CCM2 Human
Description
Definition and Genetic Context
CCM2 (Cerebral Cavernous Malformation 2) is a human gene located on chromosome 7p13 (NG_016295.1) that encodes the protein malcavernin (UniProt: Q9BSQ5). This gene is associated with autosomal dominant cerebral cavernous malformations (CCMs), vascular anomalies characterized by clusters of dilated, leaky capillaries in the brain and spinal cord .
| Gene | Protein | Genomic Location | Associated Disease |
|---|---|---|---|
| CCM2 (OMIM: 607929) | Malcavernin | 7p13 | Cerebral cavernous malformations (CCM-2) |
Molecular Structure and Isoforms
The CCM2 gene spans 10 coding exons and produces multiple alternatively spliced isoforms. Recent studies identified 50 splice variants, resulting in 22 distinct protein isoforms classified into two groups based on promoters and start codons :
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Group A: Canonical isoform (62 kDa) with a conserved N-terminal PTB domain.
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Group B: Mammalian-specific isoforms (46 kDa) derived from an alternative promoter and exon 1A.
Isoforms exhibit tissue-specific expression, with higher levels in endothelial cells, reproductive tissues, and the brain .
Biological Functions
Malcavernin serves as a scaffold protein regulating:
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Endothelial Cell Junctions:
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Angiogenesis:
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Cellular Homeostasis:
Pathogenic Mechanisms
Loss-of-function mutations in CCM2 (e.g., frameshifts, deletions) disrupt endothelial barrier function, leading to:
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RhoA Hyperactivation: Increased vascular permeability and stress fiber formation .
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MEKK3/ERK5 Dysregulation: Upregulation of pro-inflammatory and pro-angiogenic pathways .
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Junctional Defects: Reduced claudin-5, VE-cadherin, and ZO-1 expression at cell-cell contacts .
Animal Models
Therapeutic Insights
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Statins: Simvastatin rescues endothelial barrier function in heterozygous Ccm2 mice by inhibiting RhoA .
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ROCK Inhibition: Targeting ROCK2 restores cortical actin and AJ stability in CCM-deficient cells .
Genetic Variants and Databases
The CCM2 LOVD database documents 61 unique pathogenic variants, including:
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Frameshift Mutations: Predominant cause of truncated malcavernin .
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Splice-Site Variants: Linked to exon skipping and non-functional isoforms .
Future Directions
Product Specs
Q&A
What is the CCM2 gene and what is its function in vascular development?
CCM2 is one of three genes (alongside CCM1/KRIT1 and CCM3/PDCD10) that form a complex regulating vascular development, particularly in the central nervous system. The protein products interact genetically and biochemically to maintain vascular integrity . CCM2 specifically plays a crucial role in endothelial cells for proper angiogenesis, as demonstrated through genetic deletion studies .
Research methodologies used to establish CCM2 function include:
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Genetic mutation analysis in families with cerebral cavernous malformations
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Protein interaction studies showing CCM2's role in complex formation with CCM1 and CCM3
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Molecular signaling analysis revealing CCM2's regulation of the MEKK3-MEK5 pathway
What are the known CCM2 variants in human populations?
Several significant CCM2 variants have been identified:
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CCM2 Exon 2-10 Deletion: A founder mutation prevalent in the United States, traced to multiple families with common ancestors born in the 1760s-1790s in North and South Carolina .
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CCM2 c.236_237delAC: A two-base pair deletion in exon 3 creating a frameshift starting at codon Tyr79, resulting in a premature stop codon and likely haploinsufficiency through nonsense-mediated mRNA decay .
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Common Ashkenazi Jewish CCM2 mutation: Recently identified and mentioned alongside the Common Hispanic CCM1 mutation .
Researchers typically employ whole exome sequencing, targeted genetic screening, and familial pedigree analysis to identify and characterize these variants .
How do disease-causing CCM2 mutations manifest clinically?
CCM2 mutations manifest with diverse clinical presentations:
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Most symptomatic familial CCM patients present between ages 10-40 with seizures, focal neurologic deficits, headaches, or acute cerebral hemorrhage
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Up to 50% of patients with familial CCM remain asymptomatic, though most have at least one CCM visible on MRI
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Approximately 5% of patients also develop lesions in the retina
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Some patients may present with cognitive symptoms, as documented in cases with the c.236_237delAC variant
Clinical investigation methods include:
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T2*-weighted MRI to detect CCMs, cerebral microbleeds, and cavernous malformations
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Neuropsychological testing to assess cognitive function
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Cerebrospinal fluid analysis to measure relevant biomarkers like amyloid-beta-42
What molecular mechanisms mediate CCM2 function in vascular biology?
CCM2 operates through several sophisticated molecular mechanisms:
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Forms a complex with CCM1/KRIT1 and CCM3/PDCD10 that regulates endothelial cell junction formation
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Both CCM2 and its paralog CCM2L bind MEKK3 in a complex with CCM1
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CCM2 and CCM2L interfere with MEKK3 activation and its ability to phosphorylate MEK5, a downstream target
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Loss of CCM2 leads to activation of ERK5 and altered transcriptional programs in endothelial cells
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The KRIT1-CCM2-PDCD10 complex interacts with the PI3K/Akt signaling pathway, which regulates metabolism, growth, proliferation, survival, transcription, and protein synthesis
Experimental approaches used to study these mechanisms include:
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Protein-protein interaction assays
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Signaling pathway analysis with phosphorylation-specific antibodies
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Transcriptional profiling to identify downstream gene expression changes
How do animal models enhance our understanding of CCM2 pathophysiology?
