Methionine synthase: High-resolution mapping of the human gene and evaluation as a candidate locus for neural tube defects

Periconceptual folate supplementation has been found to prevent the occurre nce of many neural tube defects (NTDs). Consequently, genetic variation in folate metabolism genes is expected to contribute to the risk for neural tu be defects. Methionine synthase catalyzes the vitamin B-12-dependent conver sion of homocysteine and 5-methyltetrahydrofolate to methionine and tetrahy drofolate. The observation that homocysteine and vitamin B-12 levels are in dependent predictors of NTD risk suggested that methionine synthase could b e a candidate gene for NTDs. To assess the role of the MS gene in NTDs, we performed high-resolution physical mapping of the MS locus, isolated highly polymorphic markers linked to the MS gene, and tested for an association b etween specific MS alleles and NTDs. We mapped the MS gene to a position be tween 909 and 913 cR(1000) on chromosome 1 by radiation hybrid mapping. Pol ymorphic markers D1S1567 and D1S1568 map to locations no more than 900 and 194 kb from the MS gene, respectively. The segregation of these polymorphic markers was measured in 85 Irish NTD families. No allele of either marker showed a significant association with NTDs using the transmission disequili brium test. A lack of association was also observed for the D1919G; missens e mutation within the gene. Our results suggest that inherited variation in the MS gene does not contribute to NTD risk in this population. (C) 1999 A cademic Press.