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

Publication ,  Journal Article
Shenkar, R; Shi, C; Rebeiz, T; Stockton, RA; McDonald, DA; Mikati, AG; Zhang, L; Austin, C; Akers, AL; Gallione, CJ; Rorrer, A; Gunel, M ...
Published in: Genet Med
March 2015

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.

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Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

March 2015

Volume

17

Issue

3

Start / End Page

188 / 196

Location

United States

Related Subject Headings

  • rho-Associated Kinases
  • Young Adult
  • Stress Fibers
  • Proto-Oncogene Proteins
  • Prospective Studies
  • Mutation
  • Middle Aged
  • Mice
  • Membrane Proteins
  • Keratin-1
 

Citation

APA
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ICMJE
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Shenkar, R., Shi, C., Rebeiz, T., Stockton, R. A., McDonald, D. A., Mikati, A. G., … Awad, I. A. (2015). Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med, 17(3), 188–196. https://doi.org/10.1038/gim.2014.97
Shenkar, Robert, Changbin Shi, Tania Rebeiz, Rebecca A. Stockton, David A. McDonald, Abdul Ghani Mikati, Lingjiao Zhang, et al. “Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.Genet Med 17, no. 3 (March 2015): 188–96. https://doi.org/10.1038/gim.2014.97.
Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, et al. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med. 2015 Mar;17(3):188–96.
Shenkar, Robert, et al. “Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations.Genet Med, vol. 17, no. 3, Mar. 2015, pp. 188–96. Pubmed, doi:10.1038/gim.2014.97.
Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, De Souza JM, Lee C, Marchuk DA, Awad IA. Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med. 2015 Mar;17(3):188–196.

Published In

Genet Med

DOI

EISSN

1530-0366

Publication Date

March 2015

Volume

17

Issue

3

Start / End Page

188 / 196

Location

United States

Related Subject Headings

  • rho-Associated Kinases
  • Young Adult
  • Stress Fibers
  • Proto-Oncogene Proteins
  • Prospective Studies
  • Mutation
  • Middle Aged
  • Mice
  • Membrane Proteins
  • Keratin-1