Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling

Author:

Amyere Mustapha1,Revencu Nicole1,Helaers Raphaël1,Pairet Eleonore1,Baselga Eulalia1,Cordisco Maria1,Chung Wendy1,Dubois Josée1,Lacour Jean-Philippe1,Martorell Loreto1,Mazereeuw-Hautier Juliette1,Pyeritz Reed E.1,Amor David J.1,Bisdorff Annouk1,Blei Francine1,Bombei Hannah1,Dompmartin Anne1,Brooks David1,Dupont Juliette1,González-Enseñat Maria Antonia1,Frieden Ilona1,Gérard Marion1,Kvarnung Malin1,Hanson-Kahn Andrea Kwan1,Hudgins Louanne1,Léauté-Labrèze Christine1,McCuaig Catherine1,Metry Denise1,Parent Philippe1,Paul Carle1,Petit Florence1,Phan Alice1,Quere Isabelle1,Salhi Aicha1,Turner Anne1,Vabres Pierre1,Vicente Asuncion1,Wargon Orli1,Watanabe Shoji1,Weibel Lisa1,Wilson Ashley1,Willing Marcia1,Mulliken John B.1,Boon Laurence M.1,Vikkula Miikka1

Affiliation:

1. From Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium (M.A., R.H., M.V.); Center for Human Genetics, Cliniques Universitaires St Luc, Université catholique de Louvain, Brussels, Belgium (N.R.); Université catholique de Louvain, Brussels, Belgium (E.P.); Department of Dermatology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain (E.B.); Department of Dermatology, Hospital Garrahan, Buenos Aires, Argentina (M.C.); Strong Hospital, University of...

Abstract

Background: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. Methods: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. Results: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. Conclusions: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1 -related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1 -encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

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