Talin1 dysfunction is genetically linked to systemic capillary leak syndrome

Abstract

ABSTRACTSystemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease is currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in theTLN1gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance. Talin1 has a key role in cell adhesions by activating and linking integrins to the actin cytoskeleton. This variant causes in-frame skipping of exon 54 and is predicted to affect talin’s c-terminal actin binding site (ABS3). Modelling the SCLS-TLN1variant by mimicking the actin-binding disruption inTLN1heterozygous endothelial cells resulted in disorganized endothelial adherens junctions. Mechanistically, we established that disruption of talin’s ABS3 sequestrates talin’s interacting partner, vinculin, at cell-extracellular matrix adhesions, leading to destabilization of the endothelial barrier. We propose that pathogenic variant inTLN1underlie SCLS, providing insight into the molecular mechanism of the disease which can be explored for future therapeutic interventions.SUMMARYSystemic capillary leak syndrome (SCLS) is a rare potentially lethal disease with unknown etiology and non-specific treatment. Here, we established a heterozygous splice variant of talin1, a key cell adhesion protein, as a genetic link to a familial SCLS case.