Identification of novel rare mutations of DACT1 in human neural tube defects

Neural tube defects (NTDs) constitute the second most frequent cause of human congenital abnormalities. Complex multigenetic causes have been suggested to contribute to NTDs. The planar cell polarity (PCP) pathway plays a critical role in neural tube closure in model organisms and in human. Knockout of Dact1 (Dapper, Frodo) leads to deregulated PCP signaling with defective neural tube in mice. Here, we report that five missense heterozygote mutations of the DACT1 gene are specifically identified in 167 stillborn or miscarried Han Chinese fetuses with neural tube defects. Our biochemical analyses revealed that among the five mutations, N356K and R45W show loss‐of‐function or reduced activities in inducing Dishevelled2 (DVL2) degradation and inhibiting jun‐N‐terminal kinase (JNK) phosphorylation, implicating mutated DACT1 as a risk factor for human NTDs. Our findings, together with early reports, suggest that rare mutations of the PCP‐related genes may constitute a great contribution to human NTDs. Hum Mutat 33:1450–1455, 2012. © 2012 Wiley Periodicals, Inc.