederike, Tuncel Ali Tunç, Gleich Florian, Plessl Tanja, Froese Sean D., Garbade Sven F., Kölker Stefan, Baumgartner Matthias R. (2020), Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut, in Journal of Inherited Metabolic Disease, jimd.12297-jimd.12297.
Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency
Watkins David, Chéry Céline, Froese D. Sean, Ells Courtney, Kerachian Matin, Saskin Avi, Christensen Karen E., Gilfix Brian M., Guéant Jean-Louis, Rosenblatt David S., Bidla Gawa (2020), Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency, in Molecular Genetics and Metabolism, 130(3), 179-182.
Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase
Sokolovskaya Olga M., Plessl Tanja, Bailey Henry, Mackinnon Sabrina, Baumgartner Matthias R., Yue Wyatt W., Froese D. Sean, Taga Michiko E. (2020), Naturally occurring cobalamin (B12) analogs can function as cofactors for human methylmalonyl-CoA mutase, in Biochimie, S0300.
Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise
Dimitrov Bianca, Molema Femke, Williams Monique, Schmiesing Jessica, Mühlhausen Chris, Baumgartner Matthias R., Schumann Anke, Kölker Stefan (2020), Organic acidurias: Major gaps, new challenges, and a yet unfulfilled promise, in Journal of Inherited Metabolic Disease, jimd.12254-jimd.12254.
Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing.
C Rashka, S Hergalant, N Dreumont, A Oussalah, JM Camadro, V Marchand, Z Hassan, MR Baumgartner, DS Rosenblatt, F Feillet, JL Guéant, D Coelho (2020), Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing., in Human molecular genetics, 1969.
Reducing complexity: explaining inborn errors of metabolism and their treatment to children and adolescents
Zeltner Nina A., Welsink-Karssies Mendy M., Landolt Markus A., Bosshard-Bullinger Dominique, Keller Fabia, Bosch Annet M., Groenendijk Marike, Grünert Sarah C., Karall Daniela, Rettenbacher Beatrix, Scholl-Bürgi Sabine, Baumgartner Matthias R., Huemer Martina (2019), Reducing complexity: explaining inborn errors of metabolism and their treatment to children and adolescents, in Orphanet Journal of Rare Diseases, 14(1), 248-248.
Vitamin B 12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation
Froese D. Sean, Fowler Brian, Baumgartner Matthias R. (2019), Vitamin B 12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation, in Journal of Inherited Metabolic Disease, 42(4), 673-685.
The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways
Huemer Martina, Baumgartner Matthias R. (2019), The clinical presentation of cobalamin-related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways, in Journal of Inherited Metabolic Disease, 42(4), 686-705.
Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency
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., Baumgartner Matthias R. (2019), Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency, in Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1865(6), 1265-1272.
Newborn screening for homocystinurias: Recent recommendations versus current practice
Keller Rebecca, Chrastina Petr, Pavlíková Markéta, Gouveia Sofía, Ribes Antonia, Kölker Stefan, Blom Henk J., Baumgartner Matthias R., Bártl Josef, Dionisi‐Vici Carlo, Gleich Florian, Morris Andrew A., Kožich Viktor, Huemer Martina, Barić Ivo, Ben‐Omran Tawfeq, Blasco‐Alonso Javier, Bueno Delgado Maria A., Carducci Claudia, Cassanello Michela, Cerone Roberto, Couce Maria Luz, Crushell Ellen, Delgado Pecellin Carmen, et al. (2019), Newborn screening for homocystinurias: Recent recommendations versus current practice, in Journal of Inherited Metabolic Disease, 42(1), 128-139.
B Vitamins: Small molecules, big effects.
S Rahman, M Baumgartner (2019), B Vitamins: Small molecules, big effects., in Journal of inherited metabolic disease, 579-580.
In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria.
M Lucienne, JA Aguilar-Pimentel, OV Amarie, L Becker, J Calzada-Wack, da Silva-Buttkus P, L Garrett, SM Hölter, P Mayer-Kuckuk, B Rathkolb, J Rozman, MR Baumgartner (2019), In-depth phenotyping reveals common and novel disease symptoms in a hemizygous knock-in mouse model (Mut-ko/ki) of mut-type methylmalonic aciduria., in Biochimica et biophysica acta. Molecular basis of disease, 1866.
Tricarboxylic acid cycle enzyme activities in a mouse model of methylmalonic aciduria.
P Wongkittichote, G Cunningham, ML Summar, E Pumbo, P Forny, MR Baumgartner, KA Chapman (2019), Tricarboxylic acid cycle enzyme activities in a mouse model of methylmalonic aciduria., in Molecular genetics and metabolism, 444-451.
A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients
Guéant Jean-Louis, Chéry Céline, Oussalah Abderrahim, Nadaf Javad, Coelho David, Josse Thomas, Flayac Justine, Robert Aurélie, Koscinski Isabelle, Gastin Isabelle, Filhine-Tresarrieu Pierre, Pupavac Mihaela, Brebner Alison, Watkins David, Pastinen Tomi, Montpetit Alexandre, Hariri Fadi, Tregouët David, Raby Benjamin A, Chung Wendy K., Morange Pierre-Emmanuel, Froese D. Sean, Baumgartner Matthias R., Benoist Jean-François, et al. (2018), A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients, in Nature Communications, 9(1), 67-67.
New in vitro model derived from brain-specific Mut-/- mice confirms cerebral ammonium accumulation in methylmalonic aciduria
Remacle Noémie, Forny Patrick, Cudré-Cung Hong-Phuc, Gonzalez-Melo Mary, do Vale-Pereira Sónia, Henry Hugues, Teav Tony, Gallart-Ayala Hector, Braissant Olivier, Baumgartner Matthias, Ballhausen Diana (2018), New in vitro model derived from brain-specific Mut-/- mice confirms cerebral ammonium accumulation in methylmalonic aciduria, in Molecular Genetics and Metabolism, 124(4), 266-277.

