Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations

Wenstrom, Katharine D.; Johanning, Gary L.; Johnston, Kelley E.; DuBard, Mary B.

doi:10.1067/mob.2001.113845

Cited by 113 publications

(85 citation statements)

References 41 publications

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“…In our earlier report, we showed that impairment of MTRR expression was pronounced in the heart of Mtrr gt/gt mice compared with other tissues, and that the AdoMet/AdoHcy ratio was significantly lower in the heart of Mtrr gt/gt mice compared with that of Mtrr +/+ mice [24]. Therefore, the heart may be particularly susceptible to defects in this model A polymorphism in methylenetetrahydrofolate reductase (MTHFR) has been associated with increased risk for CHD in offspring [5][6][7][8]. MTHFR provides 5-methylTHF for the MTRcatalyzed remethylation of homocysteine to methionine, the reaction that is supported by MTRR.…”

Section: Discussionmentioning

confidence: 81%

“…Risk for these defects may also be modified by polymorphisms in genes encoding enzymes in the folate metabolic pathway. The bestcharacterized polymorphism in folate metabolism is the c.677C→T mutation in methylenetetrahydrofolate reductase (MTHFR); several studies have suggested that this variant may increase the risk for CHD [5][6][7][8] MTHFR converts methylenetetrahydrofolate (methyleneTHF) to methytetrahydrofolate (methylTHF), the primary form of folate in the circulation. Once transported into the cell, metabolized and converted into the polyglutamate form, methylTHF acts as the the carbon donor for homocysteine remethylation to yield methionine and tetrahydrofolate (THF).…”

Section: Introductionmentioning

confidence: 99%

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Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Deng

Elmore

Lawrance

et al. 2008

Molecular Genetics and Metabolism

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Low dietary folate and polymorphisms in genes of folate metabolism can influence risk for pregnancy complications and birth defects. Methionine synthase reductase (MTRR) is required for activation of methionine synthase, a folate-and vitamin B 12 -dependent enzyme. A polymorphism in MTRR (p.I22M), present in the homozygous state in 25% of many populations, may increase risk for neural tube defects. To examine the impact of MTRR deficiency on early development and congenital heart defects, we used mice harboring a gene-trapped (gt) allele in Mtrr. Female mice (Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt ) were mated with male Mtrr +/g mice. Reproductive outcomes and cardiac phenotype (presence of defects and myocardial thickness) were assessed at E14.5. Mtrrdeficient mothers had more resorptions and more delayed embryos per litter (resorptions per litter: 0.29 ± 0.13; 1.21 ± 0.41; 1.87 ± 0.38 and delayed embryos per litter: 0.07 ± 0.07; 0.14 ± 0.14; 0.60 ± 0.24 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt mothers respectively). Placentae of Mtrr gt/gt mothers were smaller and their embryos were smaller, with myocardial hypoplasia and a higher incidence of ventricular septal defects (VSD) per litter (0; 0.57 ± 0.30; 1.57 ± 0.67 in Mtrr +/+ , Mtrr +/gt , and Mtrr gt/gt groups respectively). Embryonic Mtrr gt/gt genotype was associated with reduced embryonic length, reduced embryonic and placental weight, and higher incidence of VSD, but did not affect myocardial thickness or embryonic delay. We conclude that Mtrr deficiency adversely impacts reproductive outcomes and cardiac development in mice. These findings may have implications for nutritional prevention of heart defects, particularly in women with the common MTRR polymorphism.

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Deng

Elmore

Lawrance

et al. 2008

Molecular Genetics and Metabolism

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“…Embryonic development may also be compromised by disruptions in genes that encode enzymes in the folate metabolic pathway such as methylenetetrahydrofolate reductase (MTHFR) (Wenstrom et al, 2001;Li et al, 2005;Chan et al, 2010). MTHFR synthesizes 5-methyltetrahydrofolate, the primary form of circulatory folate.…”

Section: Introductionmentioning

confidence: 99%

Moderately high intake of folic acid has a negative impact on mouse embryonic development

Mikael

Deng

Paul

et al. 2012

Birth Defects Research

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BACKGROUND:The incidence of neural tube defects has diminished considerably since the implementation of food fortification with folic acid (FA). However, the impact of excess FA intake, particularly during pregnancy, requires investigation. In a recent study, we reported that a diet supplemented with 20-fold higher FA than the recommended intake for rodents had adverse effects on embryonic mouse development at embryonic days (E)10.5 and 14.5. In this report, we examined developmental outcomes in E14.5 embryos after administering a diet supplemented with 10-fold higher FA than recommended to pregnant mice with and without a mild deficiency of methylenetetrahydrofolate reductase (MTHFR). METHODS: Pregnant mice with or without a deficiency in MTHFR were fed a control diet (recommended FA intake of 2 mg/kg diet for rodents) or an FA-supplemented diet (FASD; 10-fold higher than the recommended intake [20 mg/kg diet]). At E14.5, mice were examined for embryonic loss and growth retardation, and hearts were assessed for defects and for ventricular wall thickness. RESULTS: Maternal FA supplementation was associated with embryonic loss, embryonic delays, a higher incidence of ventricular septal defects, and thinner left and right ventricular walls, compared to mothers fed control diet. CONCLUSIONS: Our work suggests that even moderately high levels of FA supplementation may adversely affect fetal mouse development. Additional studies are warranted to evaluate the impact of high folate intake in pregnant women. Birth Defects Research (Part A) 97:47À52,

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“…Hyperhomocyst(e)inemia has been correlated with increased risk for cardiovascular disease [(5), and references cited therein], development of Alzheimer's disease (6,36,56), neural tube defects (39,51,59,60), and other adverse pregnancy outcomes including congenital cardiac defects (26,51,57,69), preeclampsia (11,(44)(45)(46), and orofacial clefts (70). It is now well established that administration of folic acid results in significant lowering of plasma total homocyst(e)ine (2,47,64,67), but the results of several large folate therapy clinical trials to reduce the progression of cardiovascular disease have been disappointing (1,12,31,34,43,64), while showing promise in others (48,53,58).…”

Section: Introductionmentioning

confidence: 99%

The Many Flavors of Hyperhomocyst(e)inemia: Insights from Transgenic and Inhibitor-Based Mouse Models of Disrupted One-Carbon Metabolism

Elmore

Matthews

2007

Antioxidants & Redox Signaling

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Mouse models that perturb homocysteine metabolism, including genetic mouse models that result in deficiencies of methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine β-synthase, and a pharmaceutically induced mouse model with a transient deficiency in betaine-homocysteine methyl transferase, have now been characterized and can be compared. Although each of these enzyme deficiencies is associated with moderate to severe hyperhomocyst(e)inemia, the broader metabolic profiles are profoundly different. In particular the various models differ in the degree to which tissue ratios of S-adenosylmethionine to S-adenosylhomocysteine are lowered in the face of elevated plasma homocyst(e)ine, and in the distribution of the tissue folate pools. These different metabolic profiles illustrate the potential complexities of hyperhomocyst(e)inemia in humans, and suggest that comparison of the disease phenotypes of the various mouse models may be extremely useful in dissecting the underlying risk factors associated with human hyperhomocyst(e)inemia.

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Association of the C677T methylenetetrahydrofolate reductase mutation and elevated homocysteine levels with congenital cardiac malformations

Cited by 113 publications

References 41 publications

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

Moderately high intake of folic acid has a negative impact on mouse embryonic development

The Many Flavors of Hyperhomocyst(e)inemia: Insights from Transgenic and Inhibitor-Based Mouse Models of Disrupted One-Carbon Metabolism

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