title: 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.
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.
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Chen
authors.affiliation: Children's Hospital of Fudan University and Institutes of Biomedical Science, Shanghai Medical College of Fudan University, Shanghai, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: An
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.|Institute of Acu-moxibustion, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Neurology, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Guo
authors.affiliation: State Key Laboratories for Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Rui
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Mei
authors.initials: M
authors.lastname: Sun
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Siv
authors.initials: S
authors.lastname: Lam Hung
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Pathology, Affiliated Children's Hospital of Capital Institute of Pediatrics, Beijing, China.
authors.forename: Jizhen
authors.initials: J
authors.lastname: Zou
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Integrated Early Childhood Development, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Biotechnology, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Niu
authors.affiliation: State Key Laboratories for Agrobiotechnology, China Agricultural University, Beijing, China.
authors.forename: Zandong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Dell Pediatric Research Institute, Department of Nutritional Sciences, The University of Texas at Austin, Austin, Texas.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts.|Department of Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Children's Hospital of Fudan University and Institutes of Biomedical Science, Shanghai Medical College of Fudan University, Shanghai, China.|Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bai-Lin
authors.initials: BL
authors.lastname: Wu
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D044466:Asian People / Q000235:genetics; D019521:Body Patterning / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002642:Chick Embryo; D002681:China; D015331:Cohort Studies; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009436:Neural Tube Defects / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D034622:RNA Interference; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; C509689:PARD3 protein, human; C115015:PKC-3 protein; D011493:Protein Kinase C
keywords: PARD3; apical tight junction formation; cranial NTDs; rare deleterious variants