Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema

• Published in: Journal of allergy and clinical immunology Vol. 141; no. 3; pp. 1009 - 1017
• Main Authors: Bafunno, Valeria, Firinu, Davide, D'Apolito, Maria, Cordisco, Giorgia, Loffredo, Stefania, Leccese, Angelica, Bova, Maria, Barca, Maria Pina, Santacroce, Rosa, Cicardi, Marco, Del Giacco, Stefano, Margaglione, Maurizio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2018; Elsevier Limited
• Subjects: Allergy and Immunology; Anaphylaxis; Angioedema; Angiopoietin; angiopoietin-1; Coagulation factor XII; Coagulation factors; Complement component C1; Deoxyribonucleic acid; DNA; Edema; Endothelial cells; gene; Hereditary angioedema; Kinases; Missense mutation; multimers; Mutation; Open source software; Permeability; Plasma; tunica interna endothelial cell kinase 2 receptor; angiopoietin-1; ANGPT2; ANGPT1; WES; gene; TIE2; F12; OMIM; multimers; HAE; C1-INH-HAE; mutation; Hereditary angioedema; FXII; U-HAE; C1-INH; tunica interna endothelial cell kinase 2 receptor; ITACA; tunica interna endothelial cell kinase-2; HAE with yet unknown genetic defect; Italian network for C1-INH-HAE; HAE due to C1-INH deficiency; angiopoietin-2; coagulation factor XII; TIE2 receptor; coagulation factor XII gene; HAE due to F12 deficiency; C1 inhibitor; FXII-HAE; whole-exome sequencing
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.05.020

Hereditary angioedema (HAE) is a rare genetic disease usually caused by mutation in 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 (hereditary angioedema with yet unknown genetic defect [U-HAE]). Identification of causative genes in patients with U-HAE is valuable for understanding the cause of the disease. We conducted genetic studies in Italian patients with U-HAE to identify novel causative genes. Among patients belonging to 10 independent families and unrelated index patients with U-HAE 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 using in silico prediction and plasma and transfected cells from both patients and control subjects. We 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 or an additional 20 patients with familial U-HAE, 22 patients with sporadic U-HAE, and 200 control subjects. 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 of the ANGPT1 p.A119S variant. The recombinant mutated ANGPT1 p.A119S formed a reduced amount of multimers and showed reduced binding capability to its receptor. ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE. [Display omitted]