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Previous Volume 358:1454-1464 April 3, 2008 Number 14 Next

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ABSTRACT

Background Vitamin B₁₂ (cobalamin) is an essential cofactor in several metabolic pathways. Intracellular conversion of cobalamin to its two coenzymes, adenosylcobalamin in mitochondria and methylcobalamin in the cytoplasm, is necessary for the homeostasis of methylmalonic acid and homocysteine. Nine defects of intracellular cobalamin metabolism have been defined by means of somatic complementation analysis. One of these defects, the cblD defect, can cause isolated methylmalonic aciduria, isolated homocystinuria, or both. Affected persons present with multisystem clinical abnormalities, including developmental, hematologic, neurologic, and metabolic findings. The gene responsible for the cblD defect has not been identified.

Methods We studied seven patients with the cblD defect, and skin fibroblasts from each were investigated in cell culture. Microcell-mediated chromosome transfer and refined genetic mapping were used to localize the responsible gene. This gene was transfected into cblD fibroblasts to test for the rescue of adenosylcobalamin and methylcobalamin synthesis.

Results The cblD gene was localized to human chromosome 2q23.2, and a candidate gene, designated MMADHC (methylmalonic aciduria, cblD type, and homocystinuria), was identified in this region. Transfection of wild-type MMADHC rescued the cellular phenotype, and the functional importance of mutant alleles was shown by means of transfection with mutant constructs. The predicted MMADHC protein has sequence homology with a bacterial ATP-binding cassette transporter and contains a putative cobalamin binding motif and a putative mitochondrial targeting sequence.

Conclusions Mutations in a gene we designated MMADHC are responsible for the cblD defect in vitamin B₁₂ metabolism. Various mutations are associated with each of the three biochemical phenotypes of the disorder.

Source Information

From the Metabolic Unit, University Children's Hospital, Basel (D.C., T.S., J.P.L.-E., B.F.), and the Division of Metabolism and Molecular Pediatrics, University Children's Hospital (M.S., M.R.B.), and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich (M.S.) — both in Switzerland; Department of Human Genetics, McGill University, and Division of Medical Genetics, McGill University Health Centre — both in Montreal (J.P.L.-E., D.S.R.); and Brunel Institute of Cancer Genetics and Pharmacogenomics, Brunel University, Uxbridge, United Kingdom (R.F.N.).

Drs. Coelho and Suormala contributed equally to this article, as did Drs. Baumgartner and Fowler.

Address reprint requests to Dr. Fowler at the Metabolic Unit, University Children's Hospital Basel, Roemergasse 8, CH-4005 Basel, Switzerland, or at brian.fowler{at}ukbb.ch.

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