title: Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.
abstract: OBJECTIVE
  The phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.
  
  
  METHODS
  We analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.
  
  
  RESULTS
  We determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.
  
  
  CONCLUSIONS
  These findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196.
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Shenkar
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Changbin
authors.initials: C
authors.lastname: Shi
authors.affiliation: Department of Neurology, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Rebeiz
authors.affiliation: Department of Pediatrics, University of California at Los Angeles, Torrance, CA 90502, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Stockton
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.|Center for Science, Math and Technology Education, North Carolina Central University, Durham, NC 27707, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: McDonald
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Abdul Ghani
authors.initials: AG
authors.lastname: Mikati
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Lingjiao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Austin
authors.affiliation: Angioma Alliance, Norfolk, VA 23510, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Akers
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Gallione
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Autumn
authors.initials: A
authors.lastname: Rorrer
authors.affiliation: Departments of Neurosurgery and Neurobiology, Yale University, New Haven, CT 06520, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Department of Pathology, Yale University, New Haven, CT 06520, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.affiliation: Department of Neurosurgery, School of Medicine, Federal University of Rio De Janeiro, Rio de Janeiro, Brazil.
authors.forename: Jorge Marcondes
authors.initials: JM
authors.lastname: De Souza
authors.affiliation: Angioma Alliance, Norfolk, VA 23510, USA.
authors.forename: Connie
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.affiliation: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.|Department of Neurology, The University of Chicago Medicine, Chicago, IL 60637, USA.
authors.forename: Issam A
authors.initials: IA
authors.lastname: Awad
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002478:Cells, Cultured; D016543:Central Nervous System Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D020786:Hemangioma, Cavernous, Central Nervous System / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053556:Keratin-1 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D055815:Young Adult; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C491616:KRT1 protein, human; D053556:Keratin-1; D008565:Membrane Proteins; C495390:PDCD10 protein, human; C559318:PDCD10 protein, mouse; D011518:Proto-Oncogene Proteins; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases