PMID- 10444342
OWN - NLM
STAT- MEDLINE
DCOM- 19990922
LR  - 20131121
IS  - 1096-7192 (Print)
IS  - 1096-7192 (Linking)
VI  - 67
IP  - 4
DP  - 1999 Aug
TI  - A common variant in methionine synthase reductase combined with low cobalamin
      (vitamin B12) increases risk for spina bifida.
PG  - 317-23
AB  - 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.
CI  - Copyright 1999 Academic Press.
FAU - Wilson, A
AU  - Wilson A
AD  - The Montreal Children's Hospital Research Institute, McGill University, Montreal,
      Quebec, Canada.
FAU - Platt, R
AU  - Platt R
FAU - Wu, Q
AU  - Wu Q
FAU - Leclerc, D
AU  - Leclerc D
FAU - Christensen, B
AU  - Christensen B
FAU - Yang, H
AU  - Yang H
FAU - Gravel, R A
AU  - Gravel RA
FAU - Rozen, R
AU  - Rozen R
LA  - eng
GR  - HL58955-01/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Genet Metab
JT  - Molecular genetics and metabolism
JID - 9805456
RN  - 04Y7590D77 (Isoleucine)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 9007-49-2 (DNA)
RN  - AE28F7PNPL (Methionine)
RN  - EC 1.5.- (Oxidoreductases Acting on CH-NH Group Donors)
RN  - EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2))
RN  - EC 2.1.1.13 (5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase)
RN  - EC 3.1.21.- (endodeoxyribonuclease NdeI)
RN  - EC 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific)
RN  - P6YC3EG204 (Vitamin B 12)
SB  - IM
MH  - 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/*genetics/metabolism
MH  - Adult
MH  - Amino Acid Substitution
MH  - Child
MH  - Child, Preschool
MH  - DNA/genetics/metabolism
MH  - Deoxyribonucleases, Type II Site-Specific/metabolism
MH  - Family Health
MH  - Female
MH  - Gene Frequency
MH  - Genetic Variation
MH  - Genotype
MH  - Homocysteine/metabolism
MH  - Humans
MH  - Isoleucine/genetics
MH  - Male
MH  - Methionine/genetics
MH  - Methylenetetrahydrofolate Reductase (NADPH2)
MH  - Oxidoreductases Acting on CH-NH Group Donors/*genetics/metabolism
MH  - Point Mutation
MH  - Polymorphism, Genetic
MH  - Regression Analysis
MH  - Risk Factors
MH  - Spinal Dysraphism/*genetics/metabolism
MH  - Vitamin B 12/*metabolism
EDAT- 1999/08/13 00:00
MHDA- 1999/08/13 00:01
CRDT- 1999/08/13 00:00
PHST- 1999/08/13 00:00 [pubmed]
PHST- 1999/08/13 00:01 [medline]
PHST- 1999/08/13 00:00 [entrez]
AID - 10.1006/mgme.1999.2879 [doi]
AID - S1096-7192(99)92879-2 [pii]
PST - ppublish
SO  - Mol Genet Metab. 1999 Aug;67(4):317-23. doi: 10.1006/mgme.1999.2879.