title: 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.affiliation: INSERM 00-14, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine Nancy, Vandoeuvre lès Nancy, France. Jean-Louis.Gueant@medecine.uhp-nancy.fr
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.forename: Rosa-Maria
authors.initials: RM
authors.lastname: Guéant-Rodriguez
authors.forename: Guido
authors.initials: G
authors.lastname: Anello
authors.forename: Paolo
authors.initials: P
authors.lastname: Bosco
authors.forename: Laurent
authors.initials: L
authors.lastname: Brunaud
authors.forename: Corrado
authors.initials: C
authors.lastname: Romano
authors.forename: Rafaele
authors.initials: R
authors.lastname: Ferri
authors.forename: Antonino
authors.initials: A
authors.lastname: Romano
authors.forename: Mirande
authors.initials: M
authors.lastname: Candito
authors.forename: Bernard
authors.initials: B
authors.lastname: Namour
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D005492:Folic Acid / Q000378:metabolism*; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics; D014155:Transcobalamins / Q000235:genetics; D014805:Vitamin B 12 / Q000378:metabolism*
chemical_list: D014155:Transcobalamins; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D014805:Vitamin B 12