Mutations in the COPII vesicle component gene SEC24B are associated with human neural tube defects

Hum Mutat. 2013 Aug;34(8):1094-101. doi: 10.1002/humu.22338. Epub 2013 May 13.


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.

Keywords: NTD; SEC24B, COPII vesicle; neural tube defects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Cell Polarity
  • Female
  • Gene Expression
  • Genetic Variation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Mice
  • Mutation, Missense*
  • Neural Tube Defects / etiology
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / pathology
  • Protein Stability
  • Protein Structure, Quaternary
  • Sequence Analysis, DNA
  • Vesicular Transport Proteins / chemistry*
  • Vesicular Transport Proteins / genetics*
  • Vesicular Transport Proteins / metabolism
  • Zebrafish / embryology
  • Zebrafish / genetics


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SEC24B protein, human
  • VANGL2 protein, human
  • Vesicular Transport Proteins