4608 lines
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Entry
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- *607929 - CCM2 SCAFFOLD PROTEIN; CCM2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607929</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607929">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000136280;t=ENST00000258781" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=83605" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607929" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000136280;t=ENST00000258781" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001029835,NM_001167934,NM_001167935,NM_001363458,NM_001363459,NM_031443,NR_030770,XM_006715785,XM_006715786,XM_011515561,XM_011515563,XM_017012671,XM_017012672,XM_047420889,XM_047420890" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_031443" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607929" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=09719&isoform_id=09719_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/CCM2" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/13436182,13899275,14250780,16877119,19684038,33341714,39645309,51094490,52545758,71067341,74733042,119581462,119581463,119581464,119581465,119581466,119581467,119581468,119581469,119581470,193783651,221042330,221044488,221044610,269308188,269308190,578813653,578813655,767945895,767945899,1034657042,1034657045,1390249254,1390249256,2217368681,2217368683" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q9BSQ5" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=83605" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000136280;t=ENST00000258781" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=CCM2" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=CCM2" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+83605" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/CCM2" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:83605" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/83605" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr7&hgg_gene=ENST00000258781.11&hgg_start=44999746&hgg_end=45076470&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/ccm2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607929[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607929[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000136280" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=CCM2" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=CCM2" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CCM2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CCM2&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA26145" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:21708" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:2384924" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/CCM2#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:2384924" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/83605/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=83605" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040712-6" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:83605" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=CCM2&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607929
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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CCM2 SCAFFOLD PROTEIN; CCM2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
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CCM2 GENE<br />
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MALCAVERNIN<br />
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CHROMOSOME 7 OPEN READING FRAME 22; C7ORF22<br />
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OSMOSENSING SCAFFOLD FOR MEKK3; OSM<br />
|
|
MGC4607
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CCM2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CCM2</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/7/243?start=-3&limit=10&highlight=243">7p13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:44999746-45076470&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">7:44,999,746-45,076,470</a> </span>
|
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</em>
|
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/7/243?start=-3&limit=10&highlight=243">
|
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7p13
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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Cerebral cavernous malformations-2
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
|
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<a href="/entry/603284"> 603284 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607929" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607929" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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|
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<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</span>
|
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</h4>
|
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
|
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<strong>Description</strong>
|
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</span>
|
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</h4>
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</div>
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<p>The CCM complex, which includes CCM1 (KRIT1; <a href="/entry/604214">604214</a>), CCM2, and CCM3 (PDCD10; <a href="/entry/609118">609118</a>), is associated with cytoskeletal elements, signal transduction components, and cell junctions (<a href="#11" class="mim-tip-reference" title="Hogan, B. M., Bussmann, J., Wolburg, H., Schulte-Merker, S. <strong>ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish.</strong> Hum. Molec. Genet. 17: 2424-2432, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469344</a>] [<a href="https://doi.org/10.1093/hmg/ddn142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469344">Hogan et al., 2008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a study of cerebral cavernous malformations type 2 (CCM2; <a href="/entry/603284">603284</a>), <a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> performed mutational analysis on a positional candidate gene, MGC4607 (CCM2), located in the critical linkage region in the UCSC human genome assembly. The gene was chosen because its translation product contains a putative PTP domain. The same domain had been found in ICAP1-alpha (<a href="/entry/607153">607153</a>), a binding partner of the CCM1 product KRIT1 (<a href="/entry/604214">604214</a>), which is mutant in cerebral cavernous malformations type 1 (<a href="/entry/116860">116860</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> named the novel protein encoded by the CCM2 gene malcavernin. They suggested that it may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation. <a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> found, from Northern blot analysis of human tissues, using the entire cDNA as a probe, that MCG4607 is most highly expressed in skeletal muscle, heart, and liver, with minimal or no expression in the colon and lung. MGC4607 is also expressed in the brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Western blot analysis, <a href="#19" class="mim-tip-reference" title="Uhlik, M. T., Abell, A. N., Johnson, N. L., Sun, W., Cuevas, B. D., Lobel-Rice, K. E., Horne, E. A., Dell'Acqua, M. L., Johnson, G. L. <strong>Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock.