دورية أكاديمية
Germline Loss-of-Function Mutations in EPHB4 cause a Second Form of Capillary Malformation–Arteriovenous Malformation (CM-AVM2) deregulating RAS-MAPK signaling.
| العنوان: | Germline Loss-of-Function Mutations in EPHB4 cause a Second Form of Capillary Malformation–Arteriovenous Malformation (CM-AVM2) deregulating RAS-MAPK signaling. |
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| المؤلفون: | Amyere, Mustapha, Revencu, Nicole, Helaers, Raphaël, Pairet, Eleonore, Baselga, Eulalia, Cordisco, Maria, Chung, Wendy, Dubois, Josée, Lacour, Jean-Philippe, Martorell, Loreto, Mazereeuw-Hautier, Juliette, Pyeritz, Reed E., Amor, David J., Bisdorff, Anouck, Blei, Francine, Bombei, Hannah, Dompmartin, Anne, Brooks, David J., González-Enseñat, Maria Antonia, Frieden, Ilona, Gerard, Marion, Kvarnung, Malin, Kwan Hanson-Kahn, Andrea, Hudgins, Louanne, Leaute-Labreze, Christine, McCuaig, Catherine, Metry, Denise, Parent, Philippe, Paul, Carle, Petit, Florence, Phan, Alice, Quere, Isabelle, Salhi, Aicha, Turner, Anne, Vabres, Pierre, Vicente, Asuncion, Wargon, Orli, Watanabe, Shoji, Weibel, Lisa, Wilson, Ashley, Willing, Marcia, Mulliken, John B., Boon, Laurence M., Vikkula, Miikka |
| المساهمون: | UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GEHU - Génétique, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, UCL - (SLuc) Service de chirurgie plastique, UCL - (SLuc) Centre de malformations vasculaires congénitales |
| المصدر: | Circulation, Vol. 136, no. 11, p. 1037-1048 (2017) |
| بيانات النشر: | Lippincott Williams & Wilkins |
| سنة النشر: | 2017 |
| المجموعة: | DIAL@USL-B (Université Saint-Louis, Bruxelles) |
| مصطلحات موضوعية: | Arteriovenous fistula, Arteriovenous malformation, Capillary, Genetics, Linkage, Vascular disease, Vascular endothelial function, Venous |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0009-7322 1524-4539 |
| العلاقة: | boreal:183933; http://hdl.handle.net/2078.1/183933Test; info:pmid/28687708; urn:ISSN:0009-7322; urn:EISSN:1524-4539 |
| DOI: | 10.1161/CIRCULATIONAHA.116.026886 |
| الإتاحة: | https://doi.org/10.1161/CIRCULATIONAHA.116.026886Test http://hdl.handle.net/2078.1/183933Test |
| حقوق: | info:eu-repo/semantics/restrictedAccess |
| رقم الانضمام: | edsbas.5698C569 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00097322 15244539 |
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| DOI: | 10.1161/CIRCULATIONAHA.116.026886 |