PMID- 10500018
OWN - NLM
STAT- MEDLINE
DCOM- 19991020
LR  - 20180330
IS  - 0002-9165 (Print)
IS  - 0002-9165 (Linking)
VI  - 70
IP  - 4
DP  - 1999 Oct
TI  - Abnormal folate metabolism and mutation in the methylenetetrahydrofolate
      reductase gene may be maternal risk factors for Down syndrome.
PG  - 495-501
AB  - BACKGROUND: Down syndrome, or trisomy 21, is a complex genetic disease resulting 
      from the presence of 3 copies of chromosome 21. The origin of the extra
      chromosome is maternal in 95% of cases and is due to the failure of normal
      chromosomal segregation during meiosis. Although advanced maternal age is a major
      risk factor for trisomy 21, most children with Down syndrome are born to mothers 
      <30 y of age. OBJECTIVE: On the basis of evidence that abnormal folate and methyl
      metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, 
      we hypothesized that the C-to-T substitution at nucleotide 677 (677C-->T)
      mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk
      factor for maternal meiotic nondisjunction and Down syndrome in young mothers.
      DESIGN: The frequency of the MTHFR 677C-->T mutation was evaluated in 57 mothers 
      of children with Down syndrome and in 50 age-matched control mothers. Ratios of
      plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were
      measured as indicators of functional folate status. RESULTS: A significant
      increase in plasma homocysteine concentrations and lymphocyte methotrexate
      cytotoxicity was observed in the mothers of children with Down syndrome,
      consistent with abnormal folate and methyl metabolism. Mothers with the 677C-->T 
      mutation had a 2.6-fold higher risk of having a child with Down syndrome than did
      mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03).
      CONCLUSION: The results of this initial study indicate that folate metabolism is 
      abnormal in mothers of children with Down syndrome and that this may be
      explained, in part, by a mutation in the MTHFR gene.
FAU - James, S J
AU  - James SJ
AD  - Food and Drug Administration-National Center for Toxicological Research, the
      Division of Biochemical Toxicology, Jefferson, AR 72079,USA. jjames@nctr.fda.gov
FAU - Pogribna, M
AU  - Pogribna M
FAU - Pogribny, I P
AU  - Pogribny IP
FAU - Melnyk, S
AU  - Melnyk S
FAU - Hine, R J
AU  - Hine RJ
FAU - Gibson, J B
AU  - Gibson JB
FAU - Yi, P
AU  - Yi P
FAU - Tafoya, D L
AU  - Tafoya DL
FAU - Swenson, D H
AU  - Swenson DH
FAU - Wilson, V L
AU  - Wilson VL
FAU - Gaylor, D W
AU  - Gaylor DW
LA  - eng
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  - Am J Clin Nutr
JT  - The American journal of clinical nutrition
JID - 0376027
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 9007-49-2 (DNA)
RN  - 935E97BOY8 (Folic Acid)
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 3.1.21.4 (Deoxyribonucleases, Type II Site-Specific)
RN  - EC 3.1.21.4 (GANTC-specific type II deoxyribonucleases)
RN  - YL5FZ2Y5U1 (Methotrexate)
SB  - AIM
SB  - IM
CIN - Am J Clin Nutr. 1999 Oct;70(4):429-30. PMID: 10500007
MH  - Adult
MH  - Alcohol Drinking/adverse effects/epidemiology
MH  - Case-Control Studies
MH  - Chromatography, High Pressure Liquid
MH  - DNA/chemistry
MH  - Deoxyribonucleases, Type II Site-Specific/chemistry
MH  - Diet Surveys
MH  - Diet, Reducing/adverse effects/statistics & numerical data
MH  - Dietary Supplements
MH  - Down Syndrome/*genetics/metabolism
MH  - Electrophoresis, Agar Gel
MH  - Female
MH  - Folic Acid/administration & dosage/*metabolism
MH  - Genotype
MH  - Homocysteine/blood
MH  - Humans
MH  - Methionine/blood
MH  - Methotrexate/pharmacology
MH  - Methylenetetrahydrofolate Reductase (NADPH2)
MH  - Oxidoreductases Acting on CH-NH Group Donors/*genetics/metabolism
MH  - Point Mutation
MH  - Polymerase Chain Reaction
MH  - Risk Factors
MH  - Surveys and Questionnaires
EDAT- 1999/09/29 00:00
MHDA- 1999/09/29 00:01
CRDT- 1999/09/29 00:00
PHST- 1999/09/29 00:00 [pubmed]
PHST- 1999/09/29 00:01 [medline]
PHST- 1999/09/29 00:00 [entrez]
AID - 10.1093/ajcn/70.4.495 [doi]
PST - ppublish
SO  - Am J Clin Nutr. 1999 Oct;70(4):495-501. doi: 10.1093/ajcn/70.4.495.