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

Shujuan ZhaoKedous Y MekbibMartijn A van der EntGarrett AllingtonAndrew PrendergastJocelyn E ChauHannah SmithJohn ShohfiJack OckenDaniel DuranCharuta G FureyLe Thi HaoPhan Q DuyBenjamin C ReevesJunhui ZhangCarol Nelson-WilliamsDi ChenBoyang LiTimothy NottoliSuxia BaiMyron RolleXue ZengWeilai DongPo-Ying FuYung-Chun WangShrikant ManePaulina PiwowarczykKatie Pricola FehnelAlfred Pokmeng SeeBermans J IskandarBeverly Aagaard-KienitzQuentin J MoyerEvan DennisEmre KiziltugAdam J KundishoraTyrone DeSpenzaAna B W GreenbergSeblewengel M KidanemariamAndrew T HaleJames M JohnstonEric M JacksonPhillip B StormShih-Shan LangWilliam E ButlerBob S CarterPaul ChapmanChristopher J StapletonAman B PatelGeorges RodeschStanislas SmajdaAlejandro BerensteinTanyeri BarakE Zeynep Erson-OmayHongyu ZhaoAndrés Moreno De LucaMark R ProctorEdward R SmithDarren B OrbachSeth L AlperStefania NicoliTitus J BoggonRichard P LiftonMurat GünelPhilip D KingSheng Chih JinKristopher T Kahle
Published in: Nature communications (2023)
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.
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