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Postzygotic mosaicism in cerebral cavernous malformation

BACKGROUND: Cerebral cavernous malformations (CCMs) can cause severe neurological morbidity but our understanding of the mechanisms that drive CCM formation and growth is still incomplete. Recent experimental data suggest that dysfunctional CCM3-deficient endothelial cell clones form cavernous lesio...

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Autores principales: Rath, Matthias, Pagenstecher, Axel, Hoischen, Alexander, Felbor, Ute
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042965/
https://www.ncbi.nlm.nih.gov/pubmed/31446422
http://dx.doi.org/10.1136/jmedgenet-2019-106182
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author Rath, Matthias
Pagenstecher, Axel
Hoischen, Alexander
Felbor, Ute
author_facet Rath, Matthias
Pagenstecher, Axel
Hoischen, Alexander
Felbor, Ute
author_sort Rath, Matthias
collection PubMed
description BACKGROUND: Cerebral cavernous malformations (CCMs) can cause severe neurological morbidity but our understanding of the mechanisms that drive CCM formation and growth is still incomplete. Recent experimental data suggest that dysfunctional CCM3-deficient endothelial cell clones form cavernous lesions in conjunction with normal endothelial cells. OBJECTIVE: In this study, we addressed the question whether endothelial cell mosaicism can be found in human cavernous tissue of CCM1 germline mutation carriers. METHODS AND RESULTS: Bringing together single-molecule molecular inversion probes in an ultra-sensitive sequencing approach with immunostaining to visualise the lack of CCM1 protein at single cell resolution, we identified a novel late postzygotic CCM1 loss-of-function variant in the cavernous tissue of a de novo CCM1 germline mutation carrier. The extended unilateral CCM had been located in the right central sulcus causing progressive proximal paresis of the left arm at the age of 15 years. Immunohistochemical analyses revealed that individual caverns are lined by both heterozygous (CCM1(+/−)) and compound heterozygous (CCM1(−/−)) endothelial cells. CONCLUSION: We here demonstrate endothelial cell mosaicism within single caverns of human CCM tissue. In line with recent in vitro data on CCM1-deficient endothelial cells, our results provide further evidence for clonal evolution in human CCM1 pathogenesis.
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spelling pubmed-70429652020-03-03 Postzygotic mosaicism in cerebral cavernous malformation Rath, Matthias Pagenstecher, Axel Hoischen, Alexander Felbor, Ute J Med Genet Somatic Mosaicism BACKGROUND: Cerebral cavernous malformations (CCMs) can cause severe neurological morbidity but our understanding of the mechanisms that drive CCM formation and growth is still incomplete. Recent experimental data suggest that dysfunctional CCM3-deficient endothelial cell clones form cavernous lesions in conjunction with normal endothelial cells. OBJECTIVE: In this study, we addressed the question whether endothelial cell mosaicism can be found in human cavernous tissue of CCM1 germline mutation carriers. METHODS AND RESULTS: Bringing together single-molecule molecular inversion probes in an ultra-sensitive sequencing approach with immunostaining to visualise the lack of CCM1 protein at single cell resolution, we identified a novel late postzygotic CCM1 loss-of-function variant in the cavernous tissue of a de novo CCM1 germline mutation carrier. The extended unilateral CCM had been located in the right central sulcus causing progressive proximal paresis of the left arm at the age of 15 years. Immunohistochemical analyses revealed that individual caverns are lined by both heterozygous (CCM1(+/−)) and compound heterozygous (CCM1(−/−)) endothelial cells. CONCLUSION: We here demonstrate endothelial cell mosaicism within single caverns of human CCM tissue. In line with recent in vitro data on CCM1-deficient endothelial cells, our results provide further evidence for clonal evolution in human CCM1 pathogenesis. BMJ Publishing Group 2020-03 2019-08-24 /pmc/articles/PMC7042965/ /pubmed/31446422 http://dx.doi.org/10.1136/jmedgenet-2019-106182 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Somatic Mosaicism
Rath, Matthias
Pagenstecher, Axel
Hoischen, Alexander
Felbor, Ute
Postzygotic mosaicism in cerebral cavernous malformation
title Postzygotic mosaicism in cerebral cavernous malformation
title_full Postzygotic mosaicism in cerebral cavernous malformation
title_fullStr Postzygotic mosaicism in cerebral cavernous malformation
title_full_unstemmed Postzygotic mosaicism in cerebral cavernous malformation
title_short Postzygotic mosaicism in cerebral cavernous malformation
title_sort postzygotic mosaicism in cerebral cavernous malformation
topic Somatic Mosaicism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042965/
https://www.ncbi.nlm.nih.gov/pubmed/31446422
http://dx.doi.org/10.1136/jmedgenet-2019-106182
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