Abstract
Congenital Zika Syndrome (CZS) occurs in up to 42% of individuals exposed to ZIKV prenatally. Deregulation in gene expression and protein levels of components of the p53 signaling pathway, such as p53 and MDM2, due to ZIKV infection has been reported. Here, we evaluate functional polymorphisms in genes of the p53 signaling pathway as risk factors to CZS. Forty children born with CZS and forty-eight children exposed to ZIKV, but born without congenital anomalies were included in this study. Gestational and sociodemographic information as well as the genotypic and allelic frequencies of functional polymorphisms in TP53, MDM2, MIR605 and LIF genes were compared between the two groups. We found children with CZS exposed predominantly in the first trimester and controls in the third trimester (p<0.001). Moreover, children with CZS were predominantly from families with a lower socioeconomic level (p=0.008). We did not find a statistically significant association between the investigated polymorphisms and development of CZS; however, by comparing individuals with CZS and lissencephaly or without lissencephaly, we found a significative difference in the allelic frequencies of the TP53 rs1042522, which is associated with a more potent p53-induced apoptosis (p=0.007). Our findings suggest that the TP53 rs1042522 polymorphism should be better investigate as a genetic risk factor for the development of lissencephaly in children with CZS.
Highlights
Zika virus (ZIKV) is a human teratogen that infects neural cells of children exposed during pregnancy and causes a spectrum of multiple congenital anomalies named Congenital Zika Syndrome (CZS), which includes microcephaly, brain calcifications, lissencephaly, ventriculomegaly, ocular alterations, among others
Based on previous evidence of differential susceptibility to ZIKV teratogenesis in humans, as well as possible involvement of the p53 signaling pathway in this outcome, we investigated the role of functional single nucleotide variants (SNVs) in genes of the p53 signaling pathway as potential susceptibility factors to CZS in a sample of Brazilian children exposed to ZIKV during pregnancy
In order to better understand the effect of ZIKV infection on the gene expression of TP53, MDM2, MIR605 and LIF, the expression data of human neuroprogenitor cells exposed and not exposed to ZIKV were evaluated
Summary
Zika virus (ZIKV) is a human teratogen that infects neural cells of children exposed during pregnancy and causes a spectrum of multiple congenital anomalies named Congenital Zika Syndrome (CZS), which includes microcephaly, brain calcifications, lissencephaly, ventriculomegaly, ocular alterations, among others (del Campo et al, 2017). In silico and in vitro studies have shown that the p53 protein, encoded by the TP53 gene, is differentially expressed in human neuroprogenitor cells (hNPCs) during ZIKV infection (El Ghouzzi et al, 2016; Zhang et al, 2016). It was demonstrated that increased p53 activity leads to an increased death rate of neural cells due to the binding of the ZIKV capsid protein to MDM2 protein, decreasing its activity as one of the main p53 negative regulators (Teng et al, 2017). We evaluated the impact of ZIKV infection on the expression of genes of this pathway in neuroprogenitor cells, the main targets of ZIKV in the developing brain
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