LACK OF ASSOCIATION BETWEEN MUTATIONS IN THE FOLATE RECEPTOR-ALPHA GENE AND SPINA-BIFIDA

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 environ mental causes. Although periconceptional supplementation of the matern al diet with folic acid has been shown to reduce the recurrence and oc currence of neural tube defects (NTDs) by up to 70%, the underlying me chanism remains unknown, Folic acid enters cells of certain tissues vi a a receptor-mediated process known as potocytosis. The folate recepto r alpha (FR-alpha) gene codes for the protein responsible for binding folate, which is the first, and only, folate-dependent step in folate transport, The FR-alpha exons, which code for mature protein and the i ntron-exon boundaries, were examined for mutations in three separate s tudies, Initial screening was performed by single-stranded conformatio nal polymorphism (SSCP) analysis in a subset of 1,688 samples obtained from a population-based case-control 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-c ontrol sample of 219 individuals who were stratified into four sub-gro ups on the basis of folate intake and pregnancy outcome. No polymorphi sm was detected in any of the four exons examined, It is unlikely that the beneficial effects of maternal folate supplementation in preventi ng NTDs acts through a mechanism involving pharmacological correction of a variant form of folate receptor alpha. (C) 1998 Wiley-Liss, Inc.