A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida.
Impairment of folate and cobalamin (vitamin B(12)) metabolism has been observed in families with neural tube defects (NTDs). Genetic variants of enzymes in the homocysteine remethylation pathway might act as predisposing factors contributing to NTD risk. The first polymorphism linked to increased NTD risk was the 677C-->T mutation in methylenetetrahydrofolate reductase (MTHFR). We now report a polymorphism in methionine synthase reductase (MTRR), the enzyme that activates cobalamin-dependent methionine synthase. This polymorphorism, 66A-->G (I22M), has an allele frequency of 0.51 and increases NTD risk when cobalamin status is low or when the MTHFR mutant genotype is present. Genotypes and cobalamin status were assessed in 56 patients with spina bifida, 58 mothers of patients, 97 control children, and 89 mothers of controls. Cases and case mothers were almost twice as likely to possess the homozygous mutant genotype when compared to controls, but this difference was not statistically significant. However, when combined with low levels of cobalamin, the risk for mothers increased nearly five times (odds ratio (OR) = 4.8, 95% CI 1.5-15.8); the OR for children with this combination was 2.5 (95% CI 0.63-9.7). In the presence of combined MTHFR and MTRR homozygous mutant genotypes, children and mothers had a fourfold and threefold increase in risk, respectively (OR = 4.1, 95% CI 1.0-16.4; and OR = 2.9, 95% CI 0.58-14.8). This study provides the first genetic link between vitamin B(12) deficiency and NTDs and supports the multifactorial origins of these common birth defects. Investigation of this polymorphism in other disorders associated with altered homocysteine metabolism, such as vascular disease, is clearly warranted.
Wilson
A
A
The Montreal Children's Hospital Research Institute, McGill University, Montreal, Quebec, Canada.
Platt
R
R
Wu
Q
Q
Leclerc
D
D
Christensen
B
B
Yang
H
H
Gravel
R A
RA
Rozen
R
R
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000378:metabolism; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D012307:Risk Factors; D016135:Spinal Dysraphism / Q000235:genetics* / Q000378:metabolism; D014805:Vitamin B 12 / Q000378:metabolism*
D007532:Isoleucine; D006710:Homocysteine; D004247:DNA; D008715:Methionine; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C037106:endodeoxyribonuclease NdeI; D015252:Deoxyribonucleases, Type II Site-Specific; D014805:Vitamin B 12