title: 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-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), 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 significantly 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-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha 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.
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City 52242-1083, USA.
authors.forename: D
authors.initials: D
authors.lastname: Trembath
authors.forename: A L
authors.initials: AL
authors.lastname: Sherbondy
authors.forename: D C
authors.initials: DC
authors.lastname: Vandyke
authors.forename: G M
authors.initials: GM
authors.lastname: Shaw
authors.forename: K
authors.initials: K
authors.lastname: Todoroff
authors.forename: E J
authors.initials: EJ
authors.lastname: Lammer
authors.forename: R H
authors.initials: RH
authors.lastname: Finnell
authors.forename: S
authors.initials: S
authors.lastname: Marker
authors.forename: G
authors.initials: G
authors.lastname: Lerner
authors.forename: J C
authors.initials: JC
authors.lastname: Murray
mesh_terms: D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005326:Fetal Proteins; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism*; D005787:Gene Frequency; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D051379:Mice; D015146:Midwestern United States; D008969:Molecular Sequence Data; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism; D010088:Oxidoreductases / Q000235:genetics; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000235:genetics*; D000098908:Brachyury Protein
chemical_list: D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid; D018398:Homeodomain Proteins; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D010088:Oxidoreductases; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D011956:Receptors, Cell Surface; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000098908:Brachyury Protein; C548696:FOLR1 protein, human; C489409:PAX3 protein, human; C068686:Pax3 protein, mouse