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.
Subject(s)
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/genetics , DNA-Binding Proteins/genetics , Fetal Proteins , Folic Acid/metabolism , Homeodomain Proteins/genetics , Neural Tube Defects/genetics , Receptors, Cell Surface , T-Box Domain Proteins , Transcription Factors/genetics , 5,10-Methylenetetrahydrofolate Reductase (FADH2) , Alleles , Animals , Base Sequence , Carrier Proteins/genetics , Exons , Folate Receptor 1 , Folate Receptors, GPI-Anchored , Folic Acid/genetics , Gene Frequency , Humans , Linkage Disequilibrium , Methylenetetrahydrofolate Reductase (NADPH2) , Mice , Midwestern United States , Molecular Sequence Data , Mutation , Neural Tube Defects/metabolism , Oxidoreductases/genetics , PAX3 Transcription Factor , Paired Box Transcription Factors , Polymorphism, GeneticABSTRACT
Glucocorticoids are potent inducers of cleft palate in various laboratory animals. Recent work has demonstrated that the susceptibility of mice to the teratogenic action of glucocorticoids is strongly correlated with the number of fetal receptors for glucocorticoids. In the present study we have investigated whether there is a difference in levels of glucocorticoid receptors between individuals with or without cleft lip +/- cleft palate or isolated cleft palate. We have found that dermal fibroblasts from the affected individuals have significantly fewer glucocorticoid receptors than do fibroblasts from unaffected persons. This decrease in receptors may reflect a basic hormonal defect in these individuals, which presumably could play a role in the etiology of facial clefting.
