Human Molecular Genetics, Vol 8, 2199-2204, Copyright © 1999 by Oxford University Press
M Carter, S Ulrich, Y Oofuji, DA Williams and ME Ross
Genetic correlation of human neural tube defects (NTDs) with NTD genes
identified in mouse may unravel predisposing complex traits for assessment
of individual risk and treatment in clinical settings. Folic acid (FA) can
reduce the recurrence of NTDs in human populations by as much as 50-70%,
though the mechanism of this rescue is unknown. We examined whether Crooked
tail ( Cd ), a mouse strain prone to exencephaly, could provide a genetic
animal model for folate-responsive NTDs. The Cd locus was localized to a
0.2 cM interval of the Mouse Genome Database genetic map, identifying
tightly linked markers for genotyping prior to phenotypic expression. In a
controlled diet study, Cd was found to mimic closely the clinical response
to FA. FA supplementation reduced the recurrence risk of Cd exencephaly by
as much as 55%. This rescue was dose dependent and did not require subjects
to be inherently folate deficient. Like the female predominance of NTDs in
humans, female Cd embryos were most likely to display exencephaly and were
more responsive than males to the FA rescue. Importantly, FA
supplementation shifted the severity of Cd phenotypic expression from early
embryonic lethality to longer survival, and reduced the incidence of NTDs.
The Cd locus is distinct from the known genes associated with neurulation
defects, and isolation of this gene will assist identification of
biochemical, genetic and gender-dependent factors contributing to
folate-responsive NTDs.
ARTICLES
Crooked tail (Cd) models human folate-responsive neural tube defects
Laboratory of Molecular Neurobiology and Development, Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA and
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