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Gene–environment interactions, folate metabolism and the embryonic nervous system

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Formation of brain and spinal cord requires the successful closure of neural ectoderm into an embryonic neural tube. Defects in this process result in anencephaly or spina bifida, which together constitute a leading cause of mortality and morbidity in children, affecting all ethnic and socioeconomic groups. The subject of intensive research for decades, neural tube defects (NTDs), are understood to arise from complex interactions of genes and environmental conditions, though systems‐level details are still elusive. Despite the variety of underlying causes, a single intervention, folic acid supplementation given in the first gestational month, can measurably reduce the occurrence of NTDs in a population. Evidence for and the scope of gene‐environment interactions in the genesis of NTDs is discussed. A systems‐based approach is now possible toward studies of genetic and environmental influences underlying NTDs that will enable the assessment of individual risk and personalized optimization of prevention. Copyright © 2009 John Wiley & Sons, Inc.

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Figure 1.

Folate metabolism and its contributions to physiological processes. One carbon metabolism in the cytoplasm is depicted. Colors: blue, enzymes catalyzing folate metabolic steps; red, important products of the pathway; magenta, physiological processes which pathway products support. THF, tetrahydrofolate; DHF, dihydrofolate; dUMP, deoxyuridine‐monophosphate; Ado‐met, S‐adenosylmethionine; Ado‐hcy, S‐adenosylhomocysteine; BH4, tetrahydrobiopterin; qBH2, quinonoid dihydrobiopterin; PtdMME, phosphatidylethanolamine (monomethyl); PtdDME, phosphatidylethanolamine (dimethyl); PEMT, phosphatidylethanolamine methyltransferase. FTHFS, 10‐formyltetrahydrofolate synthase; MTHFC, methyltetrahydrofolate cyclohydrolase; MTHFD, methyltetrahydrofolate dehydrogenase; MTHFR, methyltetrahydrofolate reductase; MS, methionine synthase; cSHMT, cytoplasmic serine hydroxymethyltransferase; DHFR, dihydrofolate reductase; TS, thymidylate synthase.

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Blanche Capel

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earned her Ph.D. at the University of Pennsylvania and has been at Duke University since 1993. She earned her endowed professorship, the James B. Duke Professor of Cell Biology, for the meaningful discoveries she has made since her postdoctoral work in genetics at the National Institute for Medical Research in London. The broad goal of the research in Dr. Capel’s laboratory is to characterize the cellular and molecular basis of morphogenesis – how the body forms. She uses gonadal (gender/sex) development in the mouse as her model system and investigates a gene she helped discover, Sry, the male sex determining gene. Gonad development is unique in that a single rudimentary tissue can be induced to form one of two different organs, an ovary or testis, and she is learning all she can about this central mystery of biology.

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