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J. Biol. Chem., Vol. 279, Issue 41, 42742-42749, October 8, 2004

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The cblD Defect Causes Either Isolated or Combined Deficiency of Methylcobalamin and Adenosylcobalamin Synthesis^*

Terttu Suormala, Matthias R. Baumgartner, David Coelho, Petra Zavadakova¶, Viktor Koich¶, Hans Georg Koch||, Martin Berghaüser||, James E. Wraith**, Alberto Burlina, Adrian Sewell, Jürgen Herwig, and Brian Fowler¶¶

From the Metabolic Unit, University Children's Hospital, Römergasse 8, CH-4058 Basel, Switzerland, the ^¶Institute of Inherited Metabolic Diseases, Charles University, 1st Faculty of Medicine, 12808 Praha 2, Czech Republic, the ^||Department of Pediatrics, University Hospital, Münster D48149, Germany, the ^**Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester M27 4HA, United Kingdom, the Department of Pediatrics, University of Padua 35128, Italy, and the Department of Pediatrics, Johann Wolfgang Goethe-University, Frankfurt am Main D-60590, Germany

Intracellular cobalamin is converted to adenosylcobalamin, coenzyme for methylmalonyl-CoA mutase and to methylcobalamin, coenzyme for methionine synthase, in an incompletely understood sequence of reactions. Genetic defects of these steps are defined as cbl complementation groups of which cblC, cblD (described in only two siblings), and cblF are associated with combined homocystinuria and methylmalonic aciduria. Here we describe three unrelated patients belonging to the cblD complementation group but with distinct biochemical phenotypes different from that described in the original cblD siblings. Two patients presented with isolated homocystinuria and reduced formation of methionine and methylcobalamin in cultured fibroblasts, defined as cblD-variant 1, and one patient with isolated methylmalonic aciduria and deficient adenosylcobalamin synthesis in fibroblasts, defined as cblD-variant 2. Cell lines from the cblD-variant 1 patients clearly complemented reference lines with the same biochemical phenotype, i.e. cblE and cblG, and the cblD-variant 2 cell line complemented cells from the mutant classes with isolated deficiency of adenosylcobalamin synthesis, i.e. cblA and cblB. Also, no pathogenic sequence changes in the coding regions of genes associated with the respective biochemical phenotypes were found. These findings indicate heterogeneity within the previously defined cblD mutant class and point to further complexity of intracellular cobalamin metabolism.

Received for publication, July 9, 2004 , and in revised form, July 26, 2004.

^* This work was supported by the Swiss National Science Foundation (Grant 3200-066878), and in part by the research project VZ111100003 of Charles University, 1st Faculty of Medicine, Prague, Czech Republic. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Division of Metabolism and Molecular Pediatrics, University Children's Hospital, CH-8032 Zürich, Switzerland.

^¶¶ To whom correspondence should be addressed. Tel: 41-(0)61-685-6275; Fax: 41-(0)61-685-6566; E-mail: Brian.Fowler{at}ukbb.ch.

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