Abstract
Background and Objective: Although Down syndrome is the most frequent aneuploidy, its pathogenic molecular mechanisms are not yet fully understood. The aim of our study is to quantify—by qRT-PCR—the expression levels of both the mature forms and the pri-miRNAs of the microRNAs resident on chromosome 21 (miR(21)) in the amniotic fluid samples from Down syndrome singleton pregnancies and to estimate the impact of the differentially expressed microRNAs on Down syndrome fetal heart and amniocytes transcriptomes. Materials and methods: We collected amniotic fluid samples harvested by trained obstetricians as part of the second trimester screening/diagnostic procedure for aneuploidies to assess the trisomy 21 status by QF-PCR and karyotyping. Next, we evaluated—by Taqman qRT-PCR—the expression levels of both the mature forms and the pri-miRNA precursors of the microRNAs resident on chromosome 21 in amniotic fluid samples from singleton Down syndrome and euploid pregnancies. Further, we combined miRWalk 3.0 microRNA target prediction with GEO DataSets analysis to estimate the impact of hsa-miR-99a abnormal expression on Down syndrome heart and amniocytes transcriptome. Results: We found a statistically significant up-regulation of the mature form of miR-99a, but not pri-miR-99a, in the amniotic fluid samples from Down syndrome pregnancies with female fetuses. GATHER functional enrichment analysis of miRWalk3.0-predicted targets from Down syndrome amniocytes and fetal hearts transcriptome GEODataSets outlined both focal adhesion and cytokine–cytokine receptor interaction signaling as novel signaling pathways impacted by miR-99a and associated with cardiac defects in female Down syndrome patients. Conclusions: The significant overexpression of miR-99a, but not pri-miR-99a, points towards an alteration of the post-transcriptional mechanisms of hsa-miR-99a maturation and/or stability in the female trisomic milieu, with a potential impact on signaling pathways important for proper development of the heart.
Highlights
Down syndrome (DS) represents the most common aneuploidy in humans, with an overall incidence of 1/650–1000 live births and a pregnancy loss rate of only 30% between 12–40 weeks of gestation
In line with previous data, our analysis shows a significant enrichment in mature miR-99a in amniotic fluid (AF) samples from DS female fetus pregnancies, raising the question whether it could serve as biomarker for congenital heart defects (CHD) [25]
Partially overlapping steps controlled by an evolutionary conserved network of signaling pathways and transcriptional regulators, among which microRNAs in general play important roles [32]. miR-99a is a member of the miR-99 family of evolutionary conserved microRNAs, known for their role in cardiomyogenesis, heart regeneration, cardiac hypertrophy and post-infarction cardiac remodeling [26,33,34,35,36]
Summary
Down syndrome (DS) represents the most common aneuploidy in humans, with an overall incidence of 1/650–1000 live births and a pregnancy loss rate of only 30% between 12–40 weeks of gestation. The aim of our study is to quantify—by qRT-PCR—the expression levels of both the mature forms and the pri-miRNAs of the microRNAs resident on chromosome 21 (miR(21)) in the amniotic fluid samples from Down syndrome singleton pregnancies and to estimate the impact of the differentially expressed microRNAs on Down syndrome fetal heart and amniocytes transcriptomes. We evaluated—by Taqman qRT-PCR—the expression levels of both the mature forms and the pri-miRNA precursors of the microRNAs resident on chromosome 21 in amniotic fluid samples from singleton. We combined miRWalk 3.0 microRNA target prediction with GEO DataSets analysis to estimate the impact of hsa-miR-99a abnormal expression on Down syndrome heart and amniocytes transcriptome. GATHER functional enrichment analysis of miRWalk3.0-predicted targets from Down syndrome amniocytes and fetal hearts transcriptome
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