Targeted disruption of the methionine synthase gene in mice

Alterations in homocysteine, methionine, folate, and/or B-12 homeostasis ha ve been associated with neural tube defects, cardiovascular disease, and ca ncer. Methionine synthase, one of only two mammalian enzymes known to requi re vitamin B-12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methy l-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methion ine. Human patients with methionine synthase deficiency exhibit homocystein emia, homocysteinuria, and hypomethioninemia, They suffer from megaloblasti c anemia with or without some degree of neural dysfunction and mental retar dation. To better study the pathophysiology of methionine synthase deficien cy, we utilized gene-targeting technology to inactivate the methionine synt hase gene in mice, On average, heterozygous knockout mice from an outbred b ackground have slightly elevated plasma homocysteine and methionine compare d to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutr itional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patient s, with methionine synthase deficiency have a complete absence of enzyme ac tivity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase d eficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.