{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T14:30:08Z","timestamp":1776781808689,"version":"3.51.2"},"reference-count":29,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T00:00:00Z","timestamp":1619481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009890","name":"Provincia Autonoma di Trento","doi-asserted-by":"publisher","award":["LP6\/99 (dpg 1045\/2017)"],"award-info":[{"award-number":["LP6\/99 (dpg 1045\/2017)"]}],"id":[{"id":"10.13039\/501100009890","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MIUR\/PRIN 2017","award":["2017A5TXC3"],"award-info":[{"award-number":["2017A5TXC3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Forkhead-box C2 (FOXC2) is a transcription factor involved in lymphatic system development. FOXC2 mutations cause Lymphedema-distichiasis syndrome (LD). Recently, a natural antisense was identified, called lncRNA FOXC2-AS1, which increases FOXC2 mRNA stability. No studies have evaluated FOXC2 and FOXC2-AS1 blood expression in LD and healthy subjects. Here, we show that FOXC2 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 FOXC2 and FOXC2-AS1 expression was found in both controls and patients, excluding those with frameshift mutations. In these patients, the FOXC2-AS1\/FOXC2 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\/FOXC2 ratio, due to a decrease in FOXC2-AS1 expression. The imbalance between FOXC2 mRNA and its lncRNA could represent a molecular mechanism to reduce the amount of FOXC2 misfolded proteins, protecting cells from damage.<\/jats:p>","DOI":"10.3390\/genes12050650","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T06:19:11Z","timestamp":1619504351000},"page":"650","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Imbalance between Expression of FOXC2 and Its lncRNA in Lymphedema-Distichiasis Caused by Frameshift Mutations"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6551-6698","authenticated-orcid":false,"given":"Sara","family":"Missaglia","sequence":"first","affiliation":[{"name":"Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Universit\u00e0 Cattolica del Sacro Cuore, 20145 Milan, Italy"},{"name":"Psychology Department, Universit\u00e0 Cattolica del Sacro Cuore, 20123 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-0068","authenticated-orcid":false,"given":"Daniela","family":"Tavian","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular Biochemistry and Molecular Biology, CRIBENS, Universit\u00e0 Cattolica del Sacro Cuore, 20145 Milan, Italy"},{"name":"Psychology Department, Universit\u00e0 Cattolica del Sacro Cuore, 20123 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-2270","authenticated-orcid":false,"given":"Sandro","family":"Michelini","sequence":"additional","affiliation":[{"name":"Vascular Diagnostics and Rehabilitation Service, Marino Hospital, ASL Roma 6, 00047 Marino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-4937","authenticated-orcid":false,"given":"Paolo Enrico","family":"Maltese","sequence":"additional","affiliation":[{"name":"MAGI\u2019S Lab, 38068 Rovereto, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2857-1430","authenticated-orcid":false,"given":"Andrea","family":"Bonanomi","sequence":"additional","affiliation":[{"name":"Department of Statistical Sciences, Universit\u00e0 Cattolica del Sacro Cuore, 20123 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9552-221X","authenticated-orcid":false,"given":"Matteo","family":"Bertelli","sequence":"additional","affiliation":[{"name":"MAGI\u2019S Lab, 38068 Rovereto, Italy"},{"name":"MAGI Euregio, 39100 Bolzano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1046\/j.1365-2133.2000.03258.x","article-title":"Distichiasis-lymphoedema: Clinical features, venous function and lymphoscintigraphy","volume":"142","author":"Rosbotham","year":"2000","journal-title":"Br. J. Dermatol."},{"key":"ref_2","unstructured":"Adam, M.P., Ardinger, H.H., and Pagon, R.A. (2019). Lymphedema-Distichiasis Syndrome. GeneReviews, University of Washington."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1136\/jmg.38.11.761","article-title":"Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations","volume":"38","author":"Erickson","year":"2001","journal-title":"J. Med. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1136\/jmg.39.7.478","article-title":"Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24","volume":"39","author":"Brice","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_5","first-page":"238","article-title":"Lymphoedema-distichiasis and FOXC2: Unreported mutations, de novo mutation estimate, families without coding mutations","volume":"117","author":"Bell","year":"2005","journal-title":"Qual. Life Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrc3539","article-title":"Forkhead box proteins: Tuning forks for transcriptional harmony","volume":"13","author":"Lam","year":"2013","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18318","DOI":"10.1074\/jbc.M112.339424","article-title":"Small Ubiquitin-like Modifier (SUMO) Modification Mediates Function of the Inhibitory Domains of Developmental Regulators FOXC1 and FOXC2","volume":"287","author":"Danciu","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.1128\/MCB.01387-12","article-title":"Phosphorylation Regulates FOXC2-Mediated Transcription in Lymphatic Endothelial