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

The Journal of Experimental Medicine
Richard W PierceJordan S Pober

Abstract

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.

References

Jul 5, 2003·Current Biology : CB·Krister WennerbergSteen H Hansen
Aug 1, 1960·The American Journal of Medicine·B CLARKSONE H LUCKEY
Nov 12, 2003·The Journal of Cell Biology·Ling SuSarah J Parsons
Jan 5, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Martin S KlugerJordan S Pober
May 3, 2014·American Journal of Respiratory and Critical Care Medicine·Zhihui XieKirk M Druey
Sep 15, 2014·Nature Genetics·Neil RombergRichard P Lifton
Feb 26, 2015·Pediatrics·Peter HsuKirk M Druey
May 4, 2016·The Journal of Cell Biology·Beatriz Marcos-RamiroJaime Millán
Nov 23, 2016·Small GTPases·Francisco M Vega, Anne J Ridley

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Citations

Jan 24, 2018·The Journal of Cell Biology·Igor KovačevićPeter L Hordijk
Jul 13, 2018·Circulation. Genomic and Precision Medicine·Li HeWang Min
Jun 25, 2018·European Journal of Pediatrics·Marie-Ange BozziniSebastiano A G Lava
May 16, 2019·Current Opinion in Pediatrics·Saquib A Lakhani, Richard Pierce
Dec 23, 2020·Pediatrics International : Official Journal of the Japan Pediatric Society·Sohsaku YamanouchiKazunari Kaneko
May 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Alamzeb KhanRichard W Pierce

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Methods Mentioned

BETA
electron microscopy
Confocal microscopy
GTPase
pulldown
FACS
pull-down
electrophoresis
Assay
transmission electron microscopy

Software Mentioned

SAMtools
LRT
TEER
ECIS
GraphPad Prism
SIFT
MutationTaster
GraphPad
ImageJ
PolyPhen2

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