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Human Molecular Genetics Advance Access originally published online on December 16, 2008
Human Molecular Genetics 2009 18(5):911-918; doi:10.1093/hmg/ddn420
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© 2008 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells

Axel Pagenstecher1,{dagger}, Sonja Stahl2,{dagger}, Ulrich Sure3 and Ute Felbor2,*

1 Department of Neuropathology, University of Marburg, Germany 2 Department of Human Genetics, University of Würzburg, Germany 3 Department of Neurosurgery, University of Essen, Germany

* To whom correspondence should be addressed at: Department of Human Genetics, University of Würzburg, Biocentre, Am Hubland, D-97074 Würzburg, Germany. Tel: +49 9318884096; Fax: +49 9318884069; Email: felbor{at}biozentrum.uni-wuerzburg.de

Received October 22, 2008; Accepted December 8, 2008

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.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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