Human Molecular Genetics, 2001, Vol. 10, No. 5 433-443
© 2001 Oxford University Press
Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition
1Departments of Biology, Human Genetics and Pediatrics, 2Department of Medicine, 6Department of Pathology, McGill University, Montreal, Quebec H3A 1B1, Canada, 3The Jackson Laboratory, Bar Harbor, ME 04609, USA, 4National Center for Toxicological Research, Division of Biochemical Toxicology, Jefferson, AR 72079, USA, 5Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada, 7Institute of Metabolic Disease, Dallas, TX 75226, USA, 8Jean Mayer USDA Human Nutrition Research Center on Ageing, Tufts University, Boston, MA 02111, USA and 9Institute for Molecular Biology and Biotechnology, McMaster University, Hamilton, Ontario L8S 4K1, Canada
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.
+ To whom correspondence should be addressed at: McGill University—Montreal Children’s Hospital, 4060 Sainte Catherine West, Room 242, Montreal H3Z 2Z3, Canada. Tel: +1 514 934 4358; Fax: +1 514 934 4331; Email: mbjh@musica.mcgill.ca
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