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

Abstract

Pierce et al. describe a pediatric patient with a fatal systemic capillary leak syndrome (Clarkson’s disease). They identify a point mutation in p190BRhoGAP and show that patient-derived microvascular endothelial cells show prolonged activation RhoB that correlates with impaired barrier recovery after treatment with TNF compared with control cultures.

A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease)

“…In vitro studies of ECs isolated from skin of an SCLS patient demonstrated exaggerated responses to inflammatory mediators, suggesting that primary endothelial dysfunction contributes to the clinical symptoms of SCLS 8 . To test this hypothesis directly in situ, we injected histamine or morphine intradermally in patients with SCLS and healthy controls and measured the area of drug-induced skin wheals caused by fluid extravasation.…”

“…The present results advance the field by showing that SCLS patients are hyper-responsive to mediators of vascular permeability, suggesting that aberrant endothelial function contributes directly to clinical symptoms. Although SCLS patients are typically asymptomatic between episodes, dermal microvascular ECs isolated from a patient with fatal SCLS were persistently hyper-responsive to inflammatory mediators including LPS, TNFα, and IL-1β in vitro 8 . Previous histological studies of skin and muscle of SCLS patients have failed to uncover gross structural or ultrastructural abnormalities within the microvasculature that could account for this phenotype 2 .…”

“…Early studies of our initial SCLS patient cohort resulted in the identification of a small genetic interval, 3p25.3, as the highest-ranking candidate susceptibility locus ( p ~ 10 −6 ) with an odds ratio of ~41 7 . Whole exome sequencing (WES) of a single patient with fatal SCLS revealed a potentially pathogenic loss of function mutation in the gene ARHGAP5 , which encodes a known of a regulator of endothelial permeability (p190BRhoGAP) 8 . Notably, this mutation has not been detected in any other subjects with SCLS 9 .…”

The Cullin-3–Rbx1–KCTD10 complex controls endothelial barrier function via K63 ubiquitination of RhoB

“…However, these mice do display defects in vascular sprouting in the retina, impaired morphology of neurons, and thymus atrophy ( Adini et al, 2003 ; McNair et al, 2010 ; Bravo-Nuevo et al, 2011 ). In contrast to these relatively mild effects, recent publications show that increased expression of RhoB correlates with human pathologies and can even cause fatal disease, such as capillary leak syndrome ( Yang et al, 2013a ; Marcos-Ramiro et al, 2016 ; Mandik-Nayak et al, 2017 ; Pierce et al, 2017 ).…”

Progenitor-derived human endothelial cells evade alloimmunity by CRISPR/Cas9-mediated complete ablation of MHC expression

“…The effects of TNF-α or IFN-γ were confirmed by staining for PE-VCAM-1/CD106 (clone STA) and APC-PD-L1/CD274 (clone B7-H1), respectively, antigens known to be upregulated in ECs. Human dermal microvascular cells were isolated as previously described (67).…”