Disease relevance of Mthfr

• Impact of methylenetetrahydrofolate reductase deficiency and low dietary folate on the development of neural tube defects in splotch mice [1].
• We tested the hypothesis that heterozygous disruption of the Mthfr gene sensitizes mice to diet-induced hyperhomocysteinemia and endothelial dysfunction [2].
• Low dietary folate and deficiency of methylenetetrahydrofolate reductase (Mthfr) were reported to increase the risk for congenital heart defects, but contributory mechanisms have not been elucidated [3].
• To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism [4].
• Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications [5].

High impact information on Mthfr

• Mthfr(+/-) and Mthfr(+/+) mice were fed 1 of 4 diets: control, high methionine (HM), low folate (LF), or high methionine/low folate (HM/LF) [2].
• Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice [2].
• SAM/SAH ratios decreased further in Mthfr(+/+) or Mthfr(+/-) mice fed LF or LF/HM diets (P<.05) [2].
• In cerebral arterioles, endothelium-dependent dilation to 1 or 10 microM acetylcholine was markedly and selectively impaired with the HM/LF diet compared with the control diet for both Mthfr(+/+) (maximum dilation 5% +/- 2% versus 21% +/- 4%; P<.01) and Mthfr(+/-) (6% +/- 2% versus 21% +/- 3%; P<.01) mice [2].
• 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 [5].

Chemical compound and disease context of Mthfr

• We administered the alternate choline-derived methyl donor, betaine, to wild-type mice and to littermates with mild or severe hyperhomocysteinemia due to hetero- or homozygosity for a disruption of the Mthfr gene [6].
• Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation [7].

Biological context of Mthfr

• The structure of this paralogous gene and the identification of a repeat sequence at the 3' end of this pseudogene suggest that it arose by retrotransposition of a mis-spliced Mthfr transcript [8].
• During the course of this work, we observed that PCR primers in exons 1 and 2 of Mthfr generated amplicons of the expected size for the normal Mthfr transcript, using both reverse-transcribed RNA and genomic DNA as templates [8].
• METHODS: Wild-type, single Mthfr+/-mutant, single Sp/+mutant, and double mutant (Mthfr+/-, Sp/+) female mice were mated with males of the same genotype [1].
• Co-transfection of NF-kappaB and promoter constructs demonstrated Mthfr up-regulation by at least 2-fold through its downstream promoter in Neuro-2a cells; this increase was significantly reduced when the putative binding site was mutated [9].
• This study, a first step into the elucidation of Mthfr regulation, demonstrates that two TATA-less, GC-rich promoters differentially drive transcription of Mthfr in a cell-specific manner, and provides a novel link of Mthfr to possible roles in the immune response and cell survival [9].

Anatomical context of Mthfr

• NF-kappaB activation experiments in cultured cells were associated with increased Mthfr mRNA [9].
• The stress-strain relationship was shifted to the left in small mesenteric arteries from Mthfr compared to Mthfr mice, indicating that mild H-Hcy is associated with stiffer vessels [10].
• In adult male mice, MTHFR levels are highest in the testis; this finding, in conjunction with recent clinical evidence, suggest an important role for MTHFR in spermatogenesis [7].
• We postulate that the adverse effects of MTHFR deficiency on spermatogenesis, may, in part, be mediated by alterations in the transmethylation pathway and suggest that betaine supplementation may provide a means to bypass MTHFR deficiency and its adverse effects on spermatogenesis by maintaining normal methylation levels within male germ cells [7].
• In a mouse model of infection mthfr(-) mutants showed good infectivity and virulence, indicating that sufficient methionine is available within the parasitophorous vacuole to meet the needs of the parasite [11].

Associations of Mthfr with chemical compounds

• Two promoters of the murine methylenetetrahydrofolate reductase gene (Mthfr), a key enzyme in folate metabolism, were characterized in Neuro-2a, NIH/3T3 and RAW 264.7 cells [9].
• METHODS: Wild-type (+/+) and heterozygous (+/-) methylenetetrahydrofolate reductase (Mthfr) knockout mice, a new model of mild H-Hcy, were treated with vehicle or angiotensin (Ang) II infusion (400 ng/kg per min s.c.). Second-order mesenteric arteries were studied on pressurized myograph [10].
• Maternal oral administration of betaine, an alternative methyl donor, throughout pregnancy and nursing, resulted in improved testicular histology in Mthfr-/- offspring at Postnatal Day 6, but not at 8 mo of age [7].
• Supplementation of Mthfr(+/-) dams with an alternate methyl donor, betaine, reduced cerebellar abnormalities in the Mthfr(-/-) pups [12].
• Biochemical evaluations demonstrated higher availability of betaine in suckling pups, decreased accumulation of homocysteine, and decreased flux through the trans-sulphuration pathway in liver and brain of Mthfr-/- pups from betaine-supplemented dams [13].

Other interactions of Mthfr

• Investigations of the Mthfr gene should take into account the presence of the non-functional Mthfr-ps to avoid misinterpretation of results [8].
• Increased collagen type I/III accumulation and decreased elastin content in the media of mesenteric arteries was noted in Mthfr compared to Mthfr mice [10].
• Vascular NADPH oxidase activity, similar in Mthfr+/- and Mthfr+/+, increased after Ang II infusion [14].
• The curly-tail (ct) mouse, an animal model of neural tube defects, displays altered homocysteine metabolism without folate responsiveness or a defect in Mthfr [15].
• RESULTS: Plasma homocysteine in Mthfr +/- dams and in FADD-treated dams was significantly higher than that in Mthfr +/+ dams and CD-treated dams, respectively [16].

Analytical, diagnostic and therapeutic context of Mthfr

• A Mthfr-ps transcript was not detectable by sensitive RT-PCR using assays designed to simultaneously detect the authentic Mthfr transcript [8].
• To assess how impaired MTHFR activity affects folate metabolism in various tissues in vivo, we used affinity/HPLC with electrochemical detection to analyze the distribution of folates in plasma, liver, and brain of Mthfr-deficient mice [17].
• Microarray analysis of brain RNA from day 14 Mthfr(-/-) mice revealed several genes with altered expression [18].
• Western blotting revealed that ApoA-I protein levels in liver and plasma of Mthfr(+/-) mice were 52% and 62% of levels in the respective tissues of Mthfr(+/+) mice [4].
• The possible role of a mild deficiency in methylenetetrahydrofolate reductase (MTHFR) and low dietary folate in pregnancy outcomes and heart morphogenesis requires further investigation [16].

References