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FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation

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 know...

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Autores principales: Tavian, Daniela, Missaglia, Sara, Michelini, Sandro, Maltese, Paolo Enrico, Manara, Elena, Mordente, Alvaro, Bertelli, Matteo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404146/
https://www.ncbi.nlm.nih.gov/pubmed/32698337
http://dx.doi.org/10.3390/ijms21145112
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author Tavian, Daniela
Missaglia, Sara
Michelini, Sandro
Maltese, Paolo Enrico
Manara, Elena
Mordente, Alvaro
Bertelli, Matteo
author_facet Tavian, Daniela
Missaglia, Sara
Michelini, Sandro
Maltese, Paolo Enrico
Manara, Elena
Mordente, Alvaro
Bertelli, Matteo
author_sort Tavian, Daniela
collection PubMed
description 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.
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spelling pubmed-74041462020-08-11 FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation Tavian, Daniela Missaglia, Sara Michelini, Sandro Maltese, Paolo Enrico Manara, Elena Mordente, Alvaro Bertelli, Matteo Int J Mol Sci Article 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. MDPI 2020-07-20 /pmc/articles/PMC7404146/ /pubmed/32698337 http://dx.doi.org/10.3390/ijms21145112 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tavian, Daniela
Missaglia, Sara
Michelini, Sandro
Maltese, Paolo Enrico
Manara, Elena
Mordente, Alvaro
Bertelli, Matteo
FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation
title FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation
title_full FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation
title_fullStr FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation
title_full_unstemmed FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation
title_short FOXC2 Disease Mutations Identified in Lymphedema Distichiasis Patients Impair Transcriptional Activity and Cell Proliferation
title_sort foxc2 disease mutations identified in lymphedema distichiasis patients impair transcriptional activity and cell proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404146/
https://www.ncbi.nlm.nih.gov/pubmed/32698337
http://dx.doi.org/10.3390/ijms21145112
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