Analysis of select folate pathway genes, PAX3, and human T in a midwestern neural tube defect population

Abstract

Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10–methylenetetrahydrofolate reductase (MTHFR), folate receptors-α (FOLR1; hereafter abbreviated “FR-α”) and -β (FOLR2; hereafter, “FR-β”), methionine synthase (hereinafter, “MS”), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala→Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala→Glu mutation which was signficantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-β, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-α revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs. Teratology 59:331–341, 1999. © 1999 Wiley-Liss, Inc.