NDLI: The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome.

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The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Martínez-Frías, M. L.
Description	Country affiliation: Spain Author Affiliation: Martínez-Frías ML ( ECEMC, Centro de Investigación sobre Anomalías Congénitas, Instituto de Salud Carlos III (ISCIII), Centre for Biomedical Research on Rare Diseases, ISCIII, Madrid, Spain. mlmartinez.frias@isciii.es)
Abstract	Studies on the structure of the methylenetetrahydrofolate reductase (MTHFR) gene and the mechanisms by which folate may reduce homocysteine levels in bacteria and in humans have provided a rationale to understand the conflicting epidemiological observations between the studies on the 677C-T and 1298A-C MTHFR polymorphic variants, and the risk of having an infant with Down syndrome (DS). However, three of the combined genotypes (CTCC, TTAC, and TTCC) are very infrequent in the human population. In fact, these three rare genotypes were only observed in two of the eight epidemiological studies that analyzed these genotype combinations and the risk of DS. In a study of the Indian population these three genotypes were identified in mothers of DS children but not in control mothers demonstrating a statistically significant increase in the risk of giving birth to DS infants. Conversely, the CTCC and TTAC genotypes were only observed in control mothers and not in mothers of DS infants in the Spanish study, while the TTCC genotype was not observed in any Spanish mother analyzed. These results were not related to the frequency of the T allele, since this was lower in the Indian population (21.4% among case mothers and 12.4% in control mothers) than in the Spanish population (33.9%). At present, several important biological aspects on the Hcy cycle are known, including: (a) the biochemical structure and function of the MTHFR enzyme, (b) the biological basis for the effect of the different 677C-T and 1298A-C MTHFR genotype combinations on Hcy levels, (c) that folate is not synthesized by the organism that obtained it from the diet, (d) that TT homozygotes will be at particular risk when their folate status is low because the mutant enzyme requires much higher levels of folate than the physiological one to stabilize the binding of flavin-adenosine-dinucleotide (FAD), (e) that the release of flavin is prevented by increasing the levels of folate, and (f) that the cystathionine-beta-synthase gene is located on chromosome 21. Together, these facts suggest that destabilization of the Hcy cycle in function of the levels of S-adenosylmethionine (SAM), may be modified by some embryonic and maternal genotypes, as well as by maternal nutritional status and life style. This may also influence the probability that some embryos survive to birth, but in different way for those with and without trisomy 21, as is discussed in this article.
File Format	HTM / HTML
ISSN	15524825
Issue Number	11
Volume Number	146A
e-ISSN	15524833
Journal	American Journal of Medical Genetics Part A
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2008-06-01
Publisher Place	United States
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Discipline Human Discipline Genetics Down Syndrome Epidemiology Methylenetetrahydrofolate Reductase (nadph2) Genetics Metabolism Cystathionine Beta-synthase Enzymology Female Flavin-adenine Dinucleotide Flavins Folic Acid Deficiency Genotype Homocysteine Humans Polymorphism, Single Nucleotide Risk Factors S-adenosylmethionine Structure-activity Relationship Journal Article Review
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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