Animal models have provided critical insights into CCM2 biology:
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Mouse models with constitutive or tissue-specific Ccm2 deletion established its essential role in angiogenesis, though embryonic lethality initially precluded development of relevant CCM models
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Endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice generates vascular lesions mimicking human CCMs, primarily in the cerebellum and retina—organs undergoing intense postnatal angiogenesis
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Despite pan-endothelial Ccm2 deletion, lesions are restricted to the venous bed, suggesting tissue-specific vulnerability
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Zebrafish models with ccm2l and ccm2 knockdown exhibit "big heart" phenotypes and circulation defects, along with body axis abnormalities
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Silencing of mekk3 in zebrafish rescues these phenotypes, confirming pathway specificity
These models employ sophisticated experimental approaches:
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Conditional gene deletion using Cre-loxP systems to control timing and tissue specificity
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Comparative phenotypic analysis across different deletion timepoints
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Rescue experiments to confirm gene and pathway specificity
What is the genetic basis of CCM pathogenesis in familial versus sporadic cases?
The genetic etiology differs substantially between familial and sporadic CCM cases:
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Familial CCM (20% of patients) follows an autosomal dominant inheritance pattern with mutations in CCM1, CCM2, or CCM3
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A "two-hit" mechanism operates in familial cases, where a germline mutation (first hit) is followed by a somatic mutation (second hit) in FCCM genes
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Familial patients typically present with multiple lesions, while sporadic cases (80% of patients) most often have a single CCM lesion
Research methodologies to investigate these differences include:
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Comparison of lesion tissue DNA with peripheral blood DNA to identify somatic mutations
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Next-generation sequencing to detect low-frequency mosaic mutations
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Family pedigree analysis to establish inheritance patterns
How does developmental timing of CCM2 loss influence disease phenotypes?
The developmental context of CCM2 loss significantly impacts disease manifestation:
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The consequences of Ccm2 loss depend critically on the developmental timing of Ccm2 ablation
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Endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions that mimic human CCM lesions
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Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice produces similar CCM lesions
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Lesions preferentially develop in tissues undergoing active angiogenesis at the time of gene deletion
Research approaches include:
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Temporally controlled gene deletion using inducible systems
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Comparative analysis of phenotypes across different deletion timepoints
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Correlation between developmental angiogenesis patterns and lesion formation
What is the relationship between CCM2 variants and cognitive function?
Emerging evidence suggests links between CCM2 variants and cognitive function:
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A family with the c.236_237delAC variant in CCM2 presented with non-progressive cognitive symptoms at relatively young age
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Neuropsychological testing revealed mild memory loss and language disturbances in affected individuals
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CSF analysis showed decreased amyloid-beta-42 but normal t-tau and borderline p-tau levels in tested individuals
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All affected individuals had cerebral microbleeds on MRI, with some also showing cavernous malformations
Investigation methods include:
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Comprehensive neuropsychological assessment (including MMSE scoring)
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Cerebrospinal fluid biomarker analysis
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Correlation of cognitive symptoms with genetic variants and neuroimaging findings
What biomarkers and experimental techniques are advancing CCM2 research?
Several innovative approaches are being developed for CCM2 research:
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Enhanced MRI techniques to detect CCM lesions and quantify their properties
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Quantitative susceptibility mapping to measure iron levels in lesions
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Permeability assessment to measure "subtle leakage" in lesions and surrounding brain tissue
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Development of blood tests that may predict CCM lesion activity
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Analysis of lesion samples obtained during surgery for research studies
According to ongoing research at the University of Chicago:
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Many patients participate in CCM research by allowing analysis of data from enhanced MRI scans
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Blood samples are collected for biomarker research
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Resected lesion samples are analyzed for molecular and genetic studies
What are the key challenges in developing therapeutic approaches for CCM2-related disorders?
Current research challenges include:
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Understanding the tissue-specific nature of lesion formation despite pan-endothelial CCM2 deletion
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Identifying targetable pathways downstream of CCM2 loss
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Developing biomarkers that can predict lesion formation or hemorrhage risk
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Creating strategies to prevent the "second hit" somatic mutations in familial cases
Research at the University of Chicago is currently focused on:
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Studying the biology and clinical behavior of CCM under NIH funding
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Developing biomarkers for disease progression
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Understanding the origin and behavior of CCM lesions
How does CCM2 expression regulation differ across tissues and conditions?
Regulation of CCM2 and its paralog CCM2L shows important tissue-specific patterns:
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CCM2L expression in endothelial cells is regulated by density, flow, and statins, unlike CCM2
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CCM2L and CCM2 show different relative expression patterns across various tissues
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Despite widespread expression, CCM2 loss leads to lesions primarily in the CNS and retina
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Binding partners and downstream effects may differ between tissue types
Understanding these regulatory differences requires:
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Transcriptional and epigenetic profiling across tissues
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Protein expression analysis in different vascular beds
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Investigation of tissue-specific binding partners and signaling outcomes
Product Science Overview
The CCM2 gene encodes a protein that is part of a complex involved in maintaining the integrity of blood vessels. Mutations in the CCM2 gene disrupt this complex, leading to the formation of cavernous malformations . The pathogenesis of CCMs follows a “two-hit” hypothesis, where both alleles of a CCM gene must be inactivated for the malformation to develop . This inactivation can occur through a combination of germline and somatic mutations .
Research on CCMs has led to the development of animal models that mimic the human disease. These models have been crucial in understanding the molecular mechanisms underlying CCM formation and in testing potential therapies . For example, mouse models with mutations in the CCM2 gene have been used to study the disease’s progression and to identify therapeutic targets .
Currently, there is no cure for CCMs, and treatment is primarily symptomatic. Surgical resection of the malformations is an option for patients with severe symptoms or recurrent hemorrhages . Ongoing research aims to develop targeted therapies that can prevent the formation or progression of CCMs by addressing the underlying genetic mutations .
