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, M, Chung, W, Dubois, J, Lacour, JP, Martorell, L, Mazereeuw-Hautier, J, Pyeritz, RE, Amor, DJ, Bisdorff, A, Blei, F, Bombei, H, Dompmartin, A, Brooks, D, Dupont, J, Gonzalez-Enseat, MA, Frieden, I, Gerard, M, Kvarnung, M, Hanson-Kahn, AK, Hudgins, L, Leaute-Labreze, C, McCuaig, C, Metry, D, Parent, P, Paul, C, Petit, F, Phan, A, Quere, I, Salhi, A, Turner, A, Vabres, P, Vicente, A, Wargon, O, Watanabe, S, Weibel, L, Wilson, A, Willing, M, Mulliken, JB, Boon, LM, Vikkula, M
Publicada:
12 sep 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:
Catholic Univ Louvain, Duve Inst, Human Mol Genet, Ave Hippocrate 74, B-1200 Brussels, Belgium
Revencu, N:
Catholic Univ Louvain, Clin Univ St Luc, Ctr Human Genet, Brussels, Belgium
Helaers, R:
Catholic Univ Louvain, Duve Inst, Human Mol Genet, Ave Hippocrate 74, B-1200 Brussels, Belgium
Pairet, E:
Catholic Univ Louvain, Brussels, Belgium
Baselga, E:
Hosp Santa Creu & Sant Pau, Dept Dermatol, Barcelona, Spain
Cordisco, M:
Hosp Garrahan, Dept Dermatol, Buenos Aires, DF, Argentina
Univ Rochester, Sch Med & Dent, Strong Hosp, Rochester, NY USA
Chung, W:
Columbia Univ, Dept Pediat & Med, New York, NY USA
Dubois, J:
St Justine Mother Child Univ Hosp, Dept Med Imaging, Montreal, PQ, Canada
Lacour, JP:
Ctr Hosp Univ Nice, Serv Dermatol, Nice, France
Martorell, L:
Hosp St Joan Deu, Genet Mol, Barcelona, Spain
Mazereeuw-Hautier, J:
Hop Larrey, Ctr Reference Malad Rares Peau, Serv Dermatol, Toulouse, France
Pyeritz, RE:
Univ Penn, Perelman Sch Med, Dept Med & Genet, Philadelphia, PA 19104 USA
Amor, DJ:
Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Parkville, Vic, Australia
Bisdorff, A:
Columbia Univ, Dept Pediat & Med, New York, NY USA
Lariboisiere Hosp, Dept Neuroradiol, Paris, France
Blei, F:
Lenox Hill Hosp, Vasc Anomalies Program, New York, NY 10021 USA
Bombei, H:
Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA
Dompmartin, A:
Univ Caen Basse Normandie, CHU Caen, Dept Dermatol, Caen, France
Brooks, D:
Wake Forest Sch Med, Dept Urol, Winston Salem, NC USA
Dupont, J:
Univ Hosp Santa Maria, Paediat Dept, Genet Serv, Lisbon, Portugal
Gonzalez-Enseat, MA:
Hosp San Juan Dios, Dept Dermatol, Barcelona, Spain
Frieden, I:
Univ Calif San Francisco, Dept Dermatol, Sch Med, San Francisco, CA 94143 USA
Gerard, M:
Univ Hosp, Dept Genet, Caen, France
Kvarnung, M:
Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden
Hanson-Kahn, AK:
Stanford Univ, Sch Med, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA
Hudgins, L:
Stanford Univ, Sch Med, Dept Pediat, Div Med Genet, Stanford, CA 94305 USA
Leaute-Labreze, C:
Hop Pellegrin Enfants, Bordeaux, France
McCuaig, C:
Hop St Justine, Montreal, PQ, Canada
Metry, D:
Texas Childrens Hosp, Dept Dermatol, Houston, TX 77030 USA
Parent, P:
CHRU Hop Morvan, Dept Pediat & Genet Med, Brest, France
Paul, C:
Paul Sabatier Univ, Dept Dermatol, Toulouse, France
Petit, F:
Hop Jeanne Flandre, Serv Genet Clin, Lille, France
Phan, A:
Claude Bernard Lyon Univ, Pediat Dermatol Unit, Lyon, France
Hop Femme Mere Enfant, Hosp Civils Lyon, Lyon, France
Quere, I:
Ctr Hosp Univ, Montpellier, France
Salhi, A:
Fac Med, Dermatol, Algiers, Algeria
Turner, A:
Sydney Childrens Hosp, Dept Med Genet, Randwick, NSW, Australia
Vabres, P:
Ctr Hosp Univ Dijon, Serv Dermatol, Dijon, Bourgogne, France
Vicente, A:
Hosp San Juan Dios, Dept Dermatol, Barcelona, Spain
Wargon, O:
Univ New South Wales, Sch Womens & Childrens Hlth, Sydney Childrens Hosp, Dept Paediat Dermatol, Sydney, NSW, Australia
Watanabe, S:
Univ Tokyo, Dept Plast & Reconstruct Surg, Hongo, Japan
Weibel, L:
Univ Childrens Hosp Zurich, Dept Pediat Dermatol, Zurich, Switzerland
Wilson, A:
Childrens Hosp New York, New York, NY USA
Willing, M:
Univ Iowa, Hosp & Clin, Iowa City, IA USA
Washington Univ, Dept Pediat, St Louis, MO 63130 USA
Boon, LM:
Harvard Med Sch, Boston Childrens Hosp, Vasc Anomalies Ctr, Boston, MA USA
Vikkula, M:
Catholic Univ Louvain, Duve Inst, Human Mol Genet, Ave Hippocrate 74, B-1200 Brussels, Belgium
Bronze, Green Accepted
|