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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...

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Autores principales: Tavian, Daniela, Missaglia, Sara, Maltese, Paolo E., Michelini, Sandro, Fiorentino, Alessandro, Ricci, Maurizio, Serrani, Roberta, Walter, Michael A., Bertelli, Matteo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2016
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.
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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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