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

Authors

• Shujuan Zhao, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Kedous Y. Mekbib, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• Martijn A. van der Ent, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
• Garrett Allington, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• Andrew Prendergast, Yale Zebrafish Research Core, Yale School of Medicine, New Haven, CT, USA.
• Jocelyn E. Chau, Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.
• Hannah Smith, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• John Shohfi, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• Jack Ocken, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Daniel Duran, Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, USA.
• Charuta G. Furey, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Le Thi Hao, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• Phan Q. Duy, Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
• Benjamin C. Reeves, Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
• Junhui Zhang, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Carol Nelson-Williams, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Di Chen, Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
• Boyang Li, Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
• Timothy Nottoli, Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
• Suxia Bai, Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
• Myron Rolle, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
• Xue Zeng, Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.
• Weilai Dong, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Po-Ying Fu, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Yung-Chun Wang, Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
• Shrikant Mane, Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
• Paulina Piwowarczyk, Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
• Katie Pricola Fehnel, Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
• Alfred Pokmeng See, Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
• Bermans J. Iskandar, Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
• Beverly Aagaard-Kienitz, Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.

Document Type

Article

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). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10), 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.

Medical Subject Headings

Humans; Animals; Mice; Vein of Galen Malformations (genetics, pathology); Endothelial Cells (pathology); Mutation; Signal Transduction (genetics); Mutation, Missense; GTPase-Activating Proteins (genetics); Vascular Diseases; Activin Receptors, Type II (genetics); p120 GTPase Activating Protein (genetics)

Publication Date

11-17-2023

Publication Title

Nature communications

E-ISSN

2041-1723

Volume

14

Issue

1

First Page

7452

PubMed ID

37978175

Digital Object Identifier (DOI)

10.1038/s41467-023-43062-z

Recommended Citation

Zhao, Shujuan; Mekbib, Kedous Y.; van der Ent, Martijn A.; Allington, Garrett; Prendergast, Andrew; Chau, Jocelyn E.; Smith, Hannah; Shohfi, John; Ocken, Jack; Duran, Daniel; Furey, Charuta G.; Hao, Le Thi; Duy, Phan Q.; Reeves, Benjamin C.; Zhang, Junhui; Nelson-Williams, Carol; Chen, Di; Li, Boyang; Nottoli, Timothy; Bai, Suxia; Rolle, Myron; Zeng, Xue; Dong, Weilai; Fu, Po-Ying; Wang, Yung-Chun; Mane, Shrikant; Piwowarczyk, Paulina; Fehnel, Katie Pricola; See, Alfred Pokmeng; Iskandar, Bermans J.; and Aagaard-Kienitz, Beverly, "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations" (2023). Neurosurgery. 2419.
https://scholar.barrowneuro.org/neurosurgery/2419