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Genet Med. 2015 Mar;17(3):188-196. doi: 10.1038/gim.2014.97. Epub 2014 Aug 14.

Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.

Author information

1
Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
2
Department of Neurology, The University of Chicago Medicine, Chicago, IL 60637, USA.
3
Department of Pediatrics, University of California at Los Angeles, Torrance, CA 90502, USA.
4
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
5
Center for Science, Math and Technology Education, North Carolina Central University, Durham, NC 27707, USA.
6
Angioma Alliance, Norfolk, VA 23510, USA.
7
Departments of Neurosurgery and Neurobiology, Yale University, New Haven, CT 06520, USA.
8
Department of Pathology, Yale University, New Haven, CT 06520, USA.
9
Department of Neurosurgery, School of Medicine, Federal University of Rio De Janeiro, Rio de Janeiro, Brazil.
#
Contributed equally

Abstract

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.

PMID:
25122144
PMCID:
PMC4329119
DOI:
10.1038/gim.2014.97
[Indexed for MEDLINE]
Free PMC Article

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