2. Academic Validation
  3. 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

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.
Xiaoli Chen 1,  Yu An 2,  Yonghui Gao 1 3,  Liu Guo 4,  Lei Rui 5,  Hua Xie 1,  Mei Sun 6,  Siv Lam Hung 7,  Xiaoming Sheng 7,  Jizhen Zou 8,  Yihua Bao 1,  Hongyan Guan 9,  Bo Niu 10,  Zandong Li 5,  Richard H Finnell 11,  James F Gusella 6 12,  Bai-Lin Wu 2 7,  Ting Zhang 1
Affiliations

Affiliations

  • 1 Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
  • 2 Children's Hospital of Fudan University and Institutes of Biomedical Science, Shanghai Medical College of Fudan University, Shanghai, China.
  • 3 Institute of Acu-moxibustion, China Academy of Chinese Medical Sciences, Beijing, China.
  • 4 Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.
  • 5 State Key Laboratories for Agrobiotechnology, China Agricultural University, Beijing, China.
  • 6 Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
  • 7 Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
  • 8 Department of Pathology, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.
  • 9 Department of Integrated Early Childhood Development, Capital Institute of Pediatrics, Beijing, China.
  • 10 Department of Biotechnology, Capital Institute of Pediatrics, Beijing, China.
  • 11 Dell Pediatric Research Institute, Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas.
  • 12 Department of Genetics, Harvard Medical School, Boston, Massachusetts.
PMID: 27925688 DOI: 10.1002/humu.23153
Abstract

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.

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