Genetic dysregulation of an endothelial Ras signaling network in vein of Galen malformations
Zhao, S.; Mekbib, K. Y.; van der Ent, M. A.; Allington, G.; Prendergast, A.; Chau, J. E.; Smith, H.; Shohfi, J.; Ocken, J.; Duran, D.; Furey, C. G.; Le, H. T.; Duy, P. Q.; Reeves, B. C.; Zhang, J.; Nelson-Williams, C.; Chen, D.; Li, B.; Nottoli, T.; Bai, S.; Rolle, M.; Zeng, X.; Dong, W.; Fu, P.-Y.; Wang, Y.-C.; Mane, S.; Piwowarczyk, P.; Fehnel, K. P.; See, A. P.; Iskandar, B. J.; Aagaard-Kienitz, B.; Kundishora, A. J.; DeSpenza, T.; Greenberg, A. B. W.; Kidanemariam, S. M.; Prendergast, A.; Johnston, J. M.; Jackson, E.; Storm, P. B.; Lang, S.-S.; Butler, W. E.; Carter, B. S.; Chapman, P.; St
Show abstract
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and severe congenital brain arteriovenous malformation, 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 (p=4.79x10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (p=1.22x10-5), which cooperates with p120 RasGAP to limit Ras activation. Other probands had pathogenic variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomics defined developing endothelial cells as a key spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant exhibited constitutive endothelial Ras/ERK/MAPK activation and impaired hierarchical development of angiogenesis-regulated arterial-capillary-venous networks, but only when carrying a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have clinical implications.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.