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A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.

Publication ,  Journal Article
McDonald, DA; Shenkar, R; Shi, C; Stockton, RA; Akers, AL; Kucherlapati, MH; Kucherlapati, R; Brainer, J; Ginsberg, MH; Awad, IA; Marchuk, DA
Published in: Hum Mol Genet
January 15, 2011

Cerebral cavernous malformations (CCMs) are vascular lesions of the central nervous system appearing as multicavernous, blood-filled capillaries, leading to headache, seizure and hemorrhagic stroke. CCM occurs either sporadically or as an autosomal dominant disorder caused by germline mutation of one of the three genes: CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10. Surgically resected human CCM lesions have provided molecular and immunohistochemical evidence for a two-hit (germline plus somatic) mutation mechanism. In contrast to the equivalent human genotype, mice heterozygous for a Ccm1- or Ccm2-null allele do not develop CCM lesions. Based on the two-hit hypothesis, we attempted to improve the penetrance of the model by crossing Ccm1 and Ccm2 heterozygotes into a mismatch repair-deficient Msh2(-/-) background. Ccm1(+/-)Msh2(-/-) mice exhibit CCM lesions with high penetrance as shown by magnetic resonance imaging and histology. Significantly, the CCM lesions range in size from early-stage, isolated caverns to large, multicavernous lesions. A subset of endothelial cells within the CCM lesions revealed somatic loss of CCM protein staining, supporting the two-hit mutation mechanism. The late-stage CCM lesions displayed many of the characteristics of human CCM lesions, including hemosiderin deposits, immune cell infiltration, increased endothelial cell proliferation and increased Rho-kinase activity. Some of these characteristics were also seen, but to a lesser extent, in early-stage lesions. Tight junctions were maintained between CCM lesion endothelial cells, but gaps were evident between endothelial cells and basement membrane was defective. In contrast, the Ccm2(+/-)Msh2(-/-) mice lacked cerebrovascular lesions. The CCM1 mouse model provides an in vivo tool to investigate CCM pathogenesis and new therapies.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

January 15, 2011

Volume

20

Issue

2

Start / End Page

211 / 222

Location

England

Related Subject Headings

  • rho-Associated Kinases
  • Proto-Oncogene Proteins
  • Phenotype
  • Mutation
  • MutS Homolog 2 Protein
  • Microtubule-Associated Proteins
  • Mice, Knockout
  • Mice
  • KRIT1 Protein
  • Humans
 

Citation

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McDonald, D. A., Shenkar, R., Shi, C., Stockton, R. A., Akers, A. L., Kucherlapati, M. H., … Marchuk, D. A. (2011). A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease. Hum Mol Genet, 20(2), 211–222. https://doi.org/10.1093/hmg/ddq433
McDonald, David A., Robert Shenkar, Changbin Shi, Rebecca A. Stockton, Amy L. Akers, Melanie H. Kucherlapati, Raju Kucherlapati, et al. “A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.Hum Mol Genet 20, no. 2 (January 15, 2011): 211–22. https://doi.org/10.1093/hmg/ddq433.
McDonald DA, Shenkar R, Shi C, Stockton RA, Akers AL, Kucherlapati MH, et al. A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease. Hum Mol Genet. 2011 Jan 15;20(2):211–22.
McDonald, David A., et al. “A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.Hum Mol Genet, vol. 20, no. 2, Jan. 2011, pp. 211–22. Pubmed, doi:10.1093/hmg/ddq433.
McDonald DA, Shenkar R, Shi C, Stockton RA, Akers AL, Kucherlapati MH, Kucherlapati R, Brainer J, Ginsberg MH, Awad IA, Marchuk DA. A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease. Hum Mol Genet. 2011 Jan 15;20(2):211–222.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

January 15, 2011

Volume

20

Issue

2

Start / End Page

211 / 222

Location

England

Related Subject Headings

  • rho-Associated Kinases
  • Proto-Oncogene Proteins
  • Phenotype
  • Mutation
  • MutS Homolog 2 Protein
  • Microtubule-Associated Proteins
  • Mice, Knockout
  • Mice
  • KRIT1 Protein
  • Humans