PURPOSE: 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.
CONCLUSION: 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.