title: Targeted disruption of the methionine synthase gene in mice.
abstract: 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.
authors.affiliation: Genetics and Molecular Biology Branch, Bethesda, National Human Genome Research Institute, Bethesda, Maryland 20892-4442, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Swanson
authors.forename: M L
authors.initials: ML
authors.lastname: Liu
authors.forename: P J
authors.initials: PJ
authors.lastname: Baker
authors.forename: L
authors.initials: L
authors.lastname: Garrett
authors.forename: M
authors.initials: M
authors.lastname: Stitzel
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Harris
authors.forename: R
authors.initials: R
authors.lastname: Banerjee
authors.forename: B
authors.initials: B
authors.lastname: Shane
authors.forename: L C
authors.initials: LC
authors.lastname: Brody
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000201:enzymology / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D018390:Gene Targeting; D006579:Heterozygote; D006710:Homocysteine / Q000097:blood; D006720:Homozygote; D006801:Humans; D008715:Methionine / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009436:Neural Tube Defects / Q000201:enzymology / Q000235:genetics; D011247:Pregnancy; D012307:Risk Factors; D014806:Vitamin B 12 Deficiency / Q000201:enzymology / Q000235:genetics
chemical_list: D017931:DNA Primers; D006710:Homocysteine; D005492:Folic Acid; D008715:Methionine; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase