Dissemin is shutting down on January 1st, 2025

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Nature Research, Nature Communications, 1(14), 2023

DOI: 10.1038/s41467-023-43062-z

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

Journal article published in 2023 by Shujuan Zhao ORCID, Kedous Y. Mekbib ORCID, Martijn A. van der Ent, Garrett Allington ORCID, Andrew Prendergast, Jocelyn E. Chau ORCID, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran ORCID, Charuta G. Furey, Le Thi Hao, Phan Q. Duy, Benjamin C. Reeves ORCID, Junhui Zhang and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.