Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition.
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.
Chen
Z
Z
Departments of Biology, Human Genetics and Pediatrics, Department of Medicine, Department of Pathology, McGill University, Montreal, Quebec H3A 1B1, Canada.
Karaplis
A C
AC
Ackerman
S L
SL
Pogribny
I P
IP
Melnyk
S
S
Lussier-Cacan
S
S
Chen
M F
MF
Pai
A
A
John
S W
SW
Smith
R S
RS
Bottiglieri
T
T
Bagley
P
P
Selhub
J
J
Rudnicki
M A
MA
James
S J
SJ
Rozen
R
R
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001483:Base Sequence; D019175:DNA Methylation; D017931:DNA Primers; D006579:Heterozygote; D006720:Homozygote; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D050356:Lipid Metabolism; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D051379:Mice; D018345:Mice, Knockout; D009420:Nervous System / Q000473:pathology*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)