| Summary: | Forkhead-box C2 (FOXC2) is a transcription factor involved in lymphatic system development. <i>FOXC2</i> mutations cause Lymphedema-distichiasis syndrome (LD). Recently, a natural antisense was identified, called lncRNA FOXC2-AS1, which increases <i>FOXC2</i> mRNA stability. No studies have evaluated <i>FOXC2</i> and FOXC2-AS1 blood expression in LD and healthy subjects. Here, we show that <i>FOXC2</i> and FOXC-AS1 expression levels were similar in both controls and patients, and a significantly higher amount of both RNAs was observed in females. A positive correlation between <i>FOXC2</i> and FOXC2-AS1 expression was found in both controls and patients, excluding those with frameshift mutations. In these patients, the FOXC2-AS1/<i>FOXC2</i> ratio was about 1:1, while it was higher in controls and patients carrying other types of mutations. The overexpression or silencing of FOXC2-AS1 determined a significant increase or reduction in FOXC2 wild-type and frameshift mutant proteins, respectively. Moreover, confocal and bioinformatic analysis revealed that these variations caused the formation of nuclear proteins aggregates also involving DNA. In conclusion, patients with frameshift mutations presented lower values of the FOXC2-AS1/<i>FOXC2</i> ratio, due to a decrease in FOXC2-AS1 expression. The imbalance between <i>FOXC2</i> mRNA and its lncRNA could represent a molecular mechanism to reduce the amount of FOXC2 misfolded proteins, protecting cells from damage.
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