Collaboration

Group / person Country
Types of collaboration
Prof. Wyatt Yue, University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Prof. Jörg Stelling, ETH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Stefan Kölker, Uni-Kinderklinik Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Olivier Devuyst, Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Michiko Taga, University of California, Berkeley United States of America (North America)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SSIEM Annual Meeting Talk given at a conference Metabolic liver disease in a tailored mouse model of mut-type methylmalonic aciduria 05.09.2019 Rotterdam, Netherlands Froese Sean; Baumgartner Matthias;
SSIEM Annual Meeting Poster CblA and mut0 type methylmalonic aciduria: Two phenotype extremes? 04.09.2019 Rotterdam, Netherlands Froese Sean; Plessl Tanja; Baumgartner Matthias;
SSIEM Annual Meeting Talk given at a conference Genetic, structural, and functional analysis of pathogenic variations causing methylmalonyl-CoA epimerase deficiency 04.09.2019 Rotterdam, Netherlands Burda Patricie; Froese Sean; Baumgartner Matthias;
SSIEM Annual Symposium Poster Reduction of complexity: explaining inborn errors of metabolism and their treatment of children and adolescents 04.09.2019 Athens, Greece Baumgartner Matthias;
Arbeitsgemeinschaft für pädiatrische Stoffwechselstörungen Jahrestagung 2019 Talk given at a conference Cobalamin: pathways & players 14.03.2019 Fulda, Germany Froese Sean;
"Remethylation disorders and methylmalonic acidurias" - 33rd Annual Conference of the Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen Talk given at a conference MMA: Clinical presentations and pathophysiological considerations 14.03.2019 Fulda, Germany Baumgartner Matthias;
"Remethylation disorders and methylmalonic acidurias" - 33rd Annual Conference of the Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen Talk given at a conference Cobalamin: pathways and players 13.03.2019 Fulda, Germany Froese Sean;
Third International Homocystinuria Patient-Expert Meeting Talk given at a conference Remethylation disorders 28.02.2019 Rom, Italy Baumgartner Matthias;
Charles University Prague at the University of Zurich Individual talk Collaborative Research in Vitamin B12 and Homocysteine Research 03.12.2018 Zürich, Switzerland Baumgartner Matthias;
SSIEM Annual Symposium Talk given at a conference Identification of a multi-protein complex for mitochondrial cobalamin and methylmalonyl-CoA processing 05.09.2018 Athen, Greece Froese Sean; Baumgartner Matthias; Plessl Tanja;
SSIEM Annual Symposium Talk given at a conference Identification of energy balance dysregulation in a mouse model of mut-type methylmalonic aciduria 04.09.2018 Athen, Greece Froese Sean; Baumgartner Matthias;
Recordati Orphan Course "Inherited vitamin responsive disorders: to the rescue of neurodegenerative diseases" Talk given at a conference Metabolic pathways, nutritional sources, B12 metabolic roles 27.06.2018 Paris, France Froese Sean;
European Metabolic Group Talk given at a conference Workshop: Methylmalonic aciduria (MMA) – new concepts of treatment. Who is doing what? 08.06.2018 Hamburg, Germany Baumgartner Matthias;


