title: Cerebral cavernous malformations arise independent of the heart of glass receptor.
abstract: OBJECTIVE
  The Heart of Glass (HEG) receptor binds KRIT1 and functions with KRIT1, CCM2, and PDCD10 in a common signaling pathway required for heart and vascular development. Mutations in KRIT1, CCM2, and PDCD10 also underlie human cerebral cavernous malformation (CCM) and postnatal loss of these genes in the mouse endothelium results in rapid CCM formation. Here, we test the role of HEG in CCM formation in mice and in humans.
  
  
  METHODS
  We constitutively or conditionally deleted Heg and Ccm2 genes in genetically modified mice. Mouse embryos, brain, and retina tissues were analyzed to assess CCM lesion formation.
  
  
  RESULTS
  In postnatal mice, CCMs form with Ccm2-/- but not with Heg-/- or Heg-/-;Ccm2+/- endothelial cells. Consistent with these findings, human patients with CCM who lack exonic mutations in KRIT1, CCM2, or PDCD10 do not have mutations in HEG.
  
  
  CONCLUSIONS
  These findings suggest that the HEG-CCM signaling functions during cardiovascular development and growth, whereas CCMs arise because of loss of HEG-independent CCM signaling in the endothelium of the central nervous system after birth.
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Xiangjian
authors.initials: X
authors.lastname: Zheng
authors.affiliation: INSERM, U740, Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, Génétique des Maladies vasculaires UMRS740, Paris, France.|AP-HP, Groupe hospitalier Saint-Louis Lariboisière-Fernand-Widal,Service de génétique, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Riant
authors.affiliation: INSERM, U740, Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, Génétique des Maladies vasculaires UMRS740, Paris, France.|AP-HP, Groupe hospitalier Saint-Louis Lariboisière-Fernand-Widal,Service de génétique, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bergametti
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Myers
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Tang
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kleaveland
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Wei
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Jisheng
authors.initials: J
authors.lastname: Yang
authors.affiliation: INSERM, U740, Paris, France.|Univ Paris Diderot, Sorbonne Paris Cité, Génétique des Maladies vasculaires UMRS740, Paris, France.|AP-HP, Groupe hospitalier Saint-Louis Lariboisière-Fernand-Widal,Service de génétique, Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Tournier-Lasserve
authors.affiliation: Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia PA 1910.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D004727:Endothelium / Q000473:pathology*; D005333:Fetus / Q000473:pathology; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000075927:KRIT1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012160:Retina / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; C584441:HEG1 protein, human; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins; C480498:osmosensing scaffold for MEKK3 protein, mouse
keywords: genetics; human; models, animal; stroke