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Finetti et al. Vessel Plus 2021;5:29 Vessel Plus
DOI: 10.20517/2574-1209.2021.49

Minireview Open Access

Non-autonomous effects of CCM genes loss

Federica Finetti, Lorenza Trabalzini

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 253100, Siena, Italy.
Correspondence to: Prof. Lorenza Trabalzini, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via
Aldo Moro 253100, Siena, Italy. E-mail: lorenza.trabalzini@unisi.it

How to cite this article: Finetti F, Trabalzini L. Non-autonomous effects of CCM genes loss. Vessel Plus 2021;5:29.
https://dx.doi.org/10.20517/2574-1209.2021.49
Received: 26 Mar 2021 First Decision: 15 Apr 2021 Revised: 23 Apr 2021 Accepted: 18 May 2021 Published: 11 Jun 2021

Academic Editor: Jun Zhang Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang

Abstract
Cerebral cavernous malformation (CCM) is a rare disease of proven genetic origin characterized by vascular
lesions affecting capillaries and small vessels of the central nervous system. CCM lesions occur in a range of
different phenotypes, including wide differences in lesion number, size, and susceptibility to intracerebral
hemorrhage. CCM lesion genesis requires loss of function of any of three genes, namely KRIT1 (CCM1),
MGC4607 (CCM2), and PDCD10 (CCM3). These genes exert pleiotropic effects regulating multiple mechanisms
involved in angiogenesis, cellular response, cell-cell and cell-matrix adhesion, cytoskeleton dynamics, and oxidative
damage protection. Familial CCM is an autosomal-dominantly inherited disease in which the loss of any of the
three CCM genes follows a two-hit mechanism. The heterozygous loss-of-function germline variants in one of the
involved genes seems to be associated with a second postzygotic mutation, according to Knudson’s two-hit model
of tumor suppressor genes. This review is an overview of very recent literature on CCM onset and progression
focused on the novel concept that the loss of a CCM gene in a single cell is sufficient to induce vascular lesions.
Mutated cells undergo clonal expansion and become able to promote the recruitment of non-mutated cells and to
induce their angiogenic switch through the increased production of angiogenic factors and downregulation of
antiangiogenic factors. A deep understanding of this process and the knowledge of unbalanced secreted factors
will be useful to design new pharmacological strategies for CCM patients.

Keywords: Cerebrovascular disease, cerebral cavernous malformation, KRIT1, CCM1, CCM2, CCM3, endothelial
cells, mosaicism

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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