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Molecular and Cellular Biology, February 2001, p. 1058-1065, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1058-1065.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Targeted Disruption of the Methionine Synthase Gene in Mice

Deborah A. Swanson,1 Mei-Lan Liu,2 Priscilla J. Baker,1 Lisa Garrett,3 Michael Stitzel,1 Jianmin Wu,4 Michelle Harris,2 Ruma Banerjee,4 Barry Shane,2 and Lawrence C. Brody1,*

Genetics and Molecular Biology Branch1 and Genetic Disease Research Branch,3 National Human Genome Research Institute, Bethesda, Maryland 20892; Department of Nutritional Sciences and Toxicology, University of California---Berkeley, Berkeley, California 947202; and Department of Biochemistry, University of Nebraska---Lincoln, Lincoln, Nebraska 685884

Received 2 November 2000/Accepted 10 November 2000

Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.

* Corresponding author. Mailing address: Genetics and Molecular Biology Branch, National Human Genome Research Institute, 49 Convent Drive, Rm. 3A14, Bethesda, MD 20892-4442. Phone: (301) 496-7824. Fax: (301) 402-4929. E-mail: lbrody{at}helix.nih.gov.

Molecular and Cellular Biology, February 2001, p. 1058-1065, Vol. 21, No. 4
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.4.1058-1065.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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