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) ...
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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.
The birth incidence of neural tube defects (NTDs) in South Africa is threefold to sixfold higher in rural compared with urban blacks. We investigated whether folate deficiency and aberrant homocysteine metabolism coul...
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The birth incidence of neural tube defects (NTDs) in South Africa is threefold to sixfold higher in rural compared with urban blacks. We investigated whether folate deficiency and aberrant homocysteine metabolism could explain the high NTD incidence in rural black populations, Plasma folate and total homocyst(e)ine (tHcy) concentrations were determined in apparently healthy rural black women (n = 107), rural black women with a history of pregnancy complicated by NTDs (n = 54), and urban blacks (n = 101). Methionine load tests were performed on the 54 women with a history of NTD-affected pregnancy and 54 controls matched for age and body mass. The presence of the 677C --> T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene was investigated in both groups by a polymerase chain reaction (PCR) of genomic DNA and Hinfl digestion of the PCR product. Apparently healthy urban black women (n = 101) had a lower (P <.001) plasma folate concentration compared with rural black women (n = 107). Women with a history of NTD-affected pregnancy did not differ significantly from controls with respect to plasma folate, fasting homocyst(e)ine, methionine, and the post-methionine load increase in plasma homocyst(e)ine, More than 50% of both of the latter groups had a post-methionine load increase in plasma tHcy less than the fifth percentile as observed in a healthy white control group. No homozygotes for the 677C --> T mutation in the MTHFR gene were found in black mothers with NTD-affected offspring or controls. It is concluded that black urbanization is characterized by a diminished folate status that is paradoxically associated with a lower NTD birth incidence. Homozygosity for the 677C --> T mutation in the gene coding for MTHFR does not constitute a genetic risk factor for NTDs in blacks. No aberrant homocysteine metabolism could be demonstrated in black women with NTD-affected pregnancies. Copyright (C) 1999 by W.B. Saunders Company.
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