Yang, X.Y., Zhou, X.Y., Wang, Q., Li, H., Chen, Y., Lei, Y.P., Ma, X.H., Kong, P., Shi, Y., Jin, L., Zhang, T., and Wang, H.Y. (2013) Mutations in the COPII Vesicle Component Gene SEC24B are Associated with Human Neural Tube Defects. Human Mutation. 34(8):1094-101.
Neural tube defects (NTDs) are severe birth malformations that affect 1 in 1000 live births. Recently, mutations in the planar cell polarity (PCP) pathway genes had been implicated in the pathogenesis of NTDs in both the mouse model and in human cohorts. Mouse models indicate that the homozygous disruption of Sec24b, which mediates the ER-to-Golgi transportation of the core PCP gene Vangl2 as a component of the COPII vesicle, will result in craniorachischisis. In this study, we found four rare missense heterozygous SEC24B mutations (p.Phe227Ser, p.Phe682Leu, p.Arg1248Gln and p.Ala1251Gly) in NTDs cases that were absent in all controls. Among them, p.Phe227Ser and p.Phe682Leu affected its protein stability and physical interaction with VANGL2. Three variants (p.Phe227Ser, p.Arg1248Gln and p.Ala1251Gly) were demonstrated to affect VANGL2 subcellular localization in cultured cells. Further functional analysis in the zebrafish including over-expression and dosage-dependent rescue study suggested that these four mutations all displayed loss-of-function effects compared to wild-type SEC24B. Our study demonstrated that functional mutations in SEC24B might contribute to the etiology of a subset of human NTDs and further expanded our knowledge of the role of PCP pathway-related genes in the pathogenesis of human neural tube defects.