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A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome

We describe a fatal case of pediatric systemic capillary leak (Clarkson’s disease) associated with a point mutation in p190BRhoGAP. Dermal microvascular endothelial cells (ECs) isolated from this patient form monolayers with similar levels and distribution of junctional proteins and transendothelial...

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Autores principales: Pierce, Richard W., Merola, Jonathan, Lavik, John Paul, Kluger, Martin S., Huttner, Anita, Khokha, Mustafa K., Pober, Jordan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716031/
https://www.ncbi.nlm.nih.gov/pubmed/29097442
http://dx.doi.org/10.1084/jem.20162143
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author Pierce, Richard W.
Merola, Jonathan
Lavik, John Paul
Kluger, Martin S.
Huttner, Anita
Khokha, Mustafa K.
Pober, Jordan S.
author_facet Pierce, Richard W.
Merola, Jonathan
Lavik, John Paul
Kluger, Martin S.
Huttner, Anita
Khokha, Mustafa K.
Pober, Jordan S.
author_sort Pierce, Richard W.
collection PubMed
description We describe a fatal case of pediatric systemic capillary leak (Clarkson’s disease) associated with a point mutation in p190BRhoGAP. Dermal microvascular endothelial cells (ECs) isolated from this patient form monolayers with similar levels and distribution of junctional proteins and transendothelial electrical resistance compared with normal human dermal microvascular ECs. However, patient-derived ECs demonstrate a greater increase in permeability and impaired recovery of barrier function in response to tumor necrosis factor (TNF) compared with normal donor EC cultures. TNF transiently activates RhoB in ECs coincident with developing leak, and inactivation of RhoB correlates with barrier recovery. The mutation in p190BRhoGAP impairs RhoB inactivation, and the mutant phenotype of patient-derived ECs is replicated by siRNA knockdown of p190BRhoGAP in normal ECs. These data suggest a previously unknown function for p190BRhoGAP in control of capillary EC barrier function that may also be important in acquired systemic capillary leak associated with critical illness in humans.
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spelling pubmed-57160312018-06-04 A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome Pierce, Richard W. Merola, Jonathan Lavik, John Paul Kluger, Martin S. Huttner, Anita Khokha, Mustafa K. Pober, Jordan S. J Exp Med Research Articles We describe a fatal case of pediatric systemic capillary leak (Clarkson’s disease) associated with a point mutation in p190BRhoGAP. Dermal microvascular endothelial cells (ECs) isolated from this patient form monolayers with similar levels and distribution of junctional proteins and transendothelial electrical resistance compared with normal human dermal microvascular ECs. However, patient-derived ECs demonstrate a greater increase in permeability and impaired recovery of barrier function in response to tumor necrosis factor (TNF) compared with normal donor EC cultures. TNF transiently activates RhoB in ECs coincident with developing leak, and inactivation of RhoB correlates with barrier recovery. The mutation in p190BRhoGAP impairs RhoB inactivation, and the mutant phenotype of patient-derived ECs is replicated by siRNA knockdown of p190BRhoGAP in normal ECs. These data suggest a previously unknown function for p190BRhoGAP in control of capillary EC barrier function that may also be important in acquired systemic capillary leak associated with critical illness in humans. The Rockefeller University Press 2017-12-04 /pmc/articles/PMC5716031/ /pubmed/29097442 http://dx.doi.org/10.1084/jem.20162143 Text en © 2017 Pierce et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Pierce, Richard W.
Merola, Jonathan
Lavik, John Paul
Kluger, Martin S.
Huttner, Anita
Khokha, Mustafa K.
Pober, Jordan S.
A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome
title A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome
title_full A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome
title_fullStr A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome
title_full_unstemmed A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome
title_short A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome
title_sort p190brhogap mutation and prolonged rhob activation in fatal systemic capillary leak syndrome
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716031/
https://www.ncbi.nlm.nih.gov/pubmed/29097442
http://dx.doi.org/10.1084/jem.20162143
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