title: Identification of novel rare mutations of DACT1 in human neural tube defects.
abstract: 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.
authors.affiliation: The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Lei
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Yang
authors.forename: Guo-Ming
authors.initials: GM
authors.lastname: Xie
authors.forename: Jun
authors.initials: J
authors.lastname: Wen
authors.forename: Chun-Quan
authors.initials: CQ
authors.lastname: Cai
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Ye-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D044466:Asian People; D016764:Cell Polarity / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491683:DACT1 protein, human; D009687:Nuclear Proteins