Public Data Commons

Hereditary angioedema (HAE) is a potentially life-threatening set of disorders characterized by recurrent episodes of swelling. The lack of specific symptoms makes the condition difficult to diagnose, leading to delays in treatment and mismanagement of the disorder. Clinical diagnostic methods are available only for forms of this disorder caused by mutations in the genes encoding C1 inhibitor and F12. Discovery of causative genes for HAE of unknown genetic basis (HAE-U) would enable diagnosis of additional patients.

We recently identified a novel candidate HAE gene. Genomic sequencing of an Inova patient with HAE-U revealed compound heterozygous mutations in TIE1, part of the angiopoietin (ANGPT)-TIE pathway that regulates vascular permeability, angiogenesis and vascular remodeling during inflammation and disease. Proteins in this pathway are targets for therapeutics under development for disorders characterized by vascular leakage including cancer and macular degeneration.

We hypothesize that the patient’s TIE1 mutations are pathogenic for HAE, and lead to dysregulation of the ANGPT-TIE pathway. To test this hypothesis, we propose a combination of computational and wet lab experiments to investigate the impact of the variants on the structure and function of TIE1. This work is expected to improve our understanding of the role of TIE1 in regulating vascular stability. This is the next critical step in the discovery of TIE1 as a novel gene for HAE, a finding readily translatable into a new clinical biomarker for the diagnosis of HAE.