Lack of association between mutations in the folate receptor-a gene and spina bifida

Robert C. Barber, Gary M. Shaw, Edward J. Lammer, Kimberly A. Greer, Timothy A. Biela, Steven W. Lacey, Cathy R. Wasserman, Richard H. Finnell

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Defects of neural tube closure are among the most common of all human malformations. Epidemiological and genetic studies indicate that most of these defects are multifactorial in origin with genetic and environmental causes. Although periconceptional supplementation of the maternal diet with folic acid has been shown to reduce the recurrence and occurrence of neural tube defects (NTDs) by up to 70%, the underlying mechanism remains unknown. Folic acid enters cells of certain tissues via a receptormediated process known as potocytosis. The folate receptor alpha (FR-a) gene codes for the protein responsible for binding folate, which is the first, and only, folate-dependent step in folate transport. The FR-a exons, which code for mature protein and the intron-exon boundaries, were examined for mutations in three separate studies. Initial screening was performed by singlestranded conformational polymorphism (SSCP) analysis in a subset of 1,688 samples obtained from a population-based casecontrol study of NTDs in California. In the second study, the DNA sequence of exons 5 and 6 was determined in a group of 50 NTD affected individuals. The final experiment involved using dideoxy fingerprinting (ddF) to screen a population-based case-control sample of 219 individuals who were stratified into four sub-groups on the basis of folate intake and pregnancy outcome. No polymorphism was detected in any of the four exons examined. It is unlikely that the beneficial effects of maternal folate supplementation in preventing NTDs acts through a mechanism involving pharmacological correction of a variant form of folate recep-tor alpha.

Original languageEnglish
Pages (from-to)310-317
Number of pages8
JournalAmerican Journal of Medical Genetics
Volume76
Issue number4
StatePublished - 1 Apr 1998

Fingerprint

Spinal Dysraphism
Folic Acid
Neural Tube Defects
Mutation
Genes
Exons
Folate Receptor 1
Mothers
Inteins
Pregnancy Outcome
Protein Binding
Population
Epidemiologic Studies
Pharmacology
Diet
Recurrence

Keywords

  • Folate receptor alpha
  • Folic acid
  • Neural tube defects

Cite this

Barber, R. C., Shaw, G. M., Lammer, E. J., Greer, K. A., Biela, T. A., Lacey, S. W., ... Finnell, R. H. (1998). Lack of association between mutations in the folate receptor-a gene and spina bifida. American Journal of Medical Genetics, 76(4), 310-317.
Barber, Robert C. ; Shaw, Gary M. ; Lammer, Edward J. ; Greer, Kimberly A. ; Biela, Timothy A. ; Lacey, Steven W. ; Wasserman, Cathy R. ; Finnell, Richard H. / Lack of association between mutations in the folate receptor-a gene and spina bifida. In: American Journal of Medical Genetics. 1998 ; Vol. 76, No. 4. pp. 310-317.
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Barber, RC, Shaw, GM, Lammer, EJ, Greer, KA, Biela, TA, Lacey, SW, Wasserman, CR & Finnell, RH 1998, 'Lack of association between mutations in the folate receptor-a gene and spina bifida', American Journal of Medical Genetics, vol. 76, no. 4, pp. 310-317.

Lack of association between mutations in the folate receptor-a gene and spina bifida. / Barber, Robert C.; Shaw, Gary M.; Lammer, Edward J.; Greer, Kimberly A.; Biela, Timothy A.; Lacey, Steven W.; Wasserman, Cathy R.; Finnell, Richard H.

In: American Journal of Medical Genetics, Vol. 76, No. 4, 01.04.1998, p. 310-317.

Research output: Contribution to journalArticle

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T1 - Lack of association between mutations in the folate receptor-a gene and spina bifida

AU - Barber, Robert C.

AU - Shaw, Gary M.

AU - Lammer, Edward J.

AU - Greer, Kimberly A.

AU - Biela, Timothy A.

AU - Lacey, Steven W.

AU - Wasserman, Cathy R.

AU - Finnell, Richard H.

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N2 - Defects of neural tube closure are among the most common of all human malformations. Epidemiological and genetic studies indicate that most of these defects are multifactorial in origin with genetic and environmental causes. Although periconceptional supplementation of the maternal diet with folic acid has been shown to reduce the recurrence and occurrence of neural tube defects (NTDs) by up to 70%, the underlying mechanism remains unknown. Folic acid enters cells of certain tissues via a receptormediated process known as potocytosis. The folate receptor alpha (FR-a) gene codes for the protein responsible for binding folate, which is the first, and only, folate-dependent step in folate transport. The FR-a exons, which code for mature protein and the intron-exon boundaries, were examined for mutations in three separate studies. Initial screening was performed by singlestranded conformational polymorphism (SSCP) analysis in a subset of 1,688 samples obtained from a population-based casecontrol study of NTDs in California. In the second study, the DNA sequence of exons 5 and 6 was determined in a group of 50 NTD affected individuals. The final experiment involved using dideoxy fingerprinting (ddF) to screen a population-based case-control sample of 219 individuals who were stratified into four sub-groups on the basis of folate intake and pregnancy outcome. No polymorphism was detected in any of the four exons examined. It is unlikely that the beneficial effects of maternal folate supplementation in preventing NTDs acts through a mechanism involving pharmacological correction of a variant form of folate recep-tor alpha.

AB - Defects of neural tube closure are among the most common of all human malformations. Epidemiological and genetic studies indicate that most of these defects are multifactorial in origin with genetic and environmental causes. Although periconceptional supplementation of the maternal diet with folic acid has been shown to reduce the recurrence and occurrence of neural tube defects (NTDs) by up to 70%, the underlying mechanism remains unknown. Folic acid enters cells of certain tissues via a receptormediated process known as potocytosis. The folate receptor alpha (FR-a) gene codes for the protein responsible for binding folate, which is the first, and only, folate-dependent step in folate transport. The FR-a exons, which code for mature protein and the intron-exon boundaries, were examined for mutations in three separate studies. Initial screening was performed by singlestranded conformational polymorphism (SSCP) analysis in a subset of 1,688 samples obtained from a population-based casecontrol study of NTDs in California. In the second study, the DNA sequence of exons 5 and 6 was determined in a group of 50 NTD affected individuals. The final experiment involved using dideoxy fingerprinting (ddF) to screen a population-based case-control sample of 219 individuals who were stratified into four sub-groups on the basis of folate intake and pregnancy outcome. No polymorphism was detected in any of the four exons examined. It is unlikely that the beneficial effects of maternal folate supplementation in preventing NTDs acts through a mechanism involving pharmacological correction of a variant form of folate recep-tor alpha.

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Barber RC, Shaw GM, Lammer EJ, Greer KA, Biela TA, Lacey SW et al. Lack of association between mutations in the folate receptor-a gene and spina bifida. American Journal of Medical Genetics. 1998 Apr 1;76(4):310-317.