Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aorticlipid deposition

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused b y nutritional and/or genetic disruptions in homocysteine metabolism. The mo st common genetic cause of hyperhomocysteinemia is the 677C-->T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with m ild enzymatic deficiency, is associated with an increased risk for neural t ube 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 ge nerated 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 homozy gous knockouts have either significantly decreased S-adenosylmethionine lev els 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.