Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations
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....
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MDPI AG
2021-04-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/12/5/650 |
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| author | Sara Missaglia Daniela Tavian Sandro Michelini Paolo Enrico Maltese Andrea Bonanomi Matteo Bertelli |
| author_facet | Sara Missaglia Daniela Tavian Sandro Michelini Paolo Enrico Maltese Andrea Bonanomi Matteo Bertelli |
| author_sort | Sara Missaglia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T11:56:27Z |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T11:56:27Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-eb7efa2c6d4c4cefb69030132f2f1a9c2023-11-21T17:19:25ZengMDPI AGGenes2073-44252021-04-0112565010.3390/genes12050650Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift MutationsSara Missaglia0Daniela Tavian1Sandro Michelini2Paolo Enrico Maltese3Andrea Bonanomi4Matteo Bertelli5Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Università Cattolica del Sacro Cuore, 20145 Milan, ItalyLaboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Università Cattolica del Sacro Cuore, 20145 Milan, ItalyVascular Diagnostics and Rehabilitation Service, Marino Hospital, ASL Roma 6, 00047 Marino, ItalyMAGI’S Lab, 38068 Rovereto, ItalyDepartment of Statistical Sciences, Università Cattolica del Sacro Cuore, 20123 Milan, ItalyMAGI’S Lab, 38068 Rovereto, ItalyForkhead-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.https://www.mdpi.com/2073-4425/12/5/650Lymphedema-distichiasis syndromeFOXC2lncRNA FOXC2-AS1gene expressionconfocal analysisnuclear aggregates |
| spellingShingle | Sara Missaglia Daniela Tavian Sandro Michelini Paolo Enrico Maltese Andrea Bonanomi Matteo Bertelli Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations Genes Lymphedema-distichiasis syndrome FOXC2 lncRNA FOXC2-AS1 gene expression confocal analysis nuclear aggregates |
| title | Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations |
| title_full | Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations |
| title_fullStr | Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations |
| title_full_unstemmed | Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations |
| title_short | Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations |
| title_sort | imbalance between expression of foxc2 and its lncrna in lymphedema distichiasis caused by frameshift mutations |
| topic | Lymphedema-distichiasis syndrome FOXC2 lncRNA FOXC2-AS1 gene expression confocal analysis nuclear aggregates |
| url | https://www.mdpi.com/2073-4425/12/5/650 |
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