Etiology and pathogenesis of human neural tube defects: insights from mouse models

Research into neural tube defects (NTDs) is now entering a rapid phase as advances in experimental embryology and genetics, together with new insights from clinical epidemiology, provide testable hypotheses of the etiology and pathogenesis of these defects. Especially important have been contributions from the study of mouse mutants. The embryologic mechanisms responsible for upper and lower NTDs appear to be distinct, correlating with genetic evidence that distinguishes these phenotypes. The complex genetic etiology of NTDs may result from the effects of several modifier genes acting on a Mendelian trait of major effect, although no candidates are readily apparent for either type of gene. Clues to etiology have come from the preventive effect of nutritional supplements, especially those involved in one-carbon metabolism. More generally, research on NTDs has yielded major insights into how genetic predisposition can interact with environmental influences to modulate the incidence and severity of congenital malformations.