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Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
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Postzygotic mosaicism in cerebral cavernous malformation
Matthias Rath1,2, Axel Pagenstecher3, Alexander Hoischen4
1Department of Human Genetics, University Medicine Greifswald, Greifswald, Germany.
Journal of Medical Genetics
|August 26, 2019
Summary
Endothelial cell mosaicism, where different cell types coexist, is found in human cerebral cavernous malformations (CCMs). This supports the clonal evolution theory in CCM pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Cerebral cavernous malformations (CCMs) cause significant neurological issues, with incomplete understanding of their development.
- Experimental data suggest CCMs arise from dysfunctional CCM3-deficient endothelial cell clones interacting with normal cells.
Purpose of the Study:
- To investigate the presence of endothelial cell mosaicism in human cavernous tissue from individuals with germline mutations in CCM1.
Main Methods:
- Utilized ultra-sensitive sequencing with single-molecule molecular inversion probes.
- Employed immunostaining for single-cell resolution visualization of CCM1 protein.
- Analyzed cavernous tissue from a de novo CCM1 germline mutation carrier.
Main Results:
- Identified a novel, late postzygotic CCM1 loss-of-function variant in the affected tissue.
- CCMs were located in the right central sulcus, causing progressive left arm paresis.
- Individual caverns showed lining by both heterozygous (CCM1+/-) and compound heterozygous (CCM1-/-) endothelial cells.
Conclusions:
- Demonstrated endothelial cell mosaicism within individual caverns of human CCM tissue.
- Results align with in vitro findings on CCM1-deficient cells.
- Provide further evidence for clonal evolution in the pathogenesis of human CCM1.
Keywords:
cerebral cavernous malformationslate postzygotic mutationpostzygotic mosaicismsmmipstwo-hit model of knudsonMore Related Videos
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