Congenital heart defects and abnormal maternal biomarkers of methionine and homocysteine metabolism ,

Hobbs, Charlotte A.; Cleves, Mario A.; Melnyk, Stepan; Zhao, Wei‐Li; James, S. Jill

doi:10.1093/ajcn/81.1.147

Cited by 160 publications

(160 citation statements)

References 42 publications

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“…A ready supply of precursors for DNA replication and methionine for AdoMet production are known to be especially important for rapidly dividing cells, as demonstrated by the megaloblastic anemia caused by folate and B 12 deficiency, and the locus-specific anti-folate effects of methotrexate and 5-fluorouracil in cancer therapy. Disturbed balance between the folate forms and perturbation of cellular methylation capacity, whether caused by genetic and/or environmental factors, place the rapidly developing embryonic heart at greater risk for malformation [20]. Using our Mthfrdeficient mouse model, we demonstrated directly that disruption of the Mthfr gene or low dietary folate adversely affect the developing heart [1].…”

Section: Introductionmentioning

confidence: 79%

“…Furthermore, elevations in homocysteine, a consequence of deficiency in dietary folate, Mthfr or Mtrr, may be detrimental. Clinical studies suggest that maternal hyperhomocysteinemia and hypomethioninemia are significant risk factors for CHD in offspring [14,20,32]. In chickens, homocysteine has been reported to induce CHD [33] and microarray analysis of cardiac neural crest cells showed differential expression of a large number of genes involved in cell migration and adhesion in response to homocysteine [34].…”

Section: Discussionmentioning

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: Introductionmentioning

confidence: 79%

Section: Discussionmentioning

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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“…Many studies suggest a positive connection between folate deficiencies, elevated Hcys levels, and increased risk of congenital defects, not only in animal models, but also in humans (Steegers-Theunissen et al, 1994;Mills et al, 1995;van der Put et al, 1997;Nelen et al, 1998;van Rooij et al, 2003;Hobbs et al, 2005). Whether the defects are a direct consequence of folate loss or an increase in Hcys levels because of folate deficiency, is still unclear.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine enhances cardiac neural crest cell attachment in vitro by increasing intracellular calcium levels

Heidenreich

Reedy

Brauer

2008

Developmental Dynamics

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Elevated homocysteine (Hcys) increases the risk of neurocristopathies. Previous studies show Hcys inhibits neural crest (NC) cell migration in vivo. However, the mechanisms responsible for this effect are unknown. Here, we evaluated the effect of Hcys on NC cell attachment in vitro and determined if any of the effects were due to altered Ca 2؉ signaling. We found Hcys enhanced NC cell attachment in a dose and substratedependent manner. Ionomycin mimicked the effect of Hcys while BAPTA-AM and 2-APB blocked the effect of Hcys on NC attachment. In contrast, inhibitors of plasma membrane Ca 2؉ channels had no effect on NC attachment. Hcys also increased the emission of the intracellular Ca 2؉ -sensitive probe, Fluo-4. These results show Hcys alters NC attachment by triggering an increase in intracellular Ca 2؉ possibly by generating inositol triphosphate. Hence, the teratogenic effect ascribed to Hcys may be due to perturbation of intracellular Ca 2؉ signaling.

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“…The most well-described developmental effect of elevated homocysteine is its ability to disrupt derivatives of the neural ectoderm. Population-based data (Steegers-Theunissen et al, 1994, 1995van der Put et al, 1996) indicate that elevated maternal homocysteine is associated with an increased risk for neural tube, neural crest defects, and heart defects including conotruncal defects, the most common type of congenital heart defect (Hobbs et al, 2005). A specific region of the cranial neural crest, usually referred to as the "cardiac neural crest," is essential for normal septation of the four-chambered heart and is a key to the formation of the normal conotruncus (Kirby et al, 1983;reviewed by Farrell et al, 1999;Hutson and Kirby, 2003).…”

Section: Introductionmentioning

confidence: 99%

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

Rosenquist

Bennett

Brauer

et al. 2007

Developmental Dynamics

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The amino acid homocysteine increases in the serum when there is insufficient folic acid or vitamin B 12 , or with certain mutations in enzymes important in methionine metabolism. Elevated homocysteine is related to increased risk for cardiovascular and other diseases in adults and elevated maternal homocysteine increases the risk for certain congenital defects, especially those that result from abnormal development of the neural crest and neural tube. Experiments with the avian embryo model have shown that elevated homocysteine perturbs neural crest/neural tube migration in vitro and in vivo. Whereas there have been numerous studies of homocysteine-induced changes in gene expression in adult cells, there is no previous report of a homocysteine-responsive transcriptome in the embryonic neural crest. We treated neural crest cells in vitro with exogenous homocysteine in a protocol that induces significant changes in neural crest cell migration. We used microarray analysis and expression profiling to identify 65 transcripts of genes of known function that were altered by homocysteine. The largest set of effected genes (19) included those with a role in cell migration and adhesion. Other major groups were genes involved in metabolism (13); DNA/RNA interaction (11); cell proliferation/apoptosis (10); and transporter/receptor (6). Although the genes identified in this experiment were consistent with prior observations of the effect of homocysteine upon neural crest cell function, none had been identified previously as response to homocysteine in adult cells.

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Congenital heart defects and abnormal maternal biomarkers of methionine and homocysteine metabolism ,

Cited by 160 publications

References 42 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

Homocysteine enhances cardiac neural crest cell attachment in vitro by increasing intracellular calcium levels

Microarray analysis of homocysteine‐responsive genes in cardiac neural crest cells in vitro

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