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

Shujuan Zhao; Kedous Y. Mekbib; Martijn A. van der Ent; Garrett Allington; Andrew Prendergast; Jocelyn E. Chau; Hannah Smith; John Shohfi; Jack Ocken; Daniel Duran; Charuta G. Furey; Le Thi Hao; Phan Q. Duy; Benjamin C. Reeves; Junhui Zhang; Carol Nelson-Williams; Di Chen; Boyang Li; Timothy Nottoli; Suxia Bai; Myron Rolle; Xue Zeng; Weilai Dong; Po Ying Fu; Yung Chun Wang; Shrikant Mane; Paulina Piwowarczyk; Katie Pricola Fehnel; Alfred Pokmeng See; Bermans J. Iskandar; Beverly Aagaard-Kienitz; Quentin J. Moyer; Evan Dennis; Emre Kiziltug; Adam J. Kundishora; Tyrone DeSpenza; Ana B.W. Greenberg; Seblewengel M. Kidanemariam; Andrew T. Hale; James M. Johnston; Eric M. Jackson; Phillip B. Storm; Shih Shan Lang; William E. Butler; Bob S. Carter; Paul Chapman; Christopher J. Stapleton; Aman B. Patel; Georges Rodesch; Stanislas Smajda; Alejandro Berenstein; Tanyeri Barak; E. Zeynep Erson-Omay; Hongyu Zhao; Andres Moreno-De-Luca; Mark R. Proctor; Edward R. Smith; Darren B. Orbach; Seth L. Alper; Stefania Nicoli; Titus J. Boggon; Richard P. Lifton; Murat Gunel; Philip D. King; Sheng Chih Jin; Kristopher T. Kahle

doi:10.1038/s41467-023-43062-z

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

Shujuan Zhao, Kedous Y. Mekbib, Martijn A. van der Ent, Garrett Allington, Andrew Prendergast, Jocelyn E. Chau, Hannah Smith, John Shohfi, Jack Ocken, Daniel Duran, Charuta G. Furey, Le Thi Hao, Phan Q. Duy, Benjamin C. Reeves, Junhui Zhang, Carol Nelson-Williams, Di Chen, Boyang Li, Timothy Nottoli, Suxia BaiMyron Rolle, Xue Zeng, Weilai Dong, Po Ying Fu, Yung Chun Wang, Shrikant Mane, Paulina Piwowarczyk, Katie Pricola Fehnel, Alfred Pokmeng See, Bermans J. Iskandar, Beverly Aagaard-Kienitz, Quentin J. Moyer, Evan Dennis, Emre Kiziltug, Adam J. Kundishora, Tyrone DeSpenza, Ana B.W. Greenberg, Seblewengel M. Kidanemariam, Andrew T. Hale, James M. Johnston, Eric M. Jackson, Phillip B. Storm, Shih Shan Lang, William E. Butler, Bob S. Carter, Paul Chapman, Christopher J. Stapleton, Aman B. Patel, Georges Rodesch, Stanislas Smajda, Alejandro Berenstein, Tanyeri Barak, E. Zeynep Erson-Omay, Hongyu Zhao, Andres Moreno-De-Luca, Mark R. Proctor, Edward R. Smith, Darren B. Orbach, Seth L. Alper, Stefania Nicoli, Titus J. Boggon, Richard P. Lifton, Murat Gunel, Philip D. King, Sheng Chih Jin, Kristopher T. Kahle

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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 10⁻⁷). 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.

Original language	English
Article number	7452
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-43062-z
State	Published - Dec 2023

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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., Hao, L. T., Duy, P. Q., Reeves, B. C., Zhang, J., Nelson-Williams, C., Chen, D., Li, B., Nottoli, T., ... Kahle, K. T. (2023). Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations. Nature communications, 14(1), Article 7452. https://doi.org/10.1038/s41467-023-43062-z

@article{d7ce00b7583e482fa1f5218e59b3f2db,

title = "Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations",

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 10−7). 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.",

author = "Shujuan Zhao and Mekbib, {Kedous Y.} and {van der Ent}, {Martijn A.} and Garrett Allington and Andrew Prendergast and Chau, {Jocelyn E.} and Hannah Smith and John Shohfi and Jack Ocken and Daniel Duran and Furey, {Charuta G.} and Hao, {Le Thi} and Duy, {Phan Q.} and Reeves, {Benjamin C.} and Junhui Zhang and Carol Nelson-Williams and Di Chen and Boyang Li and Timothy Nottoli and Suxia Bai and Myron Rolle and Xue Zeng and Weilai Dong and Fu, {Po Ying} and Wang, {Yung Chun} and Shrikant Mane and Paulina Piwowarczyk and Fehnel, {Katie Pricola} and See, {Alfred Pokmeng} and Iskandar, {Bermans J.} and Beverly Aagaard-Kienitz and Moyer, {Quentin J.} and Evan Dennis and Emre Kiziltug and Kundishora, {Adam J.} and Tyrone DeSpenza and Greenberg, {Ana B.W.} and Kidanemariam, {Seblewengel M.} and Hale, {Andrew T.} and Johnston, {James M.} and Jackson, {Eric M.} and Storm, {Phillip B.} and Lang, {Shih Shan} and Butler, {William E.} and Carter, {Bob S.} and Paul Chapman and Stapleton, {Christopher J.} and Patel, {Aman B.} and Georges Rodesch and Stanislas Smajda and Alejandro Berenstein and Tanyeri Barak and Erson-Omay, {E. Zeynep} and Hongyu Zhao and Andres Moreno-De-Luca and Proctor, {Mark R.} and Smith, {Edward R.} and Orbach, {Darren B.} and Alper, {Seth L.} and Stefania Nicoli and Boggon, {Titus J.} and Lifton, {Richard P.} and Murat Gunel and King, {Philip D.} and Jin, {Sheng Chih} and Kahle, {Kristopher T.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-43062-z",

