Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?

Abstract

One-carbon metabolism is under the influence of folate, vitamin B12 and genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR 677 C --> T and 1298 A --> C), of methionine synthase (MTR 2756 C --> G), methionine synthase reductase (MTRR 66 A --> G) and transcobalamin (TCN 776 C --> G). The pathogenesis of neural tube defect (NTD) may be related to this metabolism. The influence of the MTHFR 677 C --> T polymorphism reported in The Netherlands and Ireland can be questioned in southern Italy, France and Great Britain. MTRR, combined with a low level of vitamin B12, increases the risk of NTD and of having a child with NTD in Canada, while TCN 776 GG and MTRR 66 GG mutated genotypes associated with the MTHFR 677 CC wild-type are predictors of NTD cases in Sicily. Down syndrome (DS) is due to a failure of normal chromosomal segregation during meiosis, possibly related to one-carbon metabolism. MTHFR 677 C --> T and MTRR 66 A --> G polymorphisms are associated with a greater risk of having a child with DS in North America, Ireland and The Netherlands. In contrast, MTHFR 677 C --> T has no influence on DS risk in France and Sicily, while homocysteine and MTR 2756 AG/GG genotypes are predictors of DS risk in Sicily. In conclusion, NTD and DS are influenced by the same genetic determinants of one-carbon metabolism. The distinct data produced in different geographical areas may be explained by differences in the nutritional environment and genetic characteristics of the populations.

• Authors: Jean-Louis Guéant, Rosa-Maria Guéant-Rodriguez, Guido Anello, Paolo Bosco, Laurent Brunaud, Corrado Romano, Rafaele Ferri, Antonino Romano, Mirande Candito, Bernard Namour
• Journal: Clinical chemistry and laboratory medicine (Clin Chem Lab Med) Vol. 41 Issue 11 Pg. 1473-7 (Nov 2003) ISSN: 1434-6621 [Print] Germany
• PMID: 14656028 (Publication Type: Journal Article, Review)

Chemical References

• Transcobalamins
• Homocysteine
• Folic Acid
• Methylenetetrahydrofolate Reductase (NADPH2)
• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
• Vitamin B 12

Topics

• 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase (genetics)
• Down Syndrome (genetics, metabolism)
• Folic Acid (metabolism)
• Genotype
• Homocysteine (metabolism)
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2) (genetics)
• Neural Tube Defects (genetics, metabolism)
• Polymorphism, Genetic (genetics)
• Transcobalamins (genetics)
• Vitamin B 12 (metabolism)