DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology

Abstract

BackgroundIn the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified. ObjectiveTo identify new genetic targets associated with HAE, a large Argentine family with HAE- UNK spanning three generations was studied. MethodsWhole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. In silico analyses and experimental studies were applied to assess the role of the identified gene variant. ResultsA missense variant (p.D239N) in the DAB2IP gene was identified. The variant occurred in the C2-domain, the region interacting with VEGFR2. It was found to be rare, and predicted to have a detrimental effect on the functionality of the DAB2IP protein. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced co-localization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding. ConclusionThe study identified a novel missense variant (p.D239N) in the DAB2IP gene in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.