</strong> Nature Cell Biol. 5: 1104-1110, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14634666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14634666</a>] [<a href="https://doi.org/10.1038/ncb1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14634666">Uhlik et al. (2003)</a> found that CCM2, which they called OSM, was expressed in the majority of mouse and human cell types tested. Northern blot and in situ hybridization of mouse tissues showed highest Osm expression in nervous system and lymphoid tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14634666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> determined that the CCM2 gene contains 10 exons and spans 77.6 kb. It contains LINE and SINE elements, including Alu sequences, within intron 1 and the 3-prime region distal to exon 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By linkage analysis, <a href="#5" class="mim-tip-reference" title="Craig, H. D., Gunel, M., Cepeda, O., Johnson, E. W., Ptacek, L., Steinberg, G. K., Ogilvy, C. S., Berg, M. J., Crawford, S. C., Scott, R. M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C. T., Mettler, G., Beis, M. J., Fryer, A., Awad, I. A., Lifton, R. P. <strong>Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27.</strong> Hum. Molec. Genet. 7: 1851-1858, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9811928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9811928</a>] [<a href="https://doi.org/10.1093/hmg/7.12.1851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9811928">Craig et al. (1998)</a> mapped the CCM2 gene to chromosome 7p15-p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9811928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By yeast 2-hybrid analysis of a mouse T-cell cDNA library, <a href="#19" class="mim-tip-reference" title="Uhlik, M. T., Abell, A. N., Johnson, N. L., Sun, W., Cuevas, B. D., Lobel-Rice, K. E., Horne, E. A., Dell'Acqua, M. L., Johnson, G. L. <strong>Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock.</strong> Nature Cell Biol. 5: 1104-1110, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14634666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14634666</a>] [<a href="https://doi.org/10.1038/ncb1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14634666">Uhlik et al. (2003)</a> showed that a C-terminal fragment of mouse Osm interacted with Mekk3 (MAP3K3; <a href="/entry/602539">602539</a>), a p38 (MAPK14; <a href="/entry/600289">600289</a>) activator that responds to sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm complex was recruited to Rac1 (<a href="/entry/602048">602048</a>)- and cytoskeletal actin (see <a href="/entry/102560">102560</a>)-containing membrane ruffles in response to sorbitol treatment. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3 (MAP2K3; <a href="/entry/602315">602315</a>), with actin, and with both GDP- and GTP-loaded Rac1. <a href="#19" class="mim-tip-reference" title="Uhlik, M. T., Abell, A. N., Johnson, N. L., Sun, W., Cuevas, B. D., Lobel-Rice, K. E., Horne, E. A., Dell'Acqua, M. L., Johnson, G. L. <strong>Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock.</strong> Nature Cell Biol. 5: 1104-1110, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14634666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14634666</a>] [<a href="https://doi.org/10.1038/ncb1071" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14634666">Uhlik et al. (2003)</a> concluded that the RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity in response to osmotic shock. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14634666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Zawistowski, J. S., Stalheim, L., Uhlik, M. T., Abell, A. N., Ancrile, B. B., Johnson, G. L., Marchuk, D. A. <strong>CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis.</strong> Hum. Molec. Genet. 14: 2521-2531, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037064</a>] [<a href="https://doi.org/10.1093/hmg/ddi256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16037064">Zawistowski et al. (2005)</a> used coimmunoprecipitation, fluorescence resonance energy transfer, and subcellular localization strategies to show that KRIT1 interacted with CCM2. Analogous to the established interactions of KRIT1/ITGB1 (<a href="/entry/135630">135630</a>) and KRIT1/ICAP1, the KRIT1/CCM2 association was dependent upon phosphotyrosine-binding (PTB) domain of CCM2. A familial CCM2 L198R mutation (<a href="#0007">607929.0007</a>) abrogated the KRIT1/CCM2 interaction, suggesting that loss of this interaction may be critical in CCM pathogenesis. CCM2 and ICAP1, when bound to KRIT1 via their respective PTB domains, differentially influenced KRIT1 subcellular localization. The authors expanded upon the established involvement of CCM2 in the p38 MAPK signaling module by demonstrating that KRIT1 associated with CCM2 and MEKK3 in a ternary complex. <a href="#21" class="mim-tip-reference" title="Zawistowski, J. S., Stalheim, L., Uhlik, M. T., Abell, A. N., Ancrile, B. B., Johnson, G. L., Marchuk, D. A. <strong>CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis.</strong> Hum. Molec. Genet. 14: 2521-2531, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037064</a>] [<a href="https://doi.org/10.1093/hmg/ddi256" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16037064">Zawistowski et al. (2005)</a> proposed that the genetic heterogeneity observed in familial CCM may reflect mutation of different molecular members of a coordinated signaling complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16037064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By GST pull-down and coimmunoprecipitation analysis, <a href="#20" class="mim-tip-reference" title="Voss, K., Stahl, S., Schleider, E., Ullrich, S., Nickel, J., Mueller, T. D., Felbor, U. <strong>CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations.