A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- McDonald, DA; Shenkar, R; Shi, C; Stockton, RA; Akers, AL; Kucherlapati, MH; Kucherlapati, R; Brainer, J; Ginsberg, MH; Awad, IA; Marchuk, DA
Published Date
- January 15, 2011
Published In
Volume / Issue
- 20 / 2
Start / End Page
- 211 - 222
PubMed ID
- 20940147
Pubmed Central ID
- PMC3005897
Electronic International Standard Serial Number (EISSN)
- 1460-2083
Digital Object Identifier (DOI)
- 10.1093/hmg/ddq433
Language
- eng
Conference Location
- England