Mutation of Angiopoietin-1 Gene Associates with a New Type of Hereditary Angioedema

Publication date: Available online 8 June 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Valeria Bafunno, Davide Firinu, Maria D'Apolito, Giorgia Cordisco, Stefania Loffredo, Angelica Leccese, Maria Bova, Maria Pina Barca, Rosa Santacroce, Marco Cicardi, Stefano Del Giacco, Maurizio Margaglione.
BackgroundHereditary angioedema (HAE) is a rare genetic disease usually due to mutation within the C1 inhibitor or the coagulation Factor XII gene. However, in a series of patients with HAE no causative variants have been described and the pathophysiology of the disease remains unknown (U-HAE). Identification of causative genes in U-HAE is valuable for understanding the cause of the disease.ObjectiveWe conducted genetic studies in Italian patients with U-HAE to identify novel causative genes.MethodsAmong patients belonging to 10 independent families and unrelated index patients with U-HAE disease recruited from the Italian network for C1-INH-HAE (ITACA), we selected a large multiplex family with U-HAE and performed whole-exome sequencing. The angiopoietin-1 gene (ANGPT1) was investigated in all patients with familial or sporadic U-HAE. The effect of ANGPT1 variants was investigated by in silico prediction and using patients and control plasmas and transfected cells.ResultsWe identified a missense mutation (ANGPT1, c.807G>T, p.A119S) in a family with U-HAE. The ANGPT1 p.A119S variant was detected in all members of the index family with U-HAE but not in asymptomatic family members, nor in an additional 20 patients with familial U-HAE, 22 patients with sporadic U-HAE, and 200 controls. Protein analysis of the plasma of patients revealed a reduction of multimeric forms and a reduced ability to bind the natural receptor "tunica interna endothelial cell kinase-2" (TIE2) of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed a reduced binding capability to its receptor.ConclusionANGPT1 impairment is associated with angioedema and ANGPT1 variants can be the basis of HAE.

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Teaser

A missense variant in the angiopoietin-1 gene (ANGPT1) represents a novel and independent mechanism leading to vascular permeability and angioedema. Impairment of the endothelial ANGPT1-TIE2 ligand-receptor system may be involved in the pathophysiology of HAE.


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