Journal Article

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations

Ocken, Jack, Kidanemariam, Seblewengel M., Alper, Seth L., Mane, Shrikant, Patel, Aman B., King, Philip D., Zhao, Shujuan, Reeves, Benjamin C., Stapleton, Christopher J., Butler, William E., Duy, Phan Q., Prendergast, Andrew, Iskandar, Bermans J., Zhang, Junhui, Proctor, Mark R., Barak, Tanyeri, Jackson, Eric M., Bai, Suxia, Nelson-Williams, Carol, Duran, Daniel, Zeng, Xue, Hao, Le Thi, Mekbib, Kedous Y., Moyer, Quentin J., Zhao, Hongyu, Johnston, James M., Erson-Omay, E. Zeynep, Furey, Charuta G., Dong, Weilai, Smith, Hannah, Fehnel, Katie Pricola, Allington, Garrett, Gunel, Murat, DeSpenza, Tyrone, Hale, Andrew T., Carter, Bob S., Moreno-De-Luca, Andres, Nottoli, Timothy, Kiziltug, Emre, Kundishora, Adam J., Orbach, Darren B., Berenstein, Alejandro, Kahle, Kristopher T., Rolle, Myron, Lifton, Richard P., Greenberg, Ana B. W., Rodesch, Georges, Fu, Po-Ying, Lang, Shih-Shan, Chapman, Paul, Dennis, Evan, Wang, Yung-Chun, Piwowarczyk, Paulina, Jin, Sheng Chih, Aagaard-Kienitz, Beverly, Chau, Jocelyn E., See, Alfred Pokmeng, Storm, Phillip B., Li, Boyang, van der Ent, Martijn A., Boggon, Titus J., Chen, Di, Ni

2023

Overview

To 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. Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/31 / 45/23 / 631/208/1516 / 64/116 / 64/60 / 692/308/2056 / 692/699/75/593 / Activin Receptors, Type II - genetics / Angiogenesis / Animals / Brain / Congenital defects / Endothelial cells / Endothelial Cells - pathology / Genomic analysis / GTPase-Activating Proteins - genetics / Humanities and Social Sciences / Humans / Kinases / Mice / multidisciplinary / Mutation / Mutation, Missense / Notch1 protein / p120 GTPase Activating Protein - genetics / Pathogenesis / Science / Science (multidisciplinary) / Signal Transduction - genetics / Transcriptomes / Vascular Diseases / Vein of Galen Malformations - genetics / Vein of Galen Malformations - pathology / Veins / Veins & arteries