Document Detail

A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease.
MedLine Citation:
PMID:  20940147     Owner:  NLM     Status:  MEDLINE    
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.
David A McDonald; Robert Shenkar; Changbin Shi; Rebecca A Stockton; Amy L Akers; Melanie H Kucherlapati; Raju Kucherlapati; James Brainer; Mark H Ginsberg; Issam A Awad; Douglas A Marchuk
Related Documents :
12691317 - Vascular tumors of the female genital tract: a clinicopathological study of nine cases.
21826797 - Raman spectroscopy: a potential tool for early objective diagnosis of neoplasia in the ...
21603827 - Entodermoscopy: dermoscopy for the diagnosis of pediculosis.
8210777 - Placental thrombi and related problems.
12207607 - Hydroa vacciniforme-like primary cutaneous cd8-positive t-cell lymphoma.
9775307 - Teratocarcinosarcoma of the nasal cavity and ethmoid.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-10-11
Journal Detail:
Title:  Human molecular genetics     Volume:  20     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2010-12-23     Completed Date:  2011-12-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  211-22     Citation Subset:  IM    
Molecular Genetics and Microbiology Department, Duke University Medical Center, Durham, NC 27710, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Disease Models, Animal*
Endothelial Cells / pathology
Hemangioma, Cavernous, Central Nervous System / genetics*,  pathology*
Mice, Knockout
Microtubule-Associated Proteins / deficiency,  genetics
MutS Homolog 2 Protein / deficiency,  genetics
Proto-Oncogene Proteins / deficiency,  genetics
rho-Associated Kinases / metabolism
Grant Support
Reg. No./Substance:
0/Ccm1 protein, mouse; 0/Microtubule-Associated Proteins; 0/Proto-Oncogene Proteins; EC Kinases; EC protein, mouse; EC Homolog 2 Protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Protein kinase A regulates caspase-1 via Ets-1 in bone stromal cell-derived lesions: a link between ...
Next Document:  The Machado-Joseph disease-associated mutant form of ataxin-3 regulates parkin ubiquitination and st...