Folic Acid Binding Protein is Crucial for Mother to Fetus Folate Transfer

PI: Richard Finnell
Texas A & M University

Background: Over the past 10-15 years there have been many news accounts about severe neurological birth defects along the U.S./Mexico border. The defects are characterized by improper or arrested growth and development of the brain and other neural tube defects. In some cases, the fetuses were partially or completely anencephalic with absolutely no chance of survival.

Research sponsored by NIH discovered folic acid deficiency as the major cause of this condition. Supplementation greatly reduced the occurrence of neural tube defects, but the fact that not all women enjoy the same protective effects from folic acid supplementation suggests that underlying genetic and environmental factors may be involved. Efforts to understand the complex gene/nutrient interactions underlying neural tube defect development have progressed slowly with most work focusing on the genes associated with the folic acid biosynthetic pathway or with transport into target cells.

Advance: To study the importance of the folic acid binding protein on the transport of folic acid into cells and its subsequent involvement in neural tube defects, researchers from Texas and Nebraska created a strain of transgenic mice in which the folic acid binding protein gene was inactivated. Using simple Mendelian genetics, they crossed animals that were heterozygous for the inactivated gene which produced some fetuses that were nullizygous. In other words, these fetal mice pups had no genes for folic acid binding protein which made them incapable of processing folic acid normally. These fetuses showed severe neural tube defects, fewer somites than wild-type mice, and they die in utero and are resorbed. Further experiments in which heterozygous dams were given folic acid supplementation did produce live nullizygous pups but neural tube defects were still present in some pups.

Implication: These experiments add additional scientific evidence of the important role folic acid plays in the development of the nervous system in mammals. Mice nullizygous for folic acid binding protein were all severely growth retarded and had severe malformations. All biochemical reactions that are folate dependent have yet to be elucidated. This new transgenic mouse strain will be a valuable tool for studying how the receptor is able to provide folate in sufficient quantities to sustain normal development. [Area of Emphasis: Biology of the Nervous System: Development and Disorders; GPRA Goal: Add to the body of knowledge about normal and abnormal biological functions and behavior (Molecular and Cellular Mechanisms)]

Citation: Piedrahita JA, Oetama B, Bennett GD, van Waes J, Kamen BA, Richardson J, Lacey SW, Anerson RGW, Finnell RH: Mice lacking the folic acid-binding protein Folbp1 are defective in early embryonic development. Nature Genetics 232: 228-232, 1999.