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FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function
Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342337/ https://www.ncbi.nlm.nih.gov/pubmed/27276711 http://dx.doi.org/10.18632/oncotarget.9797 |
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author | Tavian, Daniela Missaglia, Sara Maltese, Paolo E. Michelini, Sandro Fiorentino, Alessandro Ricci, Maurizio Serrani, Roberta Walter, Michael A. Bertelli, Matteo |
author_facet | Tavian, Daniela Missaglia, Sara Maltese, Paolo E. Michelini, Sandro Fiorentino, Alessandro Ricci, Maurizio Serrani, Roberta Walter, Michael A. Bertelli, Matteo |
author_sort | Tavian, Daniela |
collection | PubMed |
description | Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles in different developmental pathways and physiological processes. We previously described six unrelated families with primary lymphedema-distichiasis in which patients showed different FOXC2 mutations located outside of the forkhead domain. Of those, four were missense mutations, one a frameshift mutation, and the last a stop mutation. To assess their pathogenic potential, we have now examined the subcellular localization and the transactivation activity of the mutated FOXC2 proteins. All six FOXC2 mutant proteins were able to localize into the nucleus; however, the frameshift truncated protein appeared to be sequestered into nuclear aggregates. A reduction in the ability to activate FOXC1/FOXC2 response elements was detected in 50% of mutations, while the remaining ones caused an increase of protein transactivation activity. Our data reveal that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema. |
format | Online Article Text |
id | pubmed-5342337 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-53423372017-03-22 FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function Tavian, Daniela Missaglia, Sara Maltese, Paolo E. Michelini, Sandro Fiorentino, Alessandro Ricci, Maurizio Serrani, Roberta Walter, Michael A. Bertelli, Matteo Oncotarget Research Paper: Pathology Dominant mutations in the FOXC2 gene cause a form of lymphedema primarily of the limbs that usually develops at or after puberty. In 90-95% of patients, lymphedema is accompanied by distichiasis. FOXC2 is a member of the forkhead/winged-helix family of transcription factors and plays essential roles in different developmental pathways and physiological processes. We previously described six unrelated families with primary lymphedema-distichiasis in which patients showed different FOXC2 mutations located outside of the forkhead domain. Of those, four were missense mutations, one a frameshift mutation, and the last a stop mutation. To assess their pathogenic potential, we have now examined the subcellular localization and the transactivation activity of the mutated FOXC2 proteins. All six FOXC2 mutant proteins were able to localize into the nucleus; however, the frameshift truncated protein appeared to be sequestered into nuclear aggregates. A reduction in the ability to activate FOXC1/FOXC2 response elements was detected in 50% of mutations, while the remaining ones caused an increase of protein transactivation activity. Our data reveal that either a complete loss or a significant gain of FOXC2 function can cause a perturbation of lymphatic vessel formation leading to lymphedema. Impact Journals LLC 2016-06-02 /pmc/articles/PMC5342337/ /pubmed/27276711 http://dx.doi.org/10.18632/oncotarget.9797 Text en Copyright: © 2016 Tavian et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper: Pathology Tavian, Daniela Missaglia, Sara Maltese, Paolo E. Michelini, Sandro Fiorentino, Alessandro Ricci, Maurizio Serrani, Roberta Walter, Michael A. Bertelli, Matteo FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
title | FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
title_full | FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
title_fullStr | FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
title_full_unstemmed | FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
title_short | FOXC2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
title_sort | foxc2 disease-mutations identified in lymphedema-distichiasis patients cause both loss and gain of protein function |
topic | Research Paper: Pathology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342337/ https://www.ncbi.nlm.nih.gov/pubmed/27276711 http://dx.doi.org/10.18632/oncotarget.9797 |
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