title: A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.
abstract: Cavernous vascular malformations occur with a frequency of 1:200 and can cause recurrent headaches, seizures and hemorrhagic stroke if located in the brain. Familial cerebral cavernous malformations (CCMs) have been associated with germline mutations in CCM1/KRIT1, CCM2 or CCM3/PDCD10. For each of the three CCM genes, we here show complete localized loss of either CCM1, CCM2 or CCM3 protein expression depending on the inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein but not for the two others. In addition to proving loss of function at the protein level, our data are the first to demonstrate endothelial cell mosaicism within cavernous tissues and provide clear pathogenetic evidence that the endothelial cell is the cell of disease origin.
authors.affiliation: Department of Neuropathology, University of Marburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Pagenstecher
authors.forename: Sonja
authors.initials: S
authors.lastname: Stahl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.forename: Ute
authors.initials: U
authors.lastname: Felbor
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D020786:Hemangioma, Cavernous, Central Nervous System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000075927:KRIT1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; C495390:PDCD10 protein, human; D011518:Proto-Oncogene Proteins