Cells","volume":"33","author":"Ivanov","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E1002","DOI":"10.1002\/humu.21127","article-title":"Novel missense mutations in theFOXC2gene alter transcriptional activity","volume":"30","author":"Damstra","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"54228","DOI":"10.18632\/oncotarget.9797","article-title":"FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function","volume":"7","author":"Tavian","year":"2016","journal-title":"Oncotarget"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1093\/hmg\/ddi295","article-title":"The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis","volume":"14","author":"Berry","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.canlet.2017.03.018","article-title":"Antisense lncRNA FOXC2-AS1 promotes doxorubicin resistance in osteosarcoma by increasing the expression of FOXC2","volume":"396","author":"Zhang","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_13","first-page":"3","article-title":"Clinical and genetic study of 46 Italian patients with primary lymphedema","volume":"45","author":"Michelini","year":"2012","journal-title":"Lymphology"},{"key":"ref_14","first-page":"57","article-title":"Genetic Screening in a Large Cohort of Italian Patients Affected by Primary Lymphedema Using a Next Generation Sequencing (NGS) Approach","volume":"49","author":"Michelini","year":"2016","journal-title":"Lymphology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.gendis.2019.07.006","article-title":"A novel PNPLA2 mutation causing total loss of RNA and protein expression in two NLSDM siblings with early onset but slowly progressive severe myopathy","volume":"8","author":"Tavian","year":"2019","journal-title":"Genes Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Wang, Z., Fu, C., Chen, Y., Xu, F., Wang, Z., Qu, Z., and Liu, Y. (2016). FoxC2 Enhances BMP7-Mediated Anabolism in Nucleus Pulposus Cells of the Intervertebral Disc. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0147764"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"635","DOI":"10.3892\/ol.2017.6244","article-title":"Expression of FOXC2, PinX1, Ki-67 and Cyclin D1 in cutaneous cell carcinoma","volume":"14","author":"Zhao","year":"2017","journal-title":"Oncol. Lett."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Tavian, D., Missaglia, S., Michelini, S., Maltese, P.E., Manara, E., Mordente, A., and Bertelli, M. (2020). FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145112"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1097\/MOL.0000000000000536","article-title":"Sex differences in metabolism and cardiometabolic disorders","volume":"29","author":"Krishnan","year":"2018","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11892-018-1031-3","article-title":"Gender and Sex Differences in Adipose Tissue","volume":"18","author":"Chang","year":"2018","journal-title":"Curr. Diabetes Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13919","DOI":"10.1038\/s41598-018-32154-2","article-title":"Regional Differences in mRNA and lncRNA Expression Profiles in Non-Failing Human Atria and Ventricles","volume":"8","author":"Johnson","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e03897","DOI":"10.1016\/j.heliyon.2020.e03897","article-title":"Sex-specific up-regulation of p50-associated COX-2 extragenic RNA (PACER) lncRNA in periodontitis","volume":"6","author":"Sayad","year":"2020","journal-title":"Heliyon"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.7150\/ijbs.13774","article-title":"Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation","volume":"12","author":"Zhang","year":"2016","journal-title":"Int. J. Biol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1080\/15476286.2017.1358347","article-title":"The long noncoding RNA Malat1: Its physiological and pathophysiological functions","volume":"14","author":"Zhang","year":"2017","journal-title":"RNA Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40246-017-0113-7","article-title":"Long non-coding RNAs as novel players in \u03b2 cell function and type 1 diabetes","volume":"11","author":"Mirza","year":"2017","journal-title":"Hum. Genom."},{"key":"ref_26","first-page":"1","article-title":"Long Noncoding RNAs CARMN, LUCAT1, SMILR, and MALAT1 in Thoracic Aortic Aneurysm: Validation of Biomarkers in Clinical Samples","volume":"2020","author":"Benetis","year":"2020","journal-title":"Dis. Markers"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-018-04130-x","article-title":"Theoretical principles of transcription factor traffic on folded chromatin","volume":"9","author":"Cortini","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3752","DOI":"10.1093\/nar\/gkz077","article-title":"Structural basis for DNA recognition by FOXC2","volume":"47","author":"Chen","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10906","DOI":"10.1021\/acsomega.9b00756","article-title":"Crystal Structure of FOXC2 in Complex with DNA Target","volume":"4","author":"Li","year":"2019","journal-title":"ACS Omega"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/5\/650\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:53:13Z","timestamp":1760161993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/5\/650"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":29,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["genes12050650"],"URL":"https:\/\/doi.org\/10.3390\/genes12050650","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,27]]}}}