학술논문

Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations.
Document Type
Academic Journal
Author
Zhao S; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Mekbib KY; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; van der Ent MA; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.; Allington G; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Prendergast A; Yale Zebrafish Research Core, Yale School of Medicine, New Haven, CT, USA.; Chau JE; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.; Smith H; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Shohfi J; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Ocken J; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Duran D; Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS, USA.; Furey CG; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.; Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA.; Hao LT; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Duy PQ; Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA, USA.; Reeves BC; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Zhang J; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Nelson-Williams C; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Chen D; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA.; Li B; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.; Nottoli T; Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.; Bai S; Yale Genome Editing Center, Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.; Rolle M; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Zeng X; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.; Dong W; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.; Fu PY; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Wang YC; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.; Mane S; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Piwowarczyk P; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Fehnel KP; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; See AP; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Iskandar BJ; Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.; Aagaard-Kienitz B; Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.; Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.; Moyer QJ; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Dennis E; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Kiziltug E; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Kundishora AJ; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; DeSpenza T Jr; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Greenberg ABW; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Kidanemariam SM; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.; Hale AT; Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL, USA.; Johnston JM; Department of Neurosurgery, University of Alabama School of Medicine, Birmingham, AL, USA.; Jackson EM; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Storm PB; Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Lang SS; Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Butler WE; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Carter BS; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Chapman P; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Stapleton CJ; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Patel AB; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Rodesch G; Service de Neuroradiologie Diagnostique et Thérapeutique, Hôpital Foch, Suresnes, France.; Department of Interventional Neuroradiology, Hôpital Fondation A. de Rothschild, Paris, France.; Smajda S; Department of Interventional Neuroradiology, Hôpital Fondation A. de Rothschild, Paris, France.; Berenstein A; Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Barak T; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Erson-Omay EZ; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; Zhao H; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.; Moreno-De-Luca A; Department of Radiology, Autism & Developmental Medicine Institute, Genomic Medicine Institute, Geisinger, Danville, PA, USA.; Proctor MR; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Smith ER; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Orbach DB; Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Department of Neurointerventional Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Alper SL; Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, USA.; Nicoli S; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.; Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, CT, USA.; Boggon TJ; Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT, USA.; Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.; Lifton RP; Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.; Gunel M; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.; King PD; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA. kingp@umich.edu.; Jin SC; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. jin810@wustl.edu.; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA. jin810@wustl.edu.; Kahle KT; Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Kahle.Kristopher@mgh.harvard.edu.; Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. Kahle.Kristopher@mgh.harvard.edu.; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, US. Kahle.Kristopher@mgh.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Kahle.Kristopher@mgh.harvard.edu.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
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.
(© 2023. The Author(s).)