From Genes and Mechanisms to Molecular-Targeted Therapies: The Long Climb to the Cure of Cerebral Cavernous Malformation (CCM) Disease

Retta, Saverio Francesco; Perrelli, Andrea; Trabalzini, Lorenza; Finetti, Federica

doi:10.1007/978-1-0716-0640-7_1

Cited by 14 publications

(13 citation statements)

References 141 publications

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“…Sporadic CCMs, which accounted for the majority (808 5%), usually presented as isolated lesions. Familial CCMs (15~20%) were followed by an autosomal dominant inheritance pattern and usually presented with multiple lesions (1,19,21,22). The loss of function (LOF) mutations of CCM1 (KRIT1, Krev interaction trapped protein 1) (23)(24)(25)(26)(27), CCM2 (MGC6407, encoding a protein named malcavernin) (28)(29)(30)(31)(32)(33), and CCM3 (PDCD10, Programmed cell death protein 10) (34)(35)(36) have been thought to be the culprits of familial CCM.…”

Section: Genetic Mutations and Ccm Pathogenesismentioning

confidence: 99%

“…In general, the pathological features would reveal the essence of disease, including abnormality of endothelial cell tight junctions, proliferation of glia and endothelial cells, and even the alteration in the cytoskeleton and cell volume (4,22,35). Typically, CCM lesions are mulberula-like clusters of enlarged endovascular lumens.…”

Section: Molecular Pathology and Signaling Pathway Mechanismmentioning

confidence: 99%

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Cerebral Cavernous Malformation: Immune and Inflammatory Perspectives

Peng

Ren

et al. 2022

Front. Immunol.

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Cerebral cavernous malformation (CCM) is a type of vascular anomaly that arises due to the dyshomeostasis of brain capillary networks. In the past two decades, many advances have been made in this research field. Notably, as a more reasonable current view, the CCM lesions should be attributed to the results of a great number of additional events related to the homeostasis disorder of the endothelial cell. Indeed, one of the most fascinating concerns in the research field is the inflammatory perturbation in the immune microenvironment, which would affect the disease progression as well as the patients’ outcomes. In this work, we focused on this topic, and underlined the immune-related factors’ contribution to the CCM pathologic progression.

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Section: Genetic Mutations and Ccm Pathogenesismentioning

confidence: 99%

Section: Molecular Pathology and Signaling Pathway Mechanismmentioning

confidence: 99%

Cerebral Cavernous Malformation: Immune and Inflammatory Perspectives

Peng

Ren

et al. 2022

Front. Immunol.

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“…In particular CCM deficiency have been associated with hyperactivation of the MEKK3-MEK5-ERK5 kinase cascade, that leads to KLF2 and KLF4 upregulation and subsequent altered expression of bone morphogenic protein 6 (BMP6), thrombomodulin (TM), and thrombospondin 1 [15][16][17][18] , with activation of RhoA-ROCK signaling, and with alteration of the junctional signaling including VE-cadherin and β-catenin [19,20] . A significant alteration of reactive oxygen species balance has been also extensively described [13,[21][22][23] .…”

Section: Introductionmentioning

confidence: 96%

“…At the molecular level, CCM gene loss induces the activation of different signaling pathways [12][13][14] . In particular CCM deficiency have been associated with hyperactivation of the MEKK3-MEK5-ERK5 kinase cascade, that leads to KLF2 and KLF4 upregulation and subsequent altered expression of bone morphogenic protein 6 (BMP6), thrombomodulin (TM), and thrombospondin 1 [15][16][17][18] , with activation of RhoA-ROCK signaling, and with alteration of the junctional signaling including VE-cadherin and β-catenin [19,20] .…”

Section: Introductionmentioning

confidence: 99%

Non-autonomous effects of CCM genes loss

Finetti¹,

Trabalzini²

2021

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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.

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“…However, no mutation in either of the three known CCM genes were found in 5-15% of all CCM cases with a positive family history, suggesting either the potential existence of additional CCM genes or the presence of causative variants lost by traditional sequencing methods [12,19]. Moreover, whereas an incomplete penetrance and no clear genotype-phenotype correlations have been observed to date, the wide variability in phenotypes seen among carriers of the same CCM gene mutation, such as the development of CCM lesions of various numbers and sizes, and the occurrence and recurrence of ICH, suggests that the influence of additional pathogenicity determinants, including genetic and/or environmental modifiers [20][21][22][23][24]. In particular, growing evidence points to microenvironmental stress factors, such as oxidative stress and inflammation, as crucial determinants of CCM disease pathogenesis and severity, suggesting a potential impact of inter-individual heterogeneity in susceptibility to oxidative stress and inflammatory events due to genetic modifiers [22,[24][25][26][27][28][29][30][31][32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)

et al. 2022

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Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin that predisposes to seizures, focal neurological deficits and fatal intracerebral hemorrhage. It may occur sporadically or in familial forms, segregating as an autosomal dominant condition with incomplete penetrance and highly variable expressivity. Its pathogenesis has been associated with loss-of-function mutations in three genes, namely KRIT1 (CCM1), CCM2 and PDCD10 (CCM3), which are implicated in defense mechanisms against oxidative stress and inflammation. Herein, we screened 21 Italian CCM cases using clinical exome sequencing and found six cases (~29%) with pathogenic variants in CCM genes, including a large 145–256 kb genomic deletion spanning the KRIT1 gene and flanking regions, and the KRIT1 c.1664C>T variant, which we demonstrated to activate a donor splice site in exon 16. The segregation of this cryptic splicing mutation was studied in a large Italian family (five affected and seven unaffected cases), and showed a largely heterogeneous clinical presentation, suggesting the implication of genetic modifiers. Moreover, by extending genetic analysis to a virtual panel of 23 cerebrovascular disease-related genes (Cerebro panel), we found two variants in NOTCH3 and PTEN genes, which could contribute to the abnormal oxidative stress and inflammatory responses to date implicated in CCM disease pathogenesis.

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From Genes and Mechanisms to Molecular-Targeted Therapies: The Long Climb to the Cure of Cerebral Cavernous Malformation (CCM) Disease

Cited by 14 publications

References 141 publications

Cerebral Cavernous Malformation: Immune and Inflammatory Perspectives

Cerebral Cavernous Malformation: Immune and Inflammatory Perspectives

Non-autonomous effects of CCM genes loss

Next-Generation Sequencing Advances the Genetic Diagnosis of Cerebral Cavernous Malformation (CCM)

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