title: Neural tube and craniofacial defects with special emphasis on folate pathway genes.
abstract: Neural tube and orofacial defects are common congenital malformations in humans. While etiologically heterogeneous, they are for the most part multifactorial in their pathogenesis, having both genetic and environmental components in their development. In recent years, there has been a great deal of epidemiologic evidence demonstrating that women who received multivitamins containing folic acid periconceptionally had significantly reduced occurrence and recurrence risks for producing infants with such malformations. This risk reduction is not observed in all populations, further suggestive of a genetic regulation of this phenomenon. Unfortunately, the mechanisms underlying the beneficial effects of folic acid are not well-understood. In this article, we review the relevant epidemiologic data on both neural tube defects and orofacial malformations, the fundamental embryological processes involved in closing the neural tube, and the development of the craniofacies, and propose a working hypothesis for susceptibility to these malformations. This hypothesis is based on the interworkings of cellular folate transport, focusing on the key elements involved in potocytosis. We propose that infants with mutations in the folate receptor alpha gene might be at increased risk for congenital anomalies due to a reduced binding affinity for 5-methyltetrahydrofolate, the physiologic form of folic acid. Various experimental approaches to test the working hypothesis are considered.
authors.affiliation: Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station 77843-4458, USA.
authors.forename: R H
authors.initials: RH
authors.lastname: Finnell
authors.forename: K A
authors.initials: KA
authors.lastname: Greer
authors.forename: R C
authors.initials: RC
authors.lastname: Barber
authors.forename: J A
authors.initials: JA
authors.lastname: Piedrahita
mesh_terms: D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019465:Craniofacial Abnormalities / Q000196:embryology* / Q000517:prevention & control; D019587:Dietary Supplements; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism* / Q000627:therapeutic use; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D051379:Mice; D017720:Molecular Epidemiology; D009436:Neural Tube Defects / Q000196:embryology* / Q000517:prevention & control; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D058978:Reduced Folate Carrier Protein; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013763:Tetrahydrofolates / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D011956:Receptors, Cell Surface; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; C120043:SLC19A2 protein, human; C548700:Slc19a1 protein, mouse; C492292:Slc19a2 protein, mouse; D013763:Tetrahydrofolates; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; C005984:5-methyltetrahydrofolate