| http://purl.uniprot.org/citations/20940147 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/20940147 | http://www.w3.org/2000/01/rdf-schema#comment | "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."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.org/dc/terms/identifier | "doi:10.1093/hmg/ddq433"xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Kucherlapati R."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Shi C."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Ginsberg M.H."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Marchuk D.A."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Stockton R.A."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "McDonald D.A."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Shenkar R."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Awad I.A."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Kucherlapati M.H."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Akers A.L."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/author | "Brainer J."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/date | "2011"xsd:gYear |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/name | "Hum Mol Genet"xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/pages | "211-222"xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/title | "A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease."xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://purl.uniprot.org/core/volume | "20"xsd:string |
| http://purl.uniprot.org/citations/20940147 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/20940147 |
| http://purl.uniprot.org/citations/20940147 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/20940147 |
| http://purl.uniprot.org/uniprot/#_A0A0G2JGG7-mappedCitation-20940147 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/20940147 |
| http://purl.uniprot.org/uniprot/#_A0A0G2JE71-mappedCitation-20940147 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/20940147 |
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| http://purl.uniprot.org/uniprot/#_E0CYY2-mappedCitation-20940147 | http://www.w3.org/1999/02/22-rdf-syntax-ns#object | http://purl.uniprot.org/citations/20940147 |