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Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Nakouzi GA, Nadeau JH - BMC Genet. (2014)

Bottom Line: Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies.In addition, many cases remain resistant to the beneficial effects of folic acid supplementation.Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.

ABSTRACT

Background: Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.

Results: We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

Conclusion: Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

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Related in: MedlinePlus

Gamete bias at fertilization and conceptus genotype frequencies. ‘+’ and ‘m’ designate gametes that carry the wild-type or the mutant allele, respectively. Gamete frequencies are shown on the sides of the matrix, and conceptus genotype in the cells of the matrix. Each side of the matrix represents one of sexes in each mating. A. General case, where p and q denote alternative alleles. B. Arbitrary numbers were used to illustrate the consequences of gametic bias. Note that all eggs are fertilized and litter size remains unchanged in each scenario; only the genotypic ratio changes.
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Figure 2: Gamete bias at fertilization and conceptus genotype frequencies. ‘+’ and ‘m’ designate gametes that carry the wild-type or the mutant allele, respectively. Gamete frequencies are shown on the sides of the matrix, and conceptus genotype in the cells of the matrix. Each side of the matrix represents one of sexes in each mating. A. General case, where p and q denote alternative alleles. B. Arbitrary numbers were used to illustrate the consequences of gametic bias. Note that all eggs are fertilized and litter size remains unchanged in each scenario; only the genotypic ratio changes.

Mentions: Unexpectedly, both supplemented lines showed a substantial deficiency of homozygous and heterozygous mutant embryos at the higher FA concentration. Because these single gene mutations are inherited in a Mendelian manner [27]–[29], 25% of the embryos are expected to have a wild-type genotype (+/+), 50% a heterozygous genotype (+/mutant), and 25% a homozygous mutant genotype (mutant/mutant) (Figure 2). The genotype distribution on the control diet was consistent with Mendelian expectations for both mutants, showing that segregation was normal at 2 ppm FA. By contrast, a clear deficiency was found for homozygous and heterozygous embryos conceived and maintained on 10 ppm FA (Table 2). For the supplemented Lp mutant, although the deviation from Mendelian ratios was not statistically significant, the observed numbers of homozygous and heterozygous mutant embryos was strongly reduced relative to expectations, with the percent difference comparable to results for the Apob mutant, but with a slightly smaller sample size (Table 2).


Does dietary folic acid supplementation in mouse NTD models affect neural tube development or gamete preference at fertilization?

Nakouzi GA, Nadeau JH - BMC Genet. (2014)

Gamete bias at fertilization and conceptus genotype frequencies. ‘+’ and ‘m’ designate gametes that carry the wild-type or the mutant allele, respectively. Gamete frequencies are shown on the sides of the matrix, and conceptus genotype in the cells of the matrix. Each side of the matrix represents one of sexes in each mating. A. General case, where p and q denote alternative alleles. B. Arbitrary numbers were used to illustrate the consequences of gametic bias. Note that all eggs are fertilized and litter size remains unchanged in each scenario; only the genotypic ratio changes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4151023&req=5

Figure 2: Gamete bias at fertilization and conceptus genotype frequencies. ‘+’ and ‘m’ designate gametes that carry the wild-type or the mutant allele, respectively. Gamete frequencies are shown on the sides of the matrix, and conceptus genotype in the cells of the matrix. Each side of the matrix represents one of sexes in each mating. A. General case, where p and q denote alternative alleles. B. Arbitrary numbers were used to illustrate the consequences of gametic bias. Note that all eggs are fertilized and litter size remains unchanged in each scenario; only the genotypic ratio changes.
Mentions: Unexpectedly, both supplemented lines showed a substantial deficiency of homozygous and heterozygous mutant embryos at the higher FA concentration. Because these single gene mutations are inherited in a Mendelian manner [27]–[29], 25% of the embryos are expected to have a wild-type genotype (+/+), 50% a heterozygous genotype (+/mutant), and 25% a homozygous mutant genotype (mutant/mutant) (Figure 2). The genotype distribution on the control diet was consistent with Mendelian expectations for both mutants, showing that segregation was normal at 2 ppm FA. By contrast, a clear deficiency was found for homozygous and heterozygous embryos conceived and maintained on 10 ppm FA (Table 2). For the supplemented Lp mutant, although the deviation from Mendelian ratios was not statistically significant, the observed numbers of homozygous and heterozygous mutant embryos was strongly reduced relative to expectations, with the percent difference comparable to results for the Apob mutant, but with a slightly smaller sample size (Table 2).

Bottom Line: Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies.In addition, many cases remain resistant to the beneficial effects of folic acid supplementation.Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH, USA. jnadeau@pnri.org.

ABSTRACT

Background: Neural tube defects (NTDs) are the second most common birth defect in humans. Dietary folic acid (FA) supplementation effectively and safely reduces the incidence of these often debilitating congenital anomalies. FA plays an established role in folate and homocysteine metabolism, but the means by which it suppresses occurrence of NTDs is not understood. In addition, many cases remain resistant to the beneficial effects of folic acid supplementation. To better understand the molecular, biochemical and developmental mechanisms by which FA exerts its effect on NTDs, characterized mouse models are needed that have a defined genetic basis and known response to dietary supplementation.

Results: We examined the effect of FA supplementation, at 5-fold the level in the control diet, on the NTD and vertebral phenotypes in Apobtm1Unc and Vangl2Lp mice, hereafter referred to as Apob and Lp respectively. The FA supplemented diet did not reduce the incidence or severity of NTDs in Apob or Lp mutant homozygotes or the loop-tail phenotype in Lp mutant heterozygotes, suggesting that mice with these mutant alleles are resistant to FA supplementation. Folic acid supplementation also did not affect the rate of resorptions or the size of litters, but instead skewed the embryonic genotype distribution in favor of wild-type alleles.

Conclusion: Similar genotypic biases have been reported for several NTD models, but were interpreted as diet-induced increases in the incidence and severity of NTDs that led to increased embryonic lethality. Absence of differences in resorption rates and litter sizes argue against induced embryonic lethality. We suggest an alternative interpretation, namely that FA supplementation led to strongly skewed allelic inheritance, perhaps from disturbances in polyamine metabolism that biases fertilization in favor of wild-type gametes.

Show MeSH
Related in: MedlinePlus