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

Shujuan Zhao, Kedous Y. Mekbib, Martijn A. Ent, Garrett Allington, Andrew Prendergast, Jocelyn E. Chau, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran, Charuta G. Furey, Le Thi Hao, Phan Q. Duy, Benjamin C. Reeves, Junhui Zhang, Carol Nelson-Williams, Di Chen, Boyang Li, Timothy Nottoli, Suxia Bai, Myron Rolle, Xue Zeng, Weilai Dong, Po-Ying Fu, Yung-Chun Wang, Shrikant Mane, Paulina Piwowarczyk, Katie Pricola Fehnel, Alfred Pokmeng See, Bermans J. Iskandar, Beverly Aagaard-Kienitz, Quentin J. Moyer, Evan Dennis, Emre Kiziltug, Adam J. Kundishora, Tyrone DeSpenza, Ana B. W. Greenberg, Seblewengel M. Kidanemariam, Andrew T. Hale, James M. Johnston, Eric M. Jackson, Phillip B. Storm, Shih-Shan Lang, William E. Butler, Bob S. Carter, Paul Chapman, Christopher J. Stapleton, Aman B. Patel, Georges Rodesch, Stanislas Smajda, Alejandro Berenstein, Tanyeri Barak, E. Zeynep Erson-Omay, Hongyu Zhao, Andres Moreno- De-Luca, Mark R. Proctor, Edward R. Smith, Darren B. Orbach, Seth L. Alper, Stefania Nicoli, Titus J. Boggon, Richard P. Lifton, Murat Gunel, Philip D. King (), Sheng Chih Jin () and Kristopher T. Kahle ()
Additional contact information
Shujuan Zhao: Washington University School of Medicine
Kedous Y. Mekbib: Massachusetts General Hospital, Harvard Medical School
Martijn A. Ent: University of Michigan Medical School
Garrett Allington: Massachusetts General Hospital, Harvard Medical School
Andrew Prendergast: Yale Zebrafish Research Core, Yale School of Medicine
Jocelyn E. Chau: Yale School of Medicine
Hannah Smith: Massachusetts General Hospital, Harvard Medical School
John Shohfi: Massachusetts General Hospital, Harvard Medical School
Jack Ocken: Yale School of Medicine
Daniel Duran: University of Mississippi Medical Center
Charuta G. Furey: Yale School of Medicine
Le Thi Hao: Massachusetts General Hospital, Harvard Medical School
Phan Q. Duy: University of Virginia School of Medicine
Benjamin C. Reeves: Yale School of Medicine
Junhui Zhang: Yale School of Medicine
Carol Nelson-Williams: Yale School of Medicine
Di Chen: University of Michigan Medical School
Boyang Li: Yale School of Public Health
Timothy Nottoli: Yale School of Medicine
Suxia Bai: Yale School of Medicine
Myron Rolle: Massachusetts General Hospital, Harvard Medical School
Xue Zeng: Yale School of Medicine
Weilai Dong: Yale School of Medicine
Po-Ying Fu: Washington University School of Medicine
Yung-Chun Wang: Washington University School of Medicine
Shrikant Mane: Yale School of Medicine
Paulina Piwowarczyk: Boston Children’s Hospital, Harvard Medical School
Katie Pricola Fehnel: Boston Children’s Hospital, Harvard Medical School
Alfred Pokmeng See: Boston Children’s Hospital, Harvard Medical School
Bermans J. Iskandar: University of Wisconsin School of Medicine and Public Health
Beverly Aagaard-Kienitz: University of Wisconsin School of Medicine and Public Health
Quentin J. Moyer: Massachusetts General Hospital, Harvard Medical School
Evan Dennis: Massachusetts General Hospital, Harvard Medical School
Emre Kiziltug: Massachusetts General Hospital, Harvard Medical School
Adam J. Kundishora: Yale School of Medicine
Tyrone DeSpenza: Yale School of Medicine
Ana B. W. Greenberg: Massachusetts General Hospital, Harvard Medical School
Seblewengel M. Kidanemariam: University of Ottawa
Andrew T. Hale: University of Alabama School of Medicine
James M. Johnston: University of Alabama School of Medicine
Eric M. Jackson: Johns Hopkins University School of Medicine
Phillip B. Storm: Hospital of the University of Pennsylvania
Shih-Shan Lang: Hospital of the University of Pennsylvania
William E. Butler: Massachusetts General Hospital, Harvard Medical School
Bob S. Carter: Massachusetts General Hospital, Harvard Medical School
Paul Chapman: Massachusetts General Hospital, Harvard Medical School
Christopher J. Stapleton: Massachusetts General Hospital, Harvard Medical School
Aman B. Patel: Massachusetts General Hospital, Harvard Medical School
Georges Rodesch: Service de Neuroradiologie Diagnostique et Thérapeutique, Hôpital Foch
Stanislas Smajda: Hôpital Fondation A. de Rothschild
Alejandro Berenstein: Icahn School of Medicine at Mount Sinai
Tanyeri Barak: Yale School of Medicine
E. Zeynep Erson-Omay: Yale School of Medicine
Hongyu Zhao: Yale School of Medicine
Andres Moreno- De-Luca: Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger
Mark R. Proctor: Boston Children’s Hospital, Harvard Medical School
Edward R. Smith: Boston Children’s Hospital, Harvard Medical School
Darren B. Orbach: Boston Children’s Hospital, Harvard Medical School
Seth L. Alper: Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School
Stefania Nicoli: Yale School of Medicine
Titus J. Boggon: Yale School of Medicine
Richard P. Lifton: The Rockefeller University
Murat Gunel: Yale School of Medicine
Philip D. King: University of Michigan Medical School
Sheng Chih Jin: Washington University School of Medicine
Kristopher T. Kahle: Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-43062-z

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