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 major salivary glands of mammals are represented by three pairs of organs that cooperate functionally to produce saliva for the oral cavity. While each type of gland produces a signature secretion that complements the secretions from the other glands, there is also redundancy as evidenced by secretion of functionally similar and, in some cases, identical products in the three glands. This, along with their common late initiation of development, in fetal terms, their similarities in developmental pattern, and their proximate sites of origin, suggests that a common regulatory cascade may have been shared until shortly before the onset of overt gland development. Furthermore, occasional ectopic differentiation of individual mature secretory cells in the "wrong" gland suggests that control mechanisms responsible for the distinctive cellular composition of each gland also share many common steps, with only minor differences providing the impetus for diversification. To begin to address this area, we examine here the origins of the salivary glands by reviewing the expression patterns of several genes with known morphogenetic potential that may be involved based on developmental timing and location. The possibility that factors leading to determination of the sites of mammalian salivary gland development might be homologous to the regulatory cascade leading to salivary gland formation in Drosophila is also evaluated. In a subsequent section, cellular phenotypes of neonatal and adult glands are compared and evaluated for insights into the mechanisms and lineages leading to cellular diversification. Finally, the phenomena of proliferation, repair, and regeneration in adult salivary glands are reviewed, with emphasis on the extent to which the cellular diversity is reversible and which cell type other than stem cells has the ability to redifferentiate into other cell types.

Salivary glands: a paradigm for diversity of gland development.

Iron- or copper-mediated catalysis leads to the generation of reactive oxygen species (ROS) that can attack biomolecules directly, with the consequent enhancement in membrane lipid peroxidation, DNA damage, and protein oxidation Reactive nitrogen species (RNS) can also be formed, leading to nitration of aromatic structures in addition to the oxidative deterioration of cellular components Kupffer cells, the resident macrophages of the liver, play significant roles in immunomodulation, phagocytosis, and biochemical attack Upon stimulation, liver macrophages release biologically active products related to cell injury, namely, ROS, RNS, and both immunomodulatory and fibrogenic cytokines, with production of chemokines and adhesion molecules by other cells of the liver sinusoid Iron and copper alter the functional status of Kupffer cells by enhancing their respiratory burst activity without modifying particle phagocytosis This effect is probably due to extra O2 equivalents used in the oxidation of biomolecules and/or in the activating action of iron/copper on nitric oxide synthase, in addition to those employed by NADPH oxidase activity Changes in gene expression of Kupffer cells may also be accomplished by iron and copper through modulation of the activity of transcription factors such as NF-κB, which signals the production of cytotoxic, proinflammatory, or fibrogenic mediators Thus, iron/copper-induced hepatotoxicity is a multifactorial phenomenon underlying actions due to the generation of ROS and RNS that may alter essential biomolecules with loss of their biological functions, modulate gene expression of Kupffer cells with production of cytotoxic mediators, or both

Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells.

The nucleolus: A structural and functional interpretation

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.

Onset of cell proliferation in dormant roots of Allium cepa L. bulbs. Kinetic analysis

Cell proliferation in the mouse parotid gland after unilateral parotidectomy.

Tubulin distribution in c-mitoses (induced by 1 mM colchicine) has been studied by indirect immunofluorescence with monoclonal antibodies inAllium cepa L. meristems proliferating under steady state kinetics. Two hours after colchicine treatment was initiated tubulin is detected in approximately 25% of the cells as arrowheads on the kinetochores, as if these structures stabilize microtubules against disassembly. Total disassembly of microtubules occurs in 70% of the c-mitoses six hours after the initiation of the colchicine treatment, when restitution nuclei also start appearing. After 2 to 14 hours of colchicine treatment, tubulin is detected in about 30% of the c-mitoses, both in small kinetochores-like dots and in a strand which apparently connects sister kinetochores. Other larger microtubule-like structures, up to 20 μm long, apparently unassociated with kinetochores, are assembled in the presence of cholchicine in c-mitoses after 10 hours. Such structures disappear when chromosomes decondense and the nuclear envelope reforms in the restitution nucleus; they do not seem to be related to interphase cortical microtubules which reappear in control telophase.

J. Sans

Papers

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

Onset of cell proliferation in dormant roots of Allium cepa L. bulbs. Kinetic analysis

Cell proliferation in the mouse parotid gland after unilateral parotidectomy.

Colchicine-resistant assembly of tubulin in plant mitosis

Proliferative index estimated by chromatin pattern analysis