Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.

Original languageEnglish
Pages (from-to)265-286
Number of pages22
JournalTrends in Molecular Medicine
Issue number4
StatePublished - Apr 2019


  • Vein of Galen malformation
  • arteriovenous malformation
  • cerebrovascular disorders
  • ephrin signaling
  • neurosurgery
  • vasculogenesis


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