Fowler
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Stoffwechsel und Molekulare Pädiatrie, Abteilung für » Prof. Dr. Beat Steinmann (emeritiert) » Fowler
Completed research project
| Title / Titel | THE EFFECT OF COFACTORS AND VITAMINS ON HOMOCYSTEINE METABOLISM IN HEALTH AND DISEASE | ||||||||
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| Abstract (PDF, 14 KB) | |||||||||
| Summary / Zusammenfassung | Large elevations of homocysteine as seen in inborn errors of methionine metabolism can lead to severe vascular abnormalities and markedly increased risk of premature arteriosclerosis and mortality. Milder increases of plasma homocysteine are established as an independent risk factor for cardiovascular events. In man homocysteine is formed from methionine, then either catabolised via transsulphuration or recycled by remethylation to methionine. Several vitamins, co-factors and substrates are required for both remethylation (vitamin B12 [cobalamin, Cbl], 5-methyl-tetrahydrofolate) and transsulphuration (pyridoxal phosphate). Vitamin B12 is increasingly implicated as a determinant of increased homocysteine levels. Understanding the role of severe and mild disturbances of cobalamin involved in both the rare inborn errors of metabolism and in mild hyperhomocysteinemia requires knowledge of the basic metabolic steps involved in intracellular vitamin B12 metabolism. In our project we attempt to define these steps by elucidating the basic defects in human Cbl complementation groups (Cbl A-G). Our discovery of a new mutant class of methionine synthase (MS) deficiency in two patients revealed that these two exceptional cell lines with isolated deficiency of MS (cytosolic) belong to the same complementation group, CblD, as two previously reported siblings with a combined defect of MS together with methylmalonyl CoA mutase (mitochondrial). This highly surprising finding indicates the existence of two different biochemical phenotypes within one genetic complementation class. This points to the existence of as yet undefined different metabolic steps in Cbl reduction processes either both cytosolic and mitochondrial, or just cytosolic, both coded for by the same gene. Using microcell mediated chromosome transfer and mapping analysis with 38 highly polymorphic DNA markers we were able to identify the gene (MMADHC) responsible for the CblD defect. Mutation analysis in 7 patients revealed 2 mutations in each patient including nonsense, frameshift and missense mutations. Transfections of MMADHC deficient fibroblasts with the wildtype MMADHC cDNA clearly corrected methionine and methylcobalamin synthesis. These findings indicate that the identified gene is indeed responsible for the CblD defect. Significance: Our studies provide insight into the cellular and molecular biology of intracellular Cbl processing. Knowledge gained may lead to improved treatment of patients with inherited defects of Cbl metabolism. Identification of genes will provide the basis for identification 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 subclinical functional B12 deficiency in childhood. Weitere Informationen |
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| Publications / Publikationen | Fowler B. Genetic defects of folate and cobalamin metabolism (Review). Eur J Pediatr. 157 (Suppl 2):S60-66, 1998Suormala 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, 2004 Coelho D, Baumgartner MR, Suormala T, Fowler B, CblA type methylmalonic acidemia: molecular, genetic and enzymological characterization. J Inher Metab Dis 27 (Suppl.1):233, 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, 2007 Coelho 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, in pressZwicker 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 (2008) Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J. Inher. Metab. Dis. in pressWeitere Informationen |
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| Keywords / Suchbegriffe | Vitamin B12, cobalamin, homocysteine, 5-methyl-tetrahydrofolate, methylmalonic acidurias, Cbl-complementation, pyridoxal phosphate, methyonine synthase deficiency, methylmalonyl-CoA mutase deficiency | ||||||||
| 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 2006 to Dec 2008 |