{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T14:57:12Z","timestamp":1789570632599,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T00:00:00Z","timestamp":1595203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MIUR\/PRIN","award":["n. 2017A5TXC3"],"award-info":[{"award-number":["n. 2017A5TXC3"]}]},{"name":"Provincia Autonoma di Trento under initiative LP6\/99","award":["dpg 1045\/2017"],"award-info":[{"award-number":["dpg 1045\/2017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>FOXC2 is a member of the human forkhead-box gene family and encodes a regulatory transcription factor. Mutations in FOXC2 have been associated with lymphedema distichiasis (LD), an autosomal dominant disorder that primarily affects the limbs. Most patients also show extra eyelashes, a condition known as distichiasis. We previously reported genetic and clinical findings in six unrelated families with LD. Half the patients showed missense mutations, two carried frameshift mutations and a stop mutation was identified in a last patient. Here we analyzed the subcellular localization and transactivation activity of the mutant proteins, showing that all but one (p.Y109*) localized to the nucleus. A significant reduction of transactivation activity was observed in four mutants (p.L80F, p.H199Pfs*264, p.I213Tfs*18, p.Y109*) compared with wild type FOXC2 protein, while only a partial loss of function was associated with p.V228M. The mutant p.I213V showed a very slight increase of transactivation activity. Finally, immunofluorescence analysis revealed that some mutants were sequestered into nuclear aggregates and caused a reduction of cell viability. This study offers new insights into the effect of FOXC2 mutations on protein function and shows the involvement of aberrant aggregation of FOXC2 proteins in cell death.<\/jats:p>","DOI":"10.3390\/ijms21145112","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T06:08:17Z","timestamp":1595225297000},"page":"5112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-0068","authenticated-orcid":false,"given":"Daniela","family":"Tavian","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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6551-6698","authenticated-orcid":false,"given":"Sara","family":"Missaglia","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":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Michelini","sequence":"additional","affiliation":[{"name":"Department of Vascular Rehabilitation, San Giovanni Battista Hospital, 00148 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Enrico","family":"Maltese","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, International Association of Medical Genetics, MAGI\u2019s Lab s.r.l., 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1176-3359","authenticated-orcid":false,"given":"Elena","family":"Manara","sequence":"additional","affiliation":[{"name":"MAGI EUREGIO, 39100 Bolzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvaro","family":"Mordente","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze di Laboratorio ed Infettivologiche, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy"},{"name":"Facolt\u00e0 di Scienze della Formazione, Universit\u00e0 Cattolica del Sacro Cuore, 20123 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Bertelli","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics, International Association of Medical Genetics, MAGI\u2019s Lab s.r.l., 38068 Rovereto, Italy"},{"name":"MAGI EUREGIO, 39100 Bolzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1086\/316915","article-title":"Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary Lymphedema-Distichiasis Syndrome","volume":"67","author":"Fang","year":"2000","journal-title":"Am. J. Hum. 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