Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome

Down syndrome is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. A recent preliminary study suggested that abnormal folate metabolism and the 677C→T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for Down syndrome. The present study was undertaken with a larger sample size to determine whether the MTHFR 677C→T polymorphism was associated with increased risk of having a child with Down syndrome. Methionine synthase reductase (MTRR) is another enzyme essential for normal folate metabolism. A common polymorphism in this gene was recently associated with increased risk of neural tube defects and might also contribute to increased risk for Down syndrome. The frequencies of the MTHFR 677C→T and MTRR 66A→G mutations were evaluated in DNA samples from 157 mothers of children with Down syndrome and 144 control mothers. Odds ratios were calculated for each genotype separately and for potential gene-gene interactions. The results are consistent with the preliminary observation that the MTHFR 677C→T polymorphism is more prevalent among mothers of children with Down syndrome than among control mothers, with an odds ratio of 1.91 (95% confidence interval [CI] 1.19–3.05). In addition, the homozygous MTRR 66A→G polymorphism was independently associated with a 2.57-fold increase in estimated risk (95% CI 1.33–4.99). The combined presence of both polymorphisms was associated with a greater risk of Down syndrome than was the presence of either alone, with an odds ratio of 4.08 (95% CI 1.94–8.56). The two polymorphisms appear to act without a multiplicative interaction.

https://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM248339.pdf

Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome.

The nucleolus: A structural and functional interpretation

BACKGROUND: Little is known about the effect of paternal nutrition on aneuploidy in sperm. We investigated the association of normal dietary and supplement intake of folate, zinc and antioxidants (vitamin C, vitamin E and b-carotene) with the frequency of aneuploidy in human sperm. METHODS: Sperm samples from 89 healthy, nonsmoking men from a non-clinical setting were analysed for aneuploidy using fluorescent in situ hybridization with probes for chromosomes X, Y and 21. Daily total intake (diet and supplements) for zinc, folate, vitamin C, vitamin E and b-carotene was derived from a food frequency questionnaire. Potential confounders were obtained from a self-administered questionnaire. RESULTS: After adjusting for covariates, men with high folate intake (>75th percentile) had lower frequencies of sperm with disomies X, 21, sex nullisomy, and a lower aggregate measure of sperm aneuploidy (P � 0.04) compared with men with lower intake. In adjusted continuous analyses, total folate intake was inversely associated with aggregate sperm aneuploidy (‐3.6% change/100 mg folate; 95% CI: 26.3, 20. 8) and results were similar for disomies X, 21 and sex nullisomy. No consistent associations were found between antioxidant or zinc intakes and sperm aneuploidy. CONCLUSIONS: Men with high folate intake had lower overall frequencies of several types of aneuploid sperm.

https://www.medpagetoday.com/upload/2008/3/21/den036v1.pdf

The association of folate, zinc and antioxidant intake with sperm aneuploidy in healthy non-smoking men

http://lib.ajaums.ac.ir/booklist/Am.J.Obstetric&Gynecology_April%20%20(4)_15.pdf

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

10(-6) M and 10(-5) M 5-azacytidine, demethylated around 9% and 17% of the 5-methylcytosine residues found in Allium cepa L. native DNA, respectively. Both treatments stimulated RNA synthesis in the cells of root meristems. On the other hand, the 10(-5) M treatment gave rise to multiple chromosomal anomalies in mitosis before any fall in the mitotic index was detectable, but no chromosomal breaks were ever seen. Serious lesions involved in chromatids and segregation in anaphase were preferentially found after hypomethylation of DNA sequences replicated in the second half of the previous S period: (i) sister telomeres remained unresolved at the cell equator while kinetochores had reached the poles, (ii) whole unsegregated chromosomes were pulled to one of the poles by obviously disfunctional kinetochores, resulting in an unbalanced distribution of chromatids, (iii) unsegregated chromosomes in other cells remained at the spindle equator as if kinetochores were nonfunctional, while cytoplasmic division took place before their migration to the poles. Frequently, a growing cytokinetic plate randomly cut the unsegregated chromosomes, giving rise to aneuploid nuclei. These anaphase failures are a firm basis to explain why the 10(-5) M treatment selectively depressed the rate of cell proliferation in these cells in the long run. On the other hand, if hypomethylation occurred at the first half of the previous S period, enlarged chromosomal segments were evident in most metaphases, while chromosome laggards and bridges were recorded in anaphase at rather similar frequencies after the different 5-azacytidine treatments. These data were consistently obtained both in the native mononucleate cells of meristems and in one subpopulation of synchronous cells labelled as binucleate by 5 mM caffeine.

Impaired chromosome segregation in plant anaphase after moderate hypomethylation of DNA.

In vivo exposure to 5-azacytidine (10−6M) depressed the incorporation of methyl groups to GC rich regions ofAllium cepa L. DNA. Nearly 22% of its 5-methylcytosine residues were under-methylated. The treatment stimulated 1.8 times the rate of [3H]uridine incorporation, as measured in meristems proliferating under steady state kinetics. Nucleologenesis was shortened from 2.7 to 1.6 h in synchronous binucleate cells after 5-azacytidine treatment lasting the whole S period of their previous interphase. By hypomethylating DNA sequences replicated at different times during the S period, it could be inferred that the cistron replication took place in early S. Thus, nucleogenesis was shortened to only 0.6 h after such treatment. Sequential short treatment periods using [3H]thymidine confirmed that the nucleolar organizer regions of the chromosomes replicate in early S.

Determination of the replication time of nucleolar organizer DNA after 5-azacytidine treatment for restricted parts of the S period

Stimulated nucleologenesis in meristematic cells with hypomethylated DNA

This work has been partially supported by the Project 1/83 PNUD/UNESCO; by the Comision Asesora de Politica Cientifica y Tecnica de Espaiia; by the Convenio CSIC— Universidad de Chile (Project No. 1); and by the Project B1651-8313 U de Chile.

Plant Chromatin Replicated in the Absence of Protein Synthesis

After bromosubstituting DNA sequences replicated in the first, second, or third part of the S phase, in Allium cepa L. meristematic cells, radiation at 313 nm wavelength under anoxia allowed ascription of different sequences to both the positive and negative regulation of some cycle phase transitions. The present report shows that the radiation forced cells in late G1 phase to advance into S, while those in G2 remained in G2 and cells in prophase returned to G2 when both sets of sequences involved in the positive and negative controls were bromosubstituted and later irradiated. In this way, not only G2 but also the S phase behaved as cycle phases where cells accumulated by default when signals of different sign functionally cancelled out. The treatment did not halt the rates of replication or transcription of plant bromosubstituted DNA. The irradiation under hypoxia apparently prevents the binding of regulatory proteins to Br-DNA.

/pdf/default-cycle-phases-determined-after-modifying-discrete-dna-aa0iyvhbvq.pdf

C. Leyton

Papers

Impaired chromosome segregation in plant anaphase after moderate hypomethylation of DNA.

Determination of the replication time of nucleolar organizer DNA after 5-azacytidine treatment for restricted parts of the S period

Stimulated nucleologenesis in meristematic cells with hypomethylated DNA

Plant Chromatin Replicated in the Absence of Protein Synthesis

Default cycle phases determined after modifying discrete DNA sequences in plant cells.