Nature Communications (Nov 2023)
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
- Shujuan Zhao,
- Kedous Y. Mekbib,
- Martijn A. van der 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,
- Kristopher T. Kahle
Affiliations
- Shujuan Zhao
- Department of Genetics, Washington University School of Medicine
- Kedous Y. Mekbib
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Martijn A. van der Ent
- Department of Microbiology and Immunology, University of Michigan Medical School
- Garrett Allington
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Andrew Prendergast
- Yale Zebrafish Research Core, Yale School of Medicine
- Jocelyn E. Chau
- Department of Molecular Biophysics and Biochemistry, Yale School of Medicine
- Hannah Smith
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- John Shohfi
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Jack Ocken
- Department of Neurosurgery, Yale School of Medicine
- Daniel Duran
- Department of Neurosurgery, University of Mississippi Medical Center
- Charuta G. Furey
- Department of Neurosurgery, Yale School of Medicine
- Le Thi Hao
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Phan Q. Duy
- Department of Neurosurgery, University of Virginia School of Medicine
- Benjamin C. Reeves
- Department of Neurosurgery, Yale School of Medicine
- Junhui Zhang
- Department of Genetics, Yale School of Medicine
- Carol Nelson-Williams
- Department of Genetics, Yale School of Medicine
- Di Chen
- Department of Microbiology and Immunology, University of Michigan Medical School
- Boyang Li
- Department of Biostatistics, Yale School of Public Health
- Timothy Nottoli
- Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine
- Suxia Bai
- Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine
- Myron Rolle
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Xue Zeng
- Department of Molecular Biophysics and Biochemistry, Yale School of Medicine
- Weilai Dong
- Department of Genetics, Yale School of Medicine
- Po-Ying Fu
- Department of Genetics, Washington University School of Medicine
- Yung-Chun Wang
- Department of Genetics, Washington University School of Medicine
- Shrikant Mane
- Department of Genetics, Yale School of Medicine
- Paulina Piwowarczyk
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School
- Katie Pricola Fehnel
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School
- Alfred Pokmeng See
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School
- Bermans J. Iskandar
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health
- Beverly Aagaard-Kienitz
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health
- Quentin J. Moyer
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Evan Dennis
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Emre Kiziltug
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Adam J. Kundishora
- Department of Neurosurgery, Yale School of Medicine
- Tyrone DeSpenza
- Department of Neurosurgery, Yale School of Medicine
- Ana B. W. Greenberg
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Seblewengel M. Kidanemariam
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa
- Andrew T. Hale
- Department of Neurosurgery, University of Alabama School of Medicine
- James M. Johnston
- Department of Neurosurgery, University of Alabama School of Medicine
- Eric M. Jackson
- Department of Neurosurgery, Johns Hopkins University School of Medicine
- Phillip B. Storm
- Department of Neurosurgery, Hospital of the University of Pennsylvania
- Shih-Shan Lang
- Department of Neurosurgery, Hospital of the University of Pennsylvania
- William E. Butler
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Bob S. Carter
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Paul Chapman
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Christopher J. Stapleton
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Aman B. Patel
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- Georges Rodesch
- Service de Neuroradiologie Diagnostique et Thérapeutique, Hôpital Foch
- Stanislas Smajda
- Department of Interventional Neuroradiology, Hôpital Fondation A. de Rothschild
- Alejandro Berenstein
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai
- Tanyeri Barak
- Department of Neurosurgery, Yale School of Medicine
- E. Zeynep Erson-Omay
- Department of Neurosurgery, Yale School of Medicine
- Hongyu Zhao
- Department of Genetics, Yale School of Medicine
- Andres Moreno-De-Luca
- Department of Radiology, Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger
- Mark R. Proctor
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School
- Edward R. Smith
- Department of Neurosurgery, Boston Children’s Hospital, Harvard Medical School
- Darren B. Orbach
- Department of Neurosurgery, 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
- Department of Genetics, Yale School of Medicine
- Titus J. Boggon
- Department of Molecular Biophysics and Biochemistry, Yale School of Medicine
- Richard P. Lifton
- Laboratory of Human Genetics and Genomics, The Rockefeller University
- Murat Gunel
- Department of Neurosurgery, Yale School of Medicine
- Philip D. King
- Department of Microbiology and Immunology, University of Michigan Medical School
- Sheng Chih Jin
- Department of Genetics, Washington University School of Medicine
- Kristopher T. Kahle
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School
- DOI
- https://doi.org/10.1038/s41467-023-43062-z
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 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.
