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Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy.

Jongbloet PH, Verbeek AL, den Heijer M, Roeleveld N - J. Exp. Clin. Assist. Reprod. (2008)

Bottom Line: Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C --> T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene.These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations.The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Epidemiology, Biostatistics, and Health Technology Assessment, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. p.jongbloet@skynet.be.

ABSTRACT
Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C --> T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance.

No MeSH data available.


Related in: MedlinePlus

MHTRF gene polymorphisms as well as behaviorally and/or environmentally influenced high-risk conditions cause PrOO and epigenetic DNA-alterations either independently or in combination. This results in innate developmental defects at birth (e.g. NTDs) or in adulthood (e.g. schizophrenia).
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Figure 1: MHTRF gene polymorphisms as well as behaviorally and/or environmentally influenced high-risk conditions cause PrOO and epigenetic DNA-alterations either independently or in combination. This results in innate developmental defects at birth (e.g. NTDs) or in adulthood (e.g. schizophrenia).

Mentions: The spectrum of developmental anomalies associated with MTHFR polymorphisms and/or folate deficiency appears analogous to the spectrum of anomalies related to PrOO induced by endocrine disturbances during the transitional stages of reproductive life and/or by divergent reproductive behavior, e.g. unusual maternal age or pregnancy interval [3] (see Figure 1). Low folate serum levels in Rhesus monkeys have been associated with granulosa cell impairment and with decreased estradiol and progesteron levels. Reduction of follicle growth and delayed ovulation are markers for retardation of embryonic growth and malformation [33]. Folate levels are also essential for sperm maturation, as inadequate folate intake is inversely associated with overall frequencies of several types of aneuploid sperm in healthy men [34]. The MTHFR CT and TT genotypes with inherent low folate status are candidates for compromising oocyte maturation, and may set the stage for a genetically conditioned high-risk conception analogous to those resulting from endocrine disturbances induced by environmental or behavioral conditions (see Figure 1.).


Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms resulting in suboptimal oocyte maturation: a discussion of folate status, neural tube defects, schizophrenia, and vasculopathy.

Jongbloet PH, Verbeek AL, den Heijer M, Roeleveld N - J. Exp. Clin. Assist. Reprod. (2008)

MHTRF gene polymorphisms as well as behaviorally and/or environmentally influenced high-risk conditions cause PrOO and epigenetic DNA-alterations either independently or in combination. This results in innate developmental defects at birth (e.g. NTDs) or in adulthood (e.g. schizophrenia).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2500045&req=5

Figure 1: MHTRF gene polymorphisms as well as behaviorally and/or environmentally influenced high-risk conditions cause PrOO and epigenetic DNA-alterations either independently or in combination. This results in innate developmental defects at birth (e.g. NTDs) or in adulthood (e.g. schizophrenia).
Mentions: The spectrum of developmental anomalies associated with MTHFR polymorphisms and/or folate deficiency appears analogous to the spectrum of anomalies related to PrOO induced by endocrine disturbances during the transitional stages of reproductive life and/or by divergent reproductive behavior, e.g. unusual maternal age or pregnancy interval [3] (see Figure 1). Low folate serum levels in Rhesus monkeys have been associated with granulosa cell impairment and with decreased estradiol and progesteron levels. Reduction of follicle growth and delayed ovulation are markers for retardation of embryonic growth and malformation [33]. Folate levels are also essential for sperm maturation, as inadequate folate intake is inversely associated with overall frequencies of several types of aneuploid sperm in healthy men [34]. The MTHFR CT and TT genotypes with inherent low folate status are candidates for compromising oocyte maturation, and may set the stage for a genetically conditioned high-risk conception analogous to those resulting from endocrine disturbances induced by environmental or behavioral conditions (see Figure 1.).

Bottom Line: Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C --> T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene.These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations.The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Epidemiology, Biostatistics, and Health Technology Assessment, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. p.jongbloet@skynet.be.

ABSTRACT
Several conditions apparent at birth, e.g., neural tube defects (NTDs) and cardiac anomalies, are associated with polymorphisms in folate-related genes, such as the 677C --> T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Similar associations have been established for several constitutional chronic diseases in adulthood, such as schizophrenia, cardiovascular diseases, dementia, and even neoplasias in different organ systems. This spectrum of developmental anomalies and constitutional diseases may be linked to high-risk conceptions related to preovulatory overripeness ovopathy (PrOO). Some developmental anomalies, such as NTDs, are to a large extent prevented by supplementation of folic acid before conception, but supplementation does not seem to prevent cardiovascular disease or cognitive decline. These diverging results can be elucidated by introduction of the PrOO concept, as MTHFR polymorphisms and inherent low folate levels induce both non-optimal maturation of the oocyte and unsuccessful DNA methylation and demethylation, i.e. epigenetic mutations. The PrOO concept is testable and predicts in a random population the following: (1) female carriers of specific genetic MTHFR variants exhibit more ovulatory disturbances and inherent subfecundity traits, (2) descendents from a carrier mother, when compared with those from a wild-type mother, are more frequently conceived in PrOO high-risk conditions and, thus, (3) disadvantaged in life expectancy. If so, some MTHFR polymorphisms represent a novel, genetically determined, PrOO high-risk conception category comparable to those which are environmentally and behaviorly influenced. These high-risk conditions may cause developmental anomalies and defective epigenetic reprogramming in progeny. The interaction between genetic and environmental factors is a plausible mechanism of multifactorial inheritance.

No MeSH data available.


Related in: MedlinePlus