Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by 
nutritional and/or genetic disruptions in homocysteine metabolism. The most 
common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the 
methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild 
enzymatic deficiency, is associated with an increased risk for neural tube 
defects and pregnancy complications and with a decreased risk for colon cancer 
and leukemia. Although many studies have reported that this variant is also a 
risk factor for vascular disease, this area of investigation is still 
controversial. Severe MTHFR deficiency results in homocystinuria, an inborn 
error of metabolism with neurological and vascular complications. To investigate 
the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with 
a knockout of MTHFR: Plasma total homocysteine levels in heterozygous and 
homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type 
littermates, respectively. Both heterozygous and homozygous knockouts have 
either significantly decreased S-adenosylmethionine levels or significantly 
increased S-adenosylhomocysteine levels, or both, with global DNA 
hypomethylation. The heterozygous knockout mice appear normal, whereas the 
homozygotes are smaller and show developmental retardation with cerebellar 
pathology. Abnormal lipid deposition in the proximal portion of the aorta was 
observed in older heterozygotes and homozygotes, alluding to an atherogenic 
effect of hyperhomocysteinemia in these mice.