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Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
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, 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.
Affiliation
  • Zhao S; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • Mekbib KY; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • van der Ent MA; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Allington G; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Prendergast A; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Chau JE; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Smith H; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • Shohfi J; Yale Zebrafish Research Core, Yale School of Medicine, New Haven, CT, USA.
  • Ocken J; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.
  • Duran D; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Furey CG; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Hao LT; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Duy PQ; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Reeves BC; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Zhang J; Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, USA.
  • Nelson-Williams C; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Chen D; Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
  • Li B; Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA.
  • Nottoli T; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Bai S; Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Rolle M; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Zeng X; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • Dong W; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • Fu PY; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • Wang YC; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
  • Mane S; Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Piwowarczyk P; Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
  • Fehnel KP; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • See AP; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.
  • Iskandar BJ; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • Aagaard-Kienitz B; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • Moyer QJ; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • Dennis E; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • Kiziltug E; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
  • Kundishora AJ; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • DeSpenza T; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Greenberg ABW; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kidanemariam SM; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Hale AT; Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Johnston JM; Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Jackson EM; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Storm PB; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Lang SS; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Butler WE; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Carter BS; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Chapman P; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
  • Stapleton CJ; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Patel AB; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
  • Rodesch G; Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL, USA.
  • Smajda S; Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL, USA.
Nat Commun ; 14(1): 7452, 2023 11 17.
Article in En | MEDLINE | ID: mdl-37978175
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.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vascular Diseases / Vein of Galen Malformations Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Vascular Diseases / Vein of Galen Malformations Limits: Animals / Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido