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A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells
Open accessAbstract
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.
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Cited by
Engaging neuroscience to advance translational research in brain barrier biology
Neuwelt, E. A., Bauer, B., Fahlke, C., Fricker, G., Iadecola, C., Janigro, D., Leybaert, L., Molnár, Z., O'Donnell, M. E., Povlishock, J. T., et al. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn2995 · Cited by 579
Revencu, N., Boon, L. M., Mendola, A., Cordisco, M. R., Dubois, J., Clapuyt, P., Hammer, F., Amor, D. J., Irvine, A. D., Baselga, E., et al. (2013) · Human Mutation · doi:10.1002/humu.22431 · Cited by 294
Cerebral cavernous malformations: from CCM genes to endothelial cell homeostasis
Fischer, A., Zalvide, J., Faurobert, E., Albiges-Rizo, C., & Tournier-Lasserve, E. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.02.004 · Cited by 199
Faurobert, E., Rome, C., Lisowska, J., Manet-Dupé, S., Boulday, G., Malbouyres, M., Balland, M., Bouin, A.-P., Kéramidas, M., Bouvard, D., et al. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201303044 · Cited by 114
Metadata
- Authors
- Pagenstecher, A., Stahl, S., Sure, U., & Felbor, U.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-12-16
- Volume
- 18
- Issue
- 5
- Pages
- 911-918
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2122244785
- Cited by
- 210
- References
- 0
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- CoChat. (2026). Citation check: A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. https://app.cochat.ai/papers/10.1093/hmg/ddn420
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- Pagenstecher, A., Stahl, S., Sure, U., & Felbor, U. (2009). A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddn420
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