A Novel CCM2 Gene Mutation Associated With Cerebral Cavernous Malformation

Liu, Yang; Wu, Jian; Zhang, Jing

doi:10.3389/fneur.2020.00070

Cited by 8 publications

(10 citation statements)

References 38 publications

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“…The biochemical connections between these suggest that certain therapies may be effective in multiple types of VMs. The study of abnormal proteins could facilitate the understanding of the molecular mechanisms present in the case of VMs [ 8 , 10 , 11 ].…”

Section: Discussion and Future Therapeutic Perspectives Correlated Wi...mentioning

confidence: 99%

“…Familial forms are determined by mutations transmitted in an autosomal dominant manner with incomplete penetrance, involving the CCM1 (KRIT1) gene, located on chromosome 7q21–22 [10, the CCM2 ( MGC4607 or malcavernin gene) located on chromosome 7p13–15 [ 11 ], and the PDCD10 (CCM3) gene located on chromosome 3q25.2–27 [ 12 ]. The first mutations identified were a LOF mutations in the KRIT1 gene, which encodes the protein KRIT1 (KREV1 interaction trapped 1), an evolutionarily conserved Ras-family GTPase.…”

Section: Vascular Anomalies: Ras/raf/mapk/erk Signaling Pathways (Ras...mentioning

confidence: 99%

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The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

Butnariu

Gorduza

Florea

et al. 2022

IJMS

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Vascular anomalies (VAs) are morphogenesis defects of the vascular system (arteries, capillaries, veins, lymphatic vessels) singularly or in complex combinations, sometimes with a severe impact on the quality of life. The progress made in recent years with the identification of the key molecular pathways (PI3K/AKT/mTOR and RAS/BRAF/MAPK/ERK) and the gene mutations that lead to the appearance of VAs has allowed the deciphering of their complex genetic architecture. Understanding these mechanisms is critical both for the correct definition of the phenotype and classification of VAs, as well as for the initiation of an optimal therapy and the development of new targeted therapies. The purpose of this review is to present in synthesis the current data related to the genetic factors involved in the etiology of VAs, as well as the possible directions for future research. We analyzed the data from the literature related to VAs, using databases (Google Scholar, PubMed, MEDLINE, OMIM, MedGen, Orphanet) and ClinicalTrials.gov. The obtained results revealed that the phenotypic variability of VAs is correlated with genetic heterogeneity. The identification of new genetic factors and the molecular mechanisms in which they intervene, will allow the development of modern therapies that act targeted as a personalized therapy. We emphasize the importance of the geneticist in the diagnosis and treatment of VAs, as part of a multidisciplinary team involved in the management of VAs.

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Section: Discussion and Future Therapeutic Perspectives Correlated Wi...mentioning

confidence: 99%

Section: Vascular Anomalies: Ras/raf/mapk/erk Signaling Pathways (Ras...mentioning

confidence: 99%

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

Butnariu

Gorduza

Florea

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…108 Approximately 80% of CCMs are associated with somatic mutations, while 20% are secondary to inherited germline mutations. 109 In patients that develop CCMs from somatic mutations, lesions are typically solitary, while patients with germline mutations commonly develop multiple CCMs. 46 Contemporary studies indicate that CCMs progress through two characteristic phases in their maturation.…”

Section: Macrophages In Intrinsic Pathologies Of Vascular Developmentmentioning

confidence: 99%

Peripheral macrophages in the development and progression of structural cerebrovascular pathologies

Lauzier,

Srienc,

Vellimana

et al. 2023

J Cereb Blood Flow Metab

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The human cerebrovascular system is responsible for maintaining neural function through oxygenation, nutrient supply, filtration of toxins, and additional specialized tasks. While the cerebrovascular system has resilience imparted by elaborate redundant collateral circulation from supportive tertiary structures, it is not infallible, and is susceptible to developing structural vascular abnormalities. The causes of this class of structural cerebrovascular diseases can be broadly categorized as 1) intrinsic developmental diseases resulting from genetic or other underlying aberrations (arteriovenous malformations and cavernous malformations) or 2) extrinsic acquired diseases that cause compensatory mechanisms to drive vascular remodeling (aneurysms and arteriovenous fistulae). Cerebrovascular diseases of both types pose significant risks to patients, in some cases leading to death or disability. The drivers of such diseases are extensive, yet inflammation is intimately tied to all of their progressions. Central to this inflammatory hypothesis is the role of peripheral macrophages; targeting this critical cell type may lead to diagnostic and therapeutic advancement in this area. Here, we comprehensively review the role that peripheral macrophages play in cerebrovascular pathogenesis, provide a schema through which macrophage behavior can be understood in cerebrovascular pathologies, and describe emerging diagnostic and therapeutic avenues in this area.

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“…As reported for the other two genes associated with CCM disease, all the over 70 mutations identified in PDCD10 result in protein loss of function [ 17 ]. Patients carrying mutations in the PDCD10 gene are less common than KRIT1 or CCM2 carriers; only 10% of all familial CCM cases are due to mutations in this gene, with a penetrance of about 63% [ 40 ]. However, the clinical phenotype of patients with PDCD10 mutations is often significantly more severe and symptoms onset occurs earlier in life [ 18 ].…”

Section: Ccm Pathogenesismentioning

confidence: 99%

Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells

Riolo

Ricci

Battistini

2021

Cells

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Cerebral cavernous malformations (CCMs) are vascular lesions that affect predominantly microvasculature in the brain and spinal cord. CCM can occur either in sporadic or familial form, characterized by autosomal dominant inheritance and development of multiple lesions throughout the patient’s life. Three genes associated with CCM are known: CCM1/KRIT1 (krev interaction trapped 1), CCM2/MGC4607 (encoding a protein named malcavernin), and CCM3/PDCD10 (programmed cell death 10). All the mutations identified in these genes cause a loss of function and compromise the protein functions needed for maintaining the vascular barrier integrity. Loss of function of CCM proteins causes molecular disorganization and dysfunction of endothelial adherens junctions. In this review, we provide an overall vision of the CCM pathology, starting with the genetic bases of the disease, describing the role of the proteins, until we reach the cellular level. Thus, we summarize the genetics of CCM, providing a description of CCM genes and mutation features, provided an updated knowledge of the CCM protein structure and function, and discuss the molecular mechanisms through which CCM proteins may act within endothelial cells, particularly in endothelial barrier maintenance/regulation and in cellular signaling.

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A Novel CCM2 Gene Mutation Associated With Cerebral Cavernous Malformation

Cited by 8 publications

References 38 publications

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

Peripheral macrophages in the development and progression of structural cerebrovascular pathologies

Molecular Genetic Features of Cerebral Cavernous Malformations (CCM) Patients: An Overall View from Genes to Endothelial Cells

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