Baumgartner
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Stoffwechsel und Molekulare Pädiatrie, Abteilung für » Prof. Dr. Matthias R. Baumgartner » Baumgartner
Current research project
| Title / Titel | THE EFFECT OF COFACTORS AND VITAMINS ON HOMOCYSTEINE AND METHYLMALONIC ACID METABOLISM IN HEALTH AND DISEASE | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Summary / Zusammenfassung | Large elevations of homocysteine and methlymalonic acid (MMA) as seen in rare inborn errors of intracellular vitamin B12 (cobalamin, Cbl) metabolism and in vitamin B12 deficiency can lead to severe neurological damage. Milder increases of homocysteine are associated with premature arteriosclerosis. Key players in homocysteine regulation are cobalamin, 5- methyltetrahydrofolate and S-adenosylmethionine. Understanding the role of severe and mild disturbances of homocysteine and cobalamin metabolism requires knowledge of the basic metabolic steps involved. The intracellular conversion of OH-cobalamin to the active coenzymes adenosylcobalamin in the mitochondrion and methylcobalamin in the cytosol requires a number of steps that are defined biochemically and by genetic complementation as cblA-G. We have shown that the cblD defect affects both cytosolic and mitochondrial pathways indicating that the cblD protein must play a key role in channelling of Cbl within the cell. Using microcell mediated chromosome transfer we were able to identify the gene (MMADHC) responsible for the CblD defect. The cblC gene (MMACHC) encodes a putative cobalamin transporter. Mutation studies in 118 patients revealed eleven novel mutations and confirm a correlation between particular mutations and early or late onset. The cblF gene (LMBRD1) encoding a lysosomal membrane protein was recently identified using homozygosity mapping, and we showed rescue of function in our expression system. The discovery of the genes and mutations responsible for the cblC, cblD and cblF defects are important advances in understanding these processes but many open questions remain. Significance: Knowledge gained in the proposed studies will provide insight into the so far incompletely understood cellular and molecular biology of intracellular cobalamin processing, especially the role of the intriguing cblD protein and its ability to act as a molecular switch in trafficking of this micronutrient in different cellular compartments. Identification of genes will provide the basis for the discovery of common polymorphisms which may lead to mild disturbances of homocysteine metabolism in common disease such as loss of cognitive function as well as macular degeneration in the elderly, and sub clinical cobalamin deficiency in childhood. Knowledge gained may lead to improved treatment of patients with inherited defects of cobalamin and folate metabolism as well as of patients with milder abnormalities of homocysteine and methylmalonic acid metabolism. |
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| Publications / Publikationen | Suormala T, Baumgartner MR, Coelho D, Zavadakova P, Kozich V, Koch HG, Berghäuser M, Wraith JE, Burlina A, Sewell A, Herwig J, Fowler B. The CblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem 279:42742-42749, 2004Lempp TJ, Suormala T, Siegenthaler R, Baumgartner ER, Fowler B, Steinmann B, Baumgartner MR. Mutation and biochemical analysis of mut methylmalonic aciduria in 32 European probands including 13 with the mut- form: identification of 7 novel mutations. Mol. Genet. Metab. 90:284-290, 2007Hörster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garnade SF, Kölker S, Baumgartner ER. Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Ped. Res. 62:225-230, 2007Coelho D, Suormala T, Stucki M, Lerner-Ellis JP, Rosenblatt D, Newbold RF §Baumgartner MR and §Fowler B. Gene identification of the CblD defect of vitamin B12 metabolism. N Engl J Med 358:1454-64, 2008 § both last authors contributed equallyFowler B, Leonard J, Baumgartner MR. Causes of and diagnostic approach to methylmalonic acidurias. J. Inher. Metab. Dis. 31:350-360, 2008Zwickler T, Lindner M, Aydin HI, Baumgartner MR, Bodamer O, Burlina A, Das AM, deKlerk JBC, Gökcay G, Grünewald S, Guffon N, Maier EM, Morava E, Geb S, Schwahn B, Walter JH, Wendel U, Wijburg FA, Mueller E, Kölker S, Hörster F. Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J. Inher. Metab. Dis. 31:361-367, 2008Rutsch F, Gailus S, Racine-Miousse I, Suormala T, Sagné C, Toliat M, Nürnberg G, Wittkampf T, Buers I, Sharifi A, Stucki M, Becker C, Baumgartner M, Robenek H, Marquardt T, Höhne W, Gasnier B, Rosenblatt D, Fowler B, Nürnberg P. Idenfication of the human lysosomal cobalamin exporter mutated in the cblF defect of vitamin B12 metabolism. Nature genetics 41:234-239, 2009Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy A, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B. Spectrum of mutations in MMACHC, allelic expression and evidence for genotype-phenotype correlations. Hum Mutation 30(7):1072-81, 2009Hörster F, Garbade SF, Zwickler T, Aydin HI, Bodamer OA, Burlina AB, Das AM, De Klerk JB, Dionisi-Vici C, Geb S, Gökcay G, Guffon N, Maier EM, Morava E, Walter JH, Schwahn B, Wijburg FA, Lindner M, Grünewald S, §Baumgartner MR, §Kölker S. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J Inherit Metab Dis. 32(5):630-9, 2009 § both last authors contributed equallyGailus S, Hoehne W, Gasnier B, Nürnberg P, Fowler B, Rutsch F. Insights into lysosomal cobalamin trafficking: Lessons learned from cblF disease. J Mol Med 88:459-66, 2010Gailus S, Suormala T, Toliat MR, Wittkampf T, Stucki M, Nürnberg P, Fowler B, Hennermann JB, Rutsch F. A novel mutation in LMBRD1 causes the cblF defect of vitamin B12 metabolism in a Turkish patient. J Inherit Metab Dis 33:17-24, 2010Rutsch F, Gailus S, Suormala T, Fowler B. LMBRD1: the gene for the cblF defect of vitamin B(12) metabolism. J Inherit Metab Dis Feb;34(1):121-6, 2011 |
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| Keywords / Suchbegriffe | Vitamin B12, cobalamin, homocysteine, 5-methyl-tetrahydrofolate,S-adenosylmethionine methylmalonic acidurias, Cbl-complementation, pyridoxal phosphate, methyonine synthase deficiency, methylmalonyl-CoA mutase deficiency, organic aciduria | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
SNF (Personen- und Projektförderung) |
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| Duration of Project / Projektdauer | Jan 2002 to Dec 2014 |