title: Mutations in the COPII vesicle component gene SEC24B are associated with human neural tube defects.
abstract: Neural tube defects (NTDs) are severe birth malformations that affect one in 1,000 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 overexpression and dosage-dependent rescue study suggested that these four mutations all displayed loss-of-function effects compared with 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 NTDs.
authors.affiliation: The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Yang
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Zhou
authors.forename: Qing Qing
authors.initials: QQ
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Yun-Ping
authors.initials: YP
authors.lastname: Lei
authors.forename: Xiao-Hang
authors.initials: XH
authors.lastname: Ma
authors.forename: Pan
authors.initials: P
authors.lastname: Kong
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.forename: Li
authors.initials: L
authors.lastname: Jin
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wang
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D016764:Cell Polarity; D005260:Female; D015870:Gene Expression; D014644:Genetic Variation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D009436:Neural Tube Defects / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017422:Sequence Analysis, DNA; D033921:Vesicular Transport Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C530639:SEC24B protein, human; C468513:VANGL2 protein, human; D033921:Vesicular Transport Proteins
keywords: NTD; SEC24B, COPII vesicle; neural tube defects