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

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 w here several genes, interacting with environmental factors, create the phen otype. Using a Midwestern NTD population consisting of probands, parents, a nd siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of cand idate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), fo late receptors-alpha: (FOLR1; hereafter abbreviated "FR-alpha") and -beta ( FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, t he 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 th e majority of our NTD populations. However, we discovered a silent polymorp hism in exon 6 of MTHFR which conserved a serine residue and which showed s ignificant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly a ssociated with our Iowa NTD population; however, we could not replicate thi s result either in a combined Minnesota/ Nebraska or in a California NTD po pulation. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were u nable to demonstrate linkage disequilibrium with our NTD populations. A mut ation search of FR-alpha revealed one proband with a de novo silent mutatio n 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 ass ociation between MTHFR and NTDs. Teratology 59:331-341, 1999. (C) 1999 Wile y-Liss, Inc.