The curly-tail (ct) mouse, an animal model of neural tube defects, displays altered homocysteine metabolism without folate responsiveness or a defect in Mthfr.
Maternal mild hyperhomocysteinemia is associated with increased risk for bearing children with neural tube defects (NTD). Folate intake corrects hyperhomocysteinemia and prevents up to 70% of NTD. The curly-tail (ct) mouse, an animal model for NTD, has been suggested to display features that closely resemble the human defect. We therefore investigated folate metabolism in ct mice. On control and folate-/choline-deficient diets, ct mice exhibited higher plasma homocysteine levels than control C57Bl/6 mice. This increase was associated with increased liver S-Adenosylhomocysteine and decreased S-adenosylmethionine:S-adenosylhomocysteine (SAM/SAH) ratios. Since the ct locus maps in close proximity to the gene for methylenetetrahydrofolate reductase (Mthfr), a modifier of homocysteine levels in man, we also assayed Mthfr activity and sequenced the 5(') regulatory region; these experiments suggested that Mthfr is not defective in the ct strain. Finally, we examined the influence of dietary folate on NTD incidence in the ct strain, but did not identify significant differences among the four diets used in the study. Our work suggests that altered homocysteine metabolism may contribute to the pathogenetic mechanism of the ct defect, but, unlike human NTD, nutritional or genetic deficiencies in folate metabolism do not appear to play a significant direct role.
Tran
Pamela
P
Department of Human Genetics, McGill University-Montreal Children's Hospital Research Institute, 4060 St.Catherine St. West, Room 200, QC, Canada.
Hiou-Tim
Francois
F
Frosst
Phyllis
P
Lussier-Cacan
Suzanne
S
Bagley
Pamela
P
Selhub
Jacob
J
Bottiglieri
Teodoro
T
Rozen
Rima
R
D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D020355:Cholates / Q000378:metabolism; D004195:Disease Models, Animal; D005492:Folic Acid / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism*; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D051379:Mice; D008810:Mice, Inbred C57BL; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism
D020355:Cholates; D006710:Homocysteine; D005492:Folic Acid; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2)