Association Study of PARD3 Gene Polymorphisms With Neural Tube Defects in a Chinese Han Population

Gao, Yonghui; Chen, Xiaoli; Shangguan, Shaofang; Bao, Yihua; Lü, Xiaolin; Zou, Jizhen; Guo, Jin; Dai, Yaohua; Zhang, Ting

doi:10.1177/1933719111433886

Cited by 9 publications

(14 citation statements)

References 36 publications

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“…Previous studies supported that low folate levels, and polymorphism of folate-metabolic genes were risk factors for NTDs in this region [58], [59], [60]. Genes regulating early embryonic development were also identified as risk factors of NTDs in this region [61], [62], [63]. The significant involvement of copy number variants in NTD revealed by this study further suggests the complex genetic heterogeneity underlying NTD pathogenesis in the Shanxi region.…”

Section: Discussionsupporting

confidence: 77%

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

et al. 2013

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BackgroundNeural tube defects (NTDs) are one of the most common birth defects caused by a combination of genetic and environmental factors. Currently, little is known about the genetic basis of NTDs although up to 70% of human NTDs were reported to be attributed to genetic factors. Here we performed genome-wide copy number variants (CNVs) detection in a cohort of Chinese NTD patients in order to exam the potential role of CNVs in the pathogenesis of NTDs.MethodsThe genomic DNA from eighty-five NTD cases and seventy-five matched normal controls were subjected for whole genome CNVs analysis. Non-DGV (the Database of Genomic Variants) CNVs from each group were further analyzed for their associations with NTDs. Gene content in non-DGV CNVs as well as participating pathways were examined.ResultsFifty-five and twenty-six non-DGV CNVs were detected in cases and controls respectively. Among them, forty and nineteen CNVs involve genes (genic CNV). Significantly more non-DGV CNVs and non-DGV genic CNVs were detected in NTD patients than in control (41.2% vs. 25.3%, p<0.05 and 37.6% vs. 20%, p<0.05). Non-DGV genic CNVs are associated with a 2.65-fold increased risk for NTDs (95% CI: 1.24–5.87). Interestingly, there are 41 cilia genes involved in non-DGV CNVs from NTD patients which is significantly enriched in cases compared with that in controls (24.7% vs. 9.3%, p<0.05), corresponding with a 3.19-fold increased risk for NTDs (95% CI: 1.27–8.01). Pathway analyses further suggested that two ciliogenesis pathways, tight junction and protein kinase A signaling, are top canonical pathways implicated in NTD-specific CNVs, and these two novel pathways interact with known NTD pathways.ConclusionsEvidence from the genome-wide CNV study suggests that genic CNVs, particularly ciliogenic CNVs are associated with NTDs and two ciliogenesis pathways, tight junction and protein kinase A signaling, are potential pathways involved in NTD pathogenesis.

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Section: Discussionsupporting

confidence: 77%

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

et al. 2013

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“…Previous genotyping of 53 tag PARD3 SNPs had confirmed that subjects in this cohort represent the same Chinese ethnic group [Gao, et al., ]. After removing any questionable sequencing data and common variants, a total of 60 rare PARD3 variants including synonymous, missense, and splicing variants remained for comparison (Supp.…”

Section: Resultsmentioning

confidence: 87%

“…In humans, PARD3 (MIM# 606745) intragenic microdeletions and missense mutations have been identified at high frequency in human epithelial cancer cell lines [Rothenberg, et al., ]. We previously reported a significant association between common SNPs of PARD3 (rs2496720, rs2252655, rs3851068, and rs118153230) and NTDs, and this association was more significant for cranial rather than spinal defects [Gao, et al., ]. Given the importance of PARD3 in neuroepithelial morphology, we hypothesized that rare PARD3 genomic variants are risk factors for human cranial NTDs.…”

Section: Introductionmentioning

confidence: 99%

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

Chen

Gao

et al. 2017

Human Mutation

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Increasing evidence that mutation of planar cell polarity (PCP) genes contributes to human cranial 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.

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“…In the vertebrate embryo, there are two types of neuroepithelial cell division, i.e., apicobasal and planar cell divisions [23]. The development of cell polarity plays a crucial role in the process of neurulation, being implied in the neural tube closure [23]. Neurulation represents the process of neural tube formation during early embryogenesis.…”

Section: R J M Ementioning

confidence: 99%

The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature

Munteanu

Cîrstoiu²,

Filipoiu

et al. 2020

Rom J Morphol Embryol

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Anencephaly is a severe malformation of the central nervous system (CNS), being one of the most common types of neural tube defects. It is defined as total or partial absence of the calvarium , with absence of the brain. Anencephaly has an incidence of 1 to 5 in every 1000 births, and the mortality rate is 100% during intrauterine life or within hours or days after birth. The etiology of anencephaly remains unclear, but various maternal-related environmental and genetic risk factors have been reported, which include diabetes, obesity, exposure to different drugs or toxins, genetic polymorphisms and mutations, as well as positive family history for neural tube defects. One of the most important nutritional factors in the development of anencephaly is folate deficiency. Methylenetetrahydrofolate reductase ( MTHFR ) gene codes the enzyme involved in the intracellular metabolism of folic acid; the 677C-T polymorphism of this gene causes the thermolability of the enzyme and decreased enzymatic activity, which is also dependent of folate plasmatic level. Etiopathogenesis of anencephaly includes several mutations in various other genes, such as: platelet-derived growth factor receptor alpha ( PDGFRA ), cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptor 1 ( CELSR1 ), Vang-like 1 ( VANGL1 ) and Vang-like 2 ( VANGL2 ), the last two being involved in the process of neurulation. Screening tests include maternal serum alpha-fetoprotein level and ultrasound (US) examination. During the first trimester US screening, anencephaly is now detected in all cases, but in order to decrease the complication rate of pregnancy termination, the diagnosis should be established as soon as possible, during the pregnancy confirmation US. We conclude that given that anencephaly is a severe malformation of the CNS, morphological characterization could improve the screening by US that is mandatory in the first trimester in order to plan the best, safe and early management.

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Association Study of PARD3 Gene Polymorphisms With Neural Tube Defects in a Chinese Han Population

Cited by 9 publications

References 36 publications

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

Detection of Copy Number Variants Reveals Association of Cilia Genes with Neural Tube Defects

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

The etiopathogenic and morphological spectrum of anencephaly: a comprehensive review of literature

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