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

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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.

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Most cited references 30

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Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations.

D. Rigamonti, R Clatterbuck, B Crain … (2001)

Cerebral cavernous malformations are linked to mutations of the KRIT1 gene at the CCM1 locus and to mutations at two other loci, CCM2 and CCM3, for which genes are not yet identified. There is little information regarding the function of KRIT1. Histological and immunocytochemical analysis of cavernous malformations have not shed much light on their pathophysiology. Morphological analysis of cavernous malformations was extended to the ultrastructural level by examining lesions from two patients by immunocytochemistry and electron microscopy. The lesions consisted of endothelial lined vascular sinusoids embedded in a collagen matrix. Nuclei belonging to cells distinct from endothelial cells were rare. The basal lamina of the endothelial cells consisted focally of multiple layers. No tight junctions at endothelial cell interfaces were found; however, several examined endothelial cell interfaces demonstrated apparent gaps between endothelial cell processes where basal lamina was exposed directly to the lumen of the sinusoids. Heavy hemosiderin deposits were found underlying the vascular channels within microns of the basal lamina without evidence of disrupted vessels. No astrocytic foot processes were seen within lesions. Glial fibrillary acidic protein immunocytochemistry confirmed that astrocyte processes stopped at the border of the lesions. The absence of blood-brain barrier components may lead to leakage of red blood cells into these lesions and the surrounding brain in the absence of major haemorrhage, thus accounting for the propensity of cavernous malformations to cause seizures. These data also raise the possibility that KRIT1 plays a part in the formation of endothelial cell junctions and expression of a mature vascular phenotype.

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Genetics of cavernous angiomas.

Francoise Bergametti, C Denier, Pierre Labauge … (2007)

Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of patients with a genetic form of the disease are now available. In addition, three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.

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Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients.

Michael O Alberti, Jessica A. Siegel, L. Benes … (2002)

The authors review the pertinent literature dealing with all aspects of cerebral cavernous malformations in the adult. Clinical, neuroradiological, pathological, and epidemiological aspects are presented. The clinical significance of bleeding from cavernous malformations and various hemorrhage patterns are discussed in relation to the factors that influence hemorrhage rates. Recent reports describing the genetic mechanisms of inheritance, de novo formation, and angiogenesis of cavernomas are reviewed as well. Brainstem cavernomas have received special attention, since their clinical management is controversial in the literature. Presently, microsurgical removal is favored by the majority of authors and stereotactic radiosurgery appears to be inappropriate for prevention of bleeding from a cavernoma. Our own case material consists of data of 72 patients operated upon during the past 5 years. Twenty-four patients harbored the lesion within the brainstem, 18 within the deep white matter of the hemispheres, 12 in the basal ganglia or thalamus, 11 in superficial areas of the hemisphere, and seven within the cerebellum. The perioperative morbidity rate was 29.2% (21/72) while the rate of long-term morbidity was 5.5% (4/72), with no mortality in this series. It is concluded that cerebral cavernous malformations, including lesions in critical regions of the brain, can be treated microsurgically with excellent results and an acceptable morbidity.

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Author and article information

Journal

Journal ID (nlm-ta): Hum Mol Genet

Journal ID (publisher-id): hmg

Journal ID (hwp): hmg

Title: Human Molecular Genetics

Publisher: Oxford University Press

ISSN (Print): 0964-6906

ISSN (Electronic): 1460-2083

Publication date (Print): 1 March 2009

Publication date (Electronic): 16 December 2008

Publication date PMC-release: 16 December 2008

Volume: 18

Issue: 5

Pages: 911-918

Affiliations

[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

Author notes

[†]

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

[* ]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@ 123456biozentrum.uni-wuerzburg.de

Article

Publisher ID: ddn420

DOI: 10.1093/hmg/ddn420

PMC ID: 2640205

PubMed ID: 19088124

SO-VID: a4605ecb-92dd-496c-baff-737879a8306f

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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

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Evolutionary Cell Biology

Most cited references 30

Ultrastructural and immunocytochemical evidence that an incompetent blood-brain barrier is related to the pathophysiology of cavernous malformations.

Genetics of cavernous angiomas.

Cerebral cavernomas in the adult. Review of the literature and analysis of 72 surgically treated patients.

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