Rare Deleterious PARD3 Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

Hum Mutat. 2017 Apr;38(4):378-389. doi: 10.1002/humu.23153. Epub 2017 Feb 15.


Increasing evidence that mutation of planar cell polarity (PCP) genes contributes to human cranial neural tube defect (NTD) susceptibility prompted us to hypothesize that rare variants of genes in the core apical-basal polarity (ABP) pathway are risk factors for cranial NTDs. In this study, we screened for rare genomic variation of PARD3 in 138 cranial NTD cases and 274 controls. Overall, the rare deleterious variants of PARD3 were significantly associated with increased risk for cranial NTDs (11/138 vs.7/274, P < 0.05, OR = 3.3). These NTD-specific variants were significantly enriched in the aPKC-binding region (6/138 vs. 0/274, P < 0.01). The East Asian cohort in the ExAC database and another Chinese normal cohort further supported this association. Over-expression analysis in HEK293T and MDCK cells confirmed abnormal aPKC binding or interaction for two PARD3 variants (p.P913Q and p.D783G), resulting in defective tight junction formation via disrupted aPKC binding. Functional analysis in human neural progenitor cells and chick embryos revealed that PARD3 knockdown gave rise to abnormal cell polarity and compromised the polarization process of neuroepithelial tissue. Our studies suggest that rare deleterious variants of PARD3 in the aPKC-binding region contribute to human cranial NTDs, possibly by disrupting apical tight junction formation and subsequent polarization process of the neuroepithelium.

Keywords: PARD3; apical tight junction formation; cranial NTDs; rare deleterious variants.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Asian Continental Ancestry Group / genetics
  • Body Patterning / genetics
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Chick Embryo
  • China
  • Cohort Studies
  • Dogs
  • HEK293 Cells
  • Humans
  • Madin Darby Canine Kidney Cells
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation*
  • Neural Tube Defects / ethnology
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / metabolism
  • Protein Binding
  • Protein Kinase C / metabolism*
  • RNA Interference
  • Tight Junctions / metabolism*
  • Tight Junctions / pathology


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Membrane Proteins
  • PARD3 protein, human
  • PKC-3 protein
  • Protein Kinase C