Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations

• Published in: Genetics in medicine Vol. 17; no. 3; pp. 188 - 196
• Main Authors: Shenkar, Robert, Shi, Changbin, Rebeiz, Tania, Stockton, Rebecca A., McDonald, David A., Mikati, Abdul Ghani, Zhang, Lingjiao, Austin, Cecilia, Akers, Amy L., Gallione, Carol J., Rorrer, Autumn, Gunel, Murat, Min, Wang, Marcondes de Souza, Jorge, Lee, Connie, Marchuk, Douglas A., Awad, Issam A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2015; Elsevier Limited
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 631/208/737; 692/420/2489/144; 692/699/375/1370; Adolescent; Adult; Animals; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Biomedicine; Carrier Proteins - genetics; Cells, Cultured; Central Nervous System Neoplasms - enzymology; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - pathology; Child; Child, Preschool; Disease Models, Animal; Hemangioma, Cavernous, Central Nervous System - enzymology; Hemangioma, Cavernous, Central Nervous System - genetics; Hemangioma, Cavernous, Central Nervous System - pathology; Human Genetics; Human Umbilical Vein Endothelial Cells; Humans; Infant; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Keratin-1 - genetics; Laboratory Medicine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Middle Aged; Mutation; original-research-article; Prospective Studies; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; rho-Associated Kinases - antagonists & inhibitors; rho-Associated Kinases - metabolism; Stress Fibers - drug effects; Stress Fibers - metabolism; Young Adult; cerebral cavernous malformation; Rho kinase; vascular malformations
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/gim.2014.97

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.