Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
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Published:2023-11-17
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhao ShujuanORCID, Mekbib Kedous Y.ORCID, van der Ent Martijn A., Allington GarrettORCID, Prendergast Andrew, Chau Jocelyn E.ORCID, Smith Hannah, Shohfi John, Ocken Jack, Duran DanielORCID, Furey Charuta G., Hao Le Thi, Duy Phan Q., Reeves Benjamin C.ORCID, Zhang Junhui, Nelson-Williams CarolORCID, Chen Di, Li BoyangORCID, Nottoli TimothyORCID, Bai Suxia, Rolle Myron, Zeng XueORCID, Dong WeilaiORCID, Fu Po-YingORCID, Wang Yung-Chun, Mane Shrikant, Piwowarczyk Paulina, Fehnel Katie Pricola, See Alfred Pokmeng, Iskandar Bermans J.ORCID, Aagaard-Kienitz Beverly, Moyer Quentin J., Dennis EvanORCID, Kiziltug Emre, Kundishora Adam J.ORCID, DeSpenza TyroneORCID, Greenberg Ana B. W., Kidanemariam Seblewengel M., Hale Andrew T., Johnston James M., Jackson Eric M.ORCID, Storm Phillip B., Lang Shih-Shan, Butler William E.ORCID, Carter Bob S., Chapman Paul, Stapleton Christopher J., Patel Aman B., Rodesch Georges, Smajda Stanislas, Berenstein Alejandro, Barak Tanyeri, Erson-Omay E. Zeynep, Zhao HongyuORCID, Moreno-De-Luca AndresORCID, Proctor Mark R., Smith Edward R., Orbach Darren B.ORCID, Alper Seth L.ORCID, Nicoli StefaniaORCID, Boggon Titus J.ORCID, Lifton Richard P., Gunel MuratORCID, King Philip D.ORCID, Jin Sheng ChihORCID, Kahle Kristopher T.ORCID
Abstract
AbstractTo elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10−7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10−5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a “second-hit” allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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