Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema
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 +11 more
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TLDR
Angiopoietin‐1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.Abstract:
Background 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. Objective We conducted genetic studies in Italian patients with U-HAE to identify novel causative genes. Methods 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. Results 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. Conclusion ANGPT1 impairment is associated with angioedema, and ANGPT1 variants can be the basis of HAE.read more
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Journal ArticleDOI
The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update
Marcus Maurer,Markus Magerl,I. J. Ansotegui,Emel Aygören-Pürsün,Stephen Betschel,Konrad Bork,Tom Bowen,H. Balle Boysen,Henriette Farkas,Anete Sevciovic Grumach,Michihiro Hide,Constance H. Katelaris,R. Lockey,Hilary Longhurst,W. R. Lumry,Inmaculada Martinez-Saguer,Dumitru Moldovan,Alexander Nast,Ruby Pawankar,Paul Potter,Marc A. Riedl,Bruce Ritchie,Lanny J. Rosenwasser,Mario Sánchez-Borges,Yuxiang Zhi,Bruce L. Zuraw,Timothy J. Craig +26 more
TL;DR: The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of H AE with deficient C1‐inhibitor (type 1) and HAE with dysfunctional C1-inhibitors (type 2).
Journal ArticleDOI
Hereditary angioedema with a mutation in the plasminogen gene
Konrad Bork,Karin Wulff,Lars Steinmüller-Magin,Ingrid Braenne,Petra Staubach-Renz,Günther Witzke,Jochen Hardt +6 more
TL;DR: This work sought to identify and characterize a hitherto unknown type of HAE with normal C1‐INH and without mutation in the F12 gene.
Journal ArticleDOI
The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update
Marcus Maurer,Markus Magerl,Stephen Betschel,Werner Aberer,Ignacio J. Ansotegui,Emel Aygören-Pürsün,Aleena Banerji,Noémi Bara,Isabelle Boccon-Gibod,Konrad Bork,Laurence Bouillet,Henrik Balle Boysen,Nicholas Brodszki,Paula J. Busse,Anette Bygum,Teresa Caballero,Mauro Cancian,Anthony J. Castaldo,Danny M. Cohn,Dorottya Csuka,Henriette Farkas,Mark Gompels,Richard G. Gower,Anete Sevciovic Grumach,Guillermo Guidos-Fogelbach,Michihiro Hide,Hye Ryun Kang,Allen P. Kaplan,Constance H. Katelaris,Sorena Kiani-Alikhan,Wei Li,Richard F. Lockey,Hilary Longhurst,William R. Lumry,Andrew J. MacGinnitie,Alejandro Malbrán,Inmaculada Martinez-Saguer,J.J. Matta Campos,Alexander Nast,Dinh Nguyen,Sandra Nieto‐Martinez,Ruby Pawankar,J P Gogan Peter,Grzegorz Porebski,N. Prior,Avner Reshef,Marc A. Riedl,Bruce Ritchie,Farrukh Sheikh,William B. Smith,Peter J. Spaeth,Marcin Stobiecki,E. Toubi,Lilian Varga,Karsten Weller,Andrea Zanichelli,Yuxiang Zhi,Bruce L. Zuraw,Timothy J. Craig +58 more
TL;DR: The goal of this guideline update and revision is to provide clinicians and their patients with guidance that will assist them in making rational decisions in the management of H AE with deficient C1-inhibitor (type 1) and HAE with dysfunctional C1/2 (type 2).
Journal ArticleDOI
Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin.
Konrad Bork,Karin Wulff,Heidi Rossmann,Lars Steinmüller-Magin,Ingrid Braenne,Günther Witzke,Jochen Hardt +6 more
Journal ArticleDOI
Epidemiology of Bradykinin-mediated angioedema: a systematic investigation of epidemiological studies.
TL;DR: Assessment of the epidemiological burden of Bradykinin-mediated angioedema in the USA, Germany and France found ACEI-AE is more common than C1-INH-HAE (~ 10:1), which is moreCommon than C2-inhibitor related acquired angIOedema (~10: 1).
References
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Requisite Role of Angiopoietin-1, a Ligand for the TIE2 Receptor, during Embryonic Angiogenesis
Chitra Suri,Pamela F. Jones,Sybill Patan,Sona Bartunkova,Maisonpierre Peter C,Samuel Davis,Thomas N. Sato,George D. Yancopoulos +7 more
TL;DR: It is shown that mice engineered to lack Angiopoietin-1 display angiogenic deficits reminiscent of those previously seen in mice lacking TIE2, demonstrating that AngiopOietIn-1 is a primary physiologic ligand for TIE1 and that it has critical in vivo angiogenesis actions that are distinct from VEGF and that are not reflected in the classic in vitro assays used to characterize VEGf.
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Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1.
Gavin Thurston,Chitra Suri,K. Smith,Joyce McClain,Thomas N. Sato,George D. Yancopoulos,Donald M. McDonald +6 more
TL;DR: Angiopoietin-1 may be useful for reducing microvascular leakage in diseases in which the leakage results from chronic inflammation or elevated V EGF and, in combination with VEGF, for promoting growth of nonleaky vessels.
Journal ArticleDOI
Angiopoietin-1 protects the adult vasculature against plasma leakage.
Gavin Thurston,John S. Rudge,Ella Ioffe,Hao Zhou,Leorah Ross,Susan D. Croll,Nicole Glazer,Jocelyn Holash,Donald M. McDonald,George D. Yancopoulos +9 more
TL;DR: It is shown that acute administration of angiopoietin-1 does indeed protect adult vasculature from leaking, countering the potentially lethal actions of VEGF and inflammatory agents.
Journal ArticleDOI
Control of vascular morphogenesis and homeostasis through the angiopoietin–Tie system
TL;DR: The Tie receptors and their angiopoietin (Ang) ligands have been identified as the second vascular tissue-specific receptor Tyr kinase system and provide unique insights into the functions of this vascular signalling system.
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Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group
Marco Cicardi,Werner Aberer,Aleena Banerji,Murat Bas,Jonathan A. Bernstein,Konrad Bork,Teresa Caballero,Henriette Farkas,Anete Sevciovic Grumach,Allen P. Kaplan,Marc A. Riedl,Massimo Triggiani,Andrea Zanichelli,Bruce L. Zuraw +13 more
TL;DR: Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting.
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