To investigate the relationship between common genetic variants of GRHL3 and the risk for NTDs, we performed a case-control study and a case-parent triad/control study.
However, it does not phenocopy other defects of Grhl3-null embryos such as abnormal axial curvature, cranial NTDs (exencephaly) or skin barrier defects, the latter being rescued by the Grhl3-transgene.
Hypomethylation of GRHL3 in central nervous tissue is associated with NTDs, further supporting the importance of GRHL3 and methylation in proper neural tube closure.
Among nutritional factors, inositol deficiency causes cranial NTDs in mice while supplemental inositol prevents spinal and cranial NTDs in the curly tail (Grhl3 hypomorph) mouse, rodent models of hyperglycemia or induced diabetes, and in a folate-deficiency induced NTD model.
These observations indicate a mechanistic link between altered lamin B1 function, exacerbation of the Grhl3-mediated cell proliferation defect, and enhanced susceptibility to NTDs.