Mutations in the COPII Vesicle Component Gene SEC24B are Associated with Human Neural Tube Defects

Authors

  • Xue-Yan Yang,

    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
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Xiang-Yu Zhou,

    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
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Qing Qing Wang,

    Corresponding author
    1. School of Life Sciences, Shaanxi Normal University, Xi'an, People's Republic of China
    • Correspondence to: Hong-Yan Wang, School of Life Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, People's Republic of China. E-mail: wanghy@fudan.edu.cn or Dr. Ting Zhang Department of Molecular Immunology the Capital Institute of Pediatrics, Beijing 100020, People's Republic of China. E-mail: zhangtingcv@yahoo.com.cn

    Search for more papers by this author
    • These authors contributed equally to this work.

  • Hong Li,

    1. The Center for Reproduction and Genetics, Suzhou Maternal-Child Medical Center, Suzhou General Hospital, Suzhou, People's Republic of China
    Search for more papers by this author
  • Ying Chen,

    1. The Center for Reproduction and Genetics, Suzhou Maternal-Child Medical Center, Suzhou General Hospital, Suzhou, People's Republic of China
    Search for more papers by this author
  • Yun-Ping Lei,

    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
    Search for more papers by this author
  • Xiao-Hang Ma,

    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
    Search for more papers by this author
  • Pan Kong,

    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
    Search for more papers by this author
  • Yan Shi,

    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
    Search for more papers by this author
  • Li Jin,

    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
    Search for more papers by this author
  • Ting Zhang,

    Corresponding author
    1. The Capital Institute of Pediatrics, Beijing, People's Republic of China
    • Correspondence to: Hong-Yan Wang, School of Life Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, People's Republic of China. E-mail: wanghy@fudan.edu.cn or Dr. Ting Zhang Department of Molecular Immunology the Capital Institute of Pediatrics, Beijing 100020, People's Republic of China. E-mail: zhangtingcv@yahoo.com.cn

    Search for more papers by this author
  • Hong-Yan Wang

    Corresponding author
    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. The Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
    • Correspondence to: Hong-Yan Wang, School of Life Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, People's Republic of China. E-mail: wanghy@fudan.edu.cn or Dr. Ting Zhang Department of Molecular Immunology the Capital Institute of Pediatrics, Beijing 100020, People's Republic of China. E-mail: zhangtingcv@yahoo.com.cn

    Search for more papers by this author

  • Contract grant sponsors: National Science Fund for Distinguished Young Scholars (81025003); the 973 Program (2010CB529601, 2013CB945403, 2012CB944604); the Program for Innovative Research Team in University (IRT1010); Doctoral Fund of Ministry of Education of China (20110071110026); the Commission for Science and Technology of Shanghai Municipality (10JC1401300, 11XD1400900); National Natural Science Foundation of China (31000542); Scientific Research Foundation for Returned Scholars, Ministry of Education of China.

  • Communicated by Hamish S. Scott

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.

Ancillary