Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling
Por:
Amyere M, Revencu N, Helaers R, Pairet E, Baselga E, Cordisco MR, Chung WK, Dubois J, Lacour JP, Martorell-Sampol L, Mazereeuw-Hautier J, Pyeritz RE, Amor DJ, Bisdorff A, Blei F, Bombei H, Dompmartin A, Brooks DG, Dupont J, González-Enseñat MA, Frieden IJ, Gérard M, Kvarnung M, Hanson-Kahn AK, Hudgins L, Léauté-Labrèze C, McCuaig C, Metry D, Parent P, Paul C, Petit F, Phan A, Quéré I, Salhi A, Turner AM, Vabres P, Vicente-Villa MA, Wargon O, Watanabe S, Weibel L, Wilson A, Willing M, Mulliken JB, Boon LM and Vikkula M
Publicada:
12 sep 2017
Ahead of Print:
7 jul 2017
Resumen:
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.
Filiaciones:
Amyere M:
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Revencu N:
Center for Human Genetics, Cliniques Universitaires St Luc, Université Catholique de Louvain, Brussels, Belgium
Helaers R:
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium
Pairet E:
Université Catholique de Louvain, Brussels, Belgium
Baselga E:
Department of Dermatology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain
Cordisco MR:
Department of Dermatology, Hospital Garrahan, Buenos Aires, Argentina & Strong Hospital, University of Rochester School of Medicine and Dentistry, Rochester, NY
Chung WK:
Departments of Pediatrics and Medicine, Columbia University, New York, NY
Dubois J:
Department of Medical Imaging, Sainte-Justine Mother-Child University Hospital, Montreal, Canada
Lacour JP:
Service de Dermatologie, Centre Hospitalo-Universitaire de Nice, Nice, France
Martorell-Sampol L:
Genética Molecular, Hospital Sant Joan de Déu, Barcelona, Spain
Mazereeuw-Hautier J:
Service de Dermatologie, Centre de Référence des Maladies Rares de la Peau, Hôpital Larrey, Toulouse, France
Pyeritz RE:
Departments of Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
Amor DJ:
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia
Bisdorff A:
Departments of Pediatrics and Medicine, Columbia University, New York, NY & Department of Neuroradiology, Lariboisière Hospital, Paris, France
Blei F:
Vascular Anomalies Program, Lenox Hill Hospital, New York, NY & Vascular Birthmark Institute of New York, Roosevelt Hospital, New York, NY
Bombei H:
Department of Pediatrics- Medical Genetics University of Iowa Carver College of Medicine, Iowa City, IA
Dompmartin A:
Department of Dermatology, Université de Caen Basse Normandie, CHU Caen, Caen, France
Brooks DG:
Department of Urology, Wake Forest School of Medicine, Winston Salem, NC
Dupont J:
Genetics Service, Pediatric Department, University Hospital Santa Maria, Lisbon, Portugal
González-Enseñat MA:
Department of Dermatology, Hospital Sant Joan de Déu, Barcelona, Spain
Frieden IJ:
Department of Dermatology, School of Medicine, University of California, San Francisco, San Francisco, CA
Gérard M:
Department of Genetics, University Hospital, Caen, France
Kvarnung M:
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
Hanson-Kahn AK:
Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA
Hudgins L:
Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA
Léauté-Labrèze C:
Hôpital Pellegrin Enfants, Bordeaux, France
McCuaig C:
Hôpital Sainte-Justine, Montréal, QC, Canada
Metry D:
Department of Dermatology, Texas Children's Hospital, Houston, TX
Parent P:
Département de Pédiatrie et Génétique Médicale, CHRU Hôpital Morvan, Brest, France
Paul C:
Department of Dermatology, Paul Sabatier University, Toulouse, France
Petit F:
Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU Lille, France
Phan A:
Pediatric Dermatology Unit, Claude Bernard-Lyon, University and Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Lyon, France
Quéré I:
Centre Hospitalier Universitaire, Montpellier, France
Salhi A:
Dermatolgie, Faculté de Médecine d'Alger, Alger, Algeria
Turner AM:
Department of Medical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia
Vabres P:
Service de Dermatologie, Centre Hospitalo-Universitaire Dijon-Bourgogne, Dijon, France
Vicente-Villa MA:
Department of Dermatology, Hospital Sant Joan de Déu, Barcelona, Spain
Wargon O:
Department of Pediatric Dermatology, Sydney Children's Hospital: School of Women's & Children's Health University of New South Wales, Sydney, New South Wales, Australia
Watanabe S:
Department of Plastic and Reconstructive Surgery, University of Tokyo, Tokyo, Japan
Weibel L:
Department of Pediatric Dermatology, University Children's Hospital Zurich, Zurich, Switzerland
Wilson A:
Children's Hospital of New York, New York, NY
Willing M:
University of Iowa Hospitals and Clinics, Iowa City, IA & Department of Pediatrics, Washington University, St. Louis, MI
Mulliken JB:
Vascular Anomalies Center, Boston Children's Hospital and Harvard Medical School, Boston, MA
Boon LM:
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium & Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc , Brussels, Belgium
Vikkula M:
Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium & Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc & Université Catholique de Louvain, Brussels, Belgium
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