Self-organised

Title Date Place
"Remethylation disorders and methylmalonic acidurias" - 33rd Annual Conference of the Arbeitsgemeinschaft für Pädiatrische Stoffwechselstörungen 13.03.2019 Fulda, Germany
Inherited vitamin responsive disorders: to the rescue of neurodegenerative diseases 27.06.2018 Paris, France

Awards

Title Year
Creativity Prize for best oral presentation to Patrick Forny, MD-PhD, Division of Metabolism, Kinderspital Zürich, at the Annual Retreat, Children's Research Center, University Children's Hospital Zurich; Tagungszentrum Bocken, 24.10.2019 for the Presentation Trans-omic analysis of a rare inborn error of metabolism (methlymalonic aciduria) 2019

Associated projects

Number Title Start Funding scheme
183706 Forschungstage des Kinderspitals Zürich - Hauptbahnhof Zürich, 9. / 10. November 2018 01.11.2018 Agora
156907 The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in helath and disease 01.01.2015 Project funding
138521 The effect of cofactors and vitamins on homocysteine and methylmalonic acid metabolism in helath and disease 01.01.2012 Project funding

Abstract

Background: In man, vitamin B12 (cobalamin) is required as coenzyme for only 2 reactions, both of which are essential for life. Adenosylcobalamin is the cofactor for mitochondrial methylmalonyl-CoA mutase (MUT), which converts methylmalonyl-CoA to succinyl-CoA, and methylcobalamin is required by cytosolic methionine synthase (MS) for the remethylation of homocysteine to methionine. Deficiencies of either protein, due to mutation of the enzymes themselves or incomplete processing and delivery of their cofactor forms, results in methylmalonic aciduria (MMAuria, MUT-deficiency) and/or hyperhomocystinemia (HCemia, MS-deficiency). MMAuria and HCemia related defects are rare but devastating disease-causing disorders that in their most severe forms result in death in infancy or the newborn period, while milder forms may lead to a wide range of symptoms with varying severity. Those individuals who survive the first crises often suffer serious long-term consequences, including chronic renal failure and/or neurological deterioration in MMAuria. In the past years, we have discovered several genes in intracellular cobalamin processing and have made instrumental contributions to increasing knowledge of mutational, structural, biochemical and whole organism aspects of disease mechanisms. Given the potentially severe phenotypic and pathological outcomes, there is an imminent need to search for novel therapeutic approaches. However, the ability to treat patients effectively requires a complete understanding of the processes involved - which itself is dependent upon knowledge of the basic metabolic steps. For example, recent findings of physical interaction among cobalamin pathway proteins, which is blocked by patient mutations, illustrate the need for continuous sequestration of this rare and highly reactive vitamin within protein complexes. Further, the tissue specificity of long-term complications, despite ubiquitous enzyme expression, points to a variable dependence of different tissues on the disturbed metabolic pathways and/or a higher sensitivity to the accumulating metabolites brought about by their dysfunction. In order to understand these dysfunctions, the cell types specifically affected by disease must be investigated. We have developed innovative tools which for the first time bring these affected cell types within reach, including novel mouse models of MMAuria and induced pluripotent stem cells (iPSCs) from patient fibroblasts. Finally, in order to improve treatment, the molecular basis of the currently used and any newly identified therapy must be thoroughly investigated, so that a complete understanding of their efficacy may be determined.Hypotheses: (i) Cobalamin is processed within protein interaction networks that form multi-protein complexes which are disrupted in mutation and disease. (ii) Accumulation of neurotoxic metabolites and defective mitochondria are key pathogenic mechanisms of neurological dysfunction and cell death in MMAuria.Specific Aims and Experimental Design:1. Identification and reconstruction of the MUT-associated mitochondrial complex of cobalamin and related proteins2. Determination of pathomechanisms in neuronal models of MMAuria derived from patient iPSCs and isogenic controls3. Evaluation of classical and novel therapeutic interventions in MMAuria including cobalamin and corrinoid therapy, pharmacological chaperones and antioxidant treatmentExpected value of the proposed project: Knowledge gained in the proposed studies will provide insight into the so far incompletely understood cellular and molecular biology of intracellular cobalamin processing. This has implications for not only severe disease, but also milder deficiencies, which are common in certain populations and the elderly, as well as implications for other inborn errors and wider biological processes. Our studies will increase insight into the poorly understood pathomechanisms of neurological damage in MMAuria profiting from the use of the first human iPSC and neuronal models of this disease. Further, these cell lines may provide the basis for genetic correction and future use as individualized cell therapy. Knowledge gained in MMAuria will be extendable throughout the cobalamin pathway (e.g. HCuria) as well as to related organic acid disorders (e.g. glutaric and propionic acidemia). Any treatments identified in this project can be tested in our mouse models of disease and eventually in patient cohorts to which we have access.
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