language = "English",

volume = "14",

journal = "Nature communications",

issn = "2041-1723",

number = "1",

}

Zhao, S, Mekbib, KY, van der Ent, MA, Allington, G, Prendergast, A, Chau, JE, Smith, H, Shohfi, J, Ocken, J, Duran, D, Furey, CG, Hao, LT, Duy, PQ, Reeves, BC, Zhang, J, Nelson-Williams, C, Chen, D, Li, B, Nottoli, T, Bai, S, Rolle, M, Zeng, X, Dong, W, Fu, PY, Wang, YC, Mane, S, Piwowarczyk, P, Fehnel, KP, See, AP, Iskandar, BJ, Aagaard-Kienitz, B, Moyer, QJ, Dennis, E, Kiziltug, E, Kundishora, AJ, DeSpenza, T, Greenberg, ABW, Kidanemariam, SM, Hale, AT, Johnston, JM, Jackson, EM, Storm, PB, Lang, SS, Butler, WE, Carter, BS, Chapman, P, Stapleton, CJ, Patel, AB, Rodesch, G, Smajda, S, Berenstein, A, Barak, T, Erson-Omay, EZ, Zhao, H, Moreno-De-Luca, A, Proctor, MR, Smith, ER, Orbach, DB, Alper, SL, Nicoli, S, Boggon, TJ, Lifton, RP, Gunel, M, King, PD, Jin, SC & Kahle, KT 2023, 'Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations', Nature communications, vol. 14, no. 1, 7452. https://doi.org/10.1038/s41467-023-43062-z

TY - JOUR

T1 - Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations

AU - Zhao, Shujuan

AU - Mekbib, Kedous Y.

AU - van der Ent, Martijn A.

AU - Allington, Garrett

AU - Prendergast, Andrew

AU - Chau, Jocelyn E.

AU - Smith, Hannah

AU - Shohfi, John

AU - Ocken, Jack

AU - Duran, Daniel

AU - Furey, Charuta G.

AU - Hao, Le Thi

AU - Duy, Phan Q.

AU - Reeves, Benjamin C.

AU - Zhang, Junhui

AU - Nelson-Williams, Carol

AU - Chen, Di

AU - Li, Boyang

AU - Nottoli, Timothy

AU - Bai, Suxia

AU - Rolle, Myron

AU - Zeng, Xue

AU - Dong, Weilai

AU - Fu, Po Ying

AU - Wang, Yung Chun

AU - Mane, Shrikant

AU - Piwowarczyk, Paulina

AU - Fehnel, Katie Pricola

AU - See, Alfred Pokmeng

AU - Iskandar, Bermans J.

AU - Aagaard-Kienitz, Beverly

AU - Moyer, Quentin J.

AU - Dennis, Evan

AU - Kiziltug, Emre

AU - Kundishora, Adam J.

AU - DeSpenza, Tyrone

AU - Greenberg, Ana B.W.

AU - Kidanemariam, Seblewengel M.

AU - Hale, Andrew T.

AU - Johnston, James M.

AU - Jackson, Eric M.

AU - Storm, Phillip B.

AU - Lang, Shih Shan

AU - Butler, William E.

AU - Carter, Bob S.

AU - Chapman, Paul

AU - Stapleton, Christopher J.

AU - Patel, Aman B.

AU - Rodesch, Georges

AU - Smajda, Stanislas

AU - Berenstein, Alejandro

AU - Barak, Tanyeri

AU - Erson-Omay, E. Zeynep

AU - Zhao, Hongyu

AU - Moreno-De-Luca, Andres

AU - Proctor, Mark R.

AU - Smith, Edward R.

AU - Orbach, Darren B.

AU - Alper, Seth L.

AU - Nicoli, Stefania

AU - Boggon, Titus J.

AU - Lifton, Richard P.

AU - Gunel, Murat

AU - King, Philip D.

AU - Jin, Sheng Chih

AU - Kahle, Kristopher T.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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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U2 - 10.1038/s41467-023-43062-z

DO - 10.1038/s41467-023-43062-z

M3 - Article

C2 - 37978175

AN - SCOPUS:85176952651

SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 7452

ER -

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

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