Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
复制标题
DOI：
10.1038/s41467-023-43062-z
复制
发表时间：
2023-11-17
影响因子：
16.6
通讯作者：
Kahle, Kristopher T.
中科院分区：
文献类型：
--
作者：
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.;Aagaard-Kienitz, Beverly;Moyer, Quentin J.;Dennis, Evan;Kiziltug, Emre;Kundishora, Adam J.;DeSpenza Jr, Tyrone;Greenberg, Ana B. W.;Kidanemariam, Seblewengel M.;Hale, Andrew T.;Johnston, James M.;Jackson, Eric M.;Storm, Phillip B.;Lang, Shih-Shan;Butler, William E.;Carter, Bob S.;Chapman, Paul;Stapleton, Christopher J.;Patel, Aman B.;Rodesch, Georges;Smajda, Stanislas;Berenstein, Alejandro;Barak, Tanyeri;Erson-Omay, E. Zeynep;Zhao, Hongyu;Moreno-De-Luca, Andres;Proctor, Mark R.;Smith, Edward R.;Orbach, Darren B.;Alper, Seth L.;Nicoli, Stefania;Boggon, Titus J.;Lifton, Richard P.;Gunel, Murat;King, Philip D.;Jin, Sheng Chih;Kahle, Kristopher T.
为了阐明Galen静脉畸形（VOGM）的发病机制，VOGM是最常见和最严重的先天性脑动静脉畸形，我们对310个VOGM先证者家族外显子组和336，326个人类脑血管单细胞转录组进行了综合分析。我们发现Ras抑制基因p120 RasGAP（RASA 1）在全基因组范围内具有显著的功能缺失从头变异负担（2042.5倍，p = 4.79 x 10−7）。罕见的、破坏性的传递变异体富含Ephrin受体-B4（EPHB 4）（17.5倍，p = 1.22 x 10−5），它与p120 RasGAP合作调节血管发育。其他先证者在ACVRL 1、NOTCH 1、ITGB 1和PTPN 11中存在破坏性变异。ACVRL 1变体也在多代VOGM谱系中鉴定。综合基因组分析定义发展中的内皮细胞作为一个可能的时空轨迹VOGM病理生理。表达VOGM特异性EPHB 4激酶结构域错义变体（Phe 867 Leu）的小鼠表现出发育性血管生成中断和动脉-毛细血管-静脉网络分级发育受损，但仅在存在“二次打击”等位基因的情况下。这些结果阐明了人类动静脉发育和VOGM病理生物学，并对患者及其家属产生了影响。Galen静脉畸形是一种严重的先天性脑动静脉畸形。在本文中，作者通过对310个VOGM先证者家族外显子组和336，326个人类血管系统单细胞转录组进行综合分析，以确定关键信号调节因子的突变，从而阐明VOGM的发病机制。
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. Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.
登录
查看更多内容
影响因子：
9.8
作者：
Kerr, Georgina;Sheldon, Helen;Chaikuad, Apirat;Alfano, Ivan;von Delft, Frank;Bullock, Alex N.;Harris, Adrian L.
通讯作者：
Harris, Adrian L.
影响因子：
5.3
作者：
ZhuGe Q;Wu Z;Huang L;Zhao B;Zhong M;Zheng W;GouRong C;Mao X;Xie L;Wang X;Jin K
通讯作者：
Jin K
影响因子：
4.6
作者：
Chen, Di;Geng, Xin;King, Philip D.
通讯作者：
King, Philip D.
影响因子：
0.4
作者：
Chida, Ayako;Shintani, Masaki;Nakanishi, Toshio
通讯作者：
Nakanishi, Toshio
影响因子：
30.8
作者：
通讯作者：
--