Mutations in the COPII Vesicle Component Gene SEC24B are Associated with Human Neural Tube Defects |
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Authors: | Xue‐Yan Yang Xiang‐Yu Zhou Qing Qing Wang Hong Li Ying Chen Yun‐Ping Lei Xiao‐Hang Ma Pan Kong Yan Shi Li Jin Ting Zhang Hong‐Yan Wang |
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Institution: | 1. 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;2. School of Life Sciences, Shaanxi Normal University, , Xi'an, People's Republic of China;3. The Center for Reproduction and Genetics, Suzhou Maternal‐Child Medical Center, Suzhou General Hospital, , Suzhou, People's Republic of China;4. The Capital Institute of Pediatrics, , Beijing, People's Republic of China;5. The Institutes of Biomedical Sciences, Fudan University, , Shanghai, People's Republic of China |
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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. |
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Keywords: | neural tube defects NTD SEC24B COPII vesicle |
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