title: Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutations.
abstract: Methylenetetrahydrofolate reductase (MTHFR) mutations are commonly associated with hyperhomocysteinemia, and, through their defects in homocysteine metabolism, they have been implicated as risk factors for neural tube defects and unexplained, recurrent embryo losses in early pregnancy. Folate sufficiency is thought to play an integral role in the phenotypic expression of MTHFR mutations. Samples of neonatal cord blood (n=119) and fetal tissue (n=161) were analyzed for MTHFR C677T and A1298C mutations to determine whether certain MTHFR genotype combinations were associated with decreased in utero viability. Mutation analysis revealed that all possible MTHFR genotype combinations were represented in the fetal group, demonstrating that 677T and 1298C alleles could occur in both cis and trans configurations. Combined 677CT/1298CC and 677TT/1298CC genotypes, which contain three and four mutant alleles, respectively, were not observed in the neonatal group (P=.0402). This suggests decreased viability among fetuses carrying these mutations and a possible selection disadvantage among fetuses with increased numbers of mutant MTHFR alleles. This is the first report that describes the existence of human MTHFR 677CT/1298CC and 677TT/1298CC genotypes and demonstrates their potential role in compromised fetal viability.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9.
authors.forename: P A
authors.initials: PA
authors.lastname: Isotalo
authors.forename: G A
authors.initials: GA
authors.lastname: Wells
authors.forename: J G
authors.initials: JG
authors.lastname: Donnelly
mesh_terms: D000026:Abortion, Habitual / Q000201:enzymology / Q000235:genetics; D000483:Alleles; D005260:Female; D005312:Fetal Blood / Q000201:enzymology / Q000378:metabolism; D005313:Fetal Death / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005333:Fetus / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D005787:Gene Frequency / Q000235:genetics; D020043:Genes, Essential / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D009436:Neural Tube Defects / Q000201:enzymology / Q000235:genetics; D016017:Odds Ratio; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011247:Pregnancy; D011256:Pregnancy Outcome
chemical_list: D006710:Homocysteine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)