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

Autor: 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.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Nov 17; Vol. 14 (1), pp. 7452. Date of Electronic Publication: 2023 Nov 17.
DOI: 10.1038/s41467-023-43062-z
Abstrakt: 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).)
Databáze: MEDLINE
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