</strong> Neurogenetics 8: 249-256, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17657516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17657516</a>] [<a href="https://doi.org/10.1007/s10048-007-0098-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17657516">Voss et al. (2007)</a> demonstrated that CCM2 coprecipitated and colocalized with CCM3 (PDCD10; <a href="/entry/609118">609118</a>). Yeast 2-hybrid analysis showed that CCM3 directly bound to STK25 (<a href="/entry/602255">602255</a>) and the phosphatase domain of FAP1 (<a href="/entry/600267">600267</a>). CCM3 was phosphorylated by STK25, whereas the C-terminal domain of FAP1 dephosphorylated CCM3. Further experiments showed that STK25 and CCM2 formed a protein complex. The findings linked CCM3 and STK25 with CCM2, which is part of signaling pathways that are essential for vascular development. <a href="#20" class="mim-tip-reference" title="Voss, K., Stahl, S., Schleider, E., Ullrich, S., Nickel, J., Mueller, T. D., Felbor, U. <strong>CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations.</strong> Neurogenetics 8: 249-256, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17657516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17657516</a>] [<a href="https://doi.org/10.1007/s10048-007-0098-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17657516">Voss et al. (2007)</a> hypothesized that CCM3 is part of the KRIT1/CCM2 protein complex through its interaction with CCM2, and therefore may participate in CCM1-dependent modulation of ITGB1 signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17657516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RNA interference, <a href="#6" class="mim-tip-reference" title="Crose, L. E. S., Hilder, T. L., Sciaky, N., Johnson, G. L. <strong>Cerebral cavernous malformation 2 protein promotes Smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells.</strong> J. Biol. Chem. 284: 13301-13305, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19318350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19318350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19318350[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.C900009200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19318350">Crose et al. (2009)</a> showed that knockdown of Ccm2 in mouse brain endothelial cells led to increased monolayer permeability, decreased tubule formation, and reduced cell migration following wounding. These effects were associated with elevated levels of RhoA (<a href="/entry/165390">165390</a>), a small GTPase necessary for cytoskeletal turnover and migration. Coimmunoprecipitation analysis revealed that both Ccm2 and Mekk3 directly bound the RhoA ubiquitin ligase Smurf1 (<a href="/entry/605568">605568</a>). Domain analysis revealed that the PTB domain of Ccm2 directly bound the HECT domain of Smurf1, and the interaction targeted Smurf1 to Ccm2 complexes localized primarily at the cell periphery. Coexpression of Ccm2 and Smurf1 led to cell rounding, likely due to loss of RhoA. <a href="#6" class="mim-tip-reference" title="Crose, L. E. S., Hilder, T. L., Sciaky, N., Johnson, G. L. <strong>Cerebral cavernous malformation 2 protein promotes Smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells.</strong> J. Biol. Chem. 284: 13301-13305, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19318350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19318350</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19318350[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.C900009200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19318350">Crose et al. (2009)</a> concluded that CCM2 contributes to endothelial cell integrity by regulating SMURF1-directed RHOA degradation <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19318350" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Kleaveland, B., Zheng, X., Liu, J. J., Blum, Y., Tung, J. J., Zou, Z., Sweeney, S. M., Chen, M., Guo, L., Lu, M., Zhou, D., Kitajewski, J., Affolter, M., Ginsberg, M. H., Kahn, M. L. <strong>Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.</strong> Nature Med. 15: 169-176, 2009. Note: Erratum: Nature Med. 15: 584 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19151727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19151727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19151727[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.1918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19151727">Kleaveland et al. (2009)</a> showed that knockdown of CCM2 in human umbilical vein endothelial cells (HUVECs) via small hairpin RNA had no effect on cell size, proliferation, migration, or formation of branching structures. However, branched cords formed by CCM2-knockdown HUVECs often lacked visible lumens, suggesting a defect in endothelial tube formation. Using mice and zebrafish lacking Ccm2 and/or Heg1 (<a href="/entry/614182">614182</a>) and CCM2-knockdown HUVECs, <a href="#12" class="mim-tip-reference" title="Kleaveland, B., Zheng, X., Liu, J. J., Blum, Y., Tung, J. J., Zou, Z., Sweeney, S. M., Chen, M., Guo, L., Lu, M., Zhou, D., Kitajewski, J., Affolter, M., Ginsberg, M. H., Kahn, M. L. <strong>Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.</strong> Nature Med. 15: 169-176, 2009. Note: Erratum: Nature Med. 15: 584 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19151727/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19151727</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19151727[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.1918" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19151727">Kleaveland et al. (2009)</a> showed that CCM2-HEG1 signaling regulated endothelial tube formation and endothelial junction formation. Coimmunoprecipitation experiments and pull-down assays in transfected HEK293T cells suggested a model in which HEG1 coupled with CCM2 primarily through interaction with KRIT1 at endothelial cell-cell junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19151727" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Borikova, A. L., Dibble, C. F., Sciaky, N., Welch, C. M., Abell, A. N., Bencharit, S., Johnson, G. L. <strong>Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype.</strong> J. Biol. Chem. 285: 11760-11764, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20181950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20181950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20181950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.C109.097220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20181950">Borikova et al. (2010)</a> showed that knockdown of Ccm1, Ccm2, or Ccm3 in mouse embryonic endothelial cells induced RhoA overexpression and persistent RhoA activity at the cell edge, as well as in the cytoplasm and nucleus. RhoA activation was especially pronounced following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited formation of vessel-like tubes and invasion of extracellular matrix. Knockdown or inhibition of Rock2 countered these effects and was associated with inhibition of RhoA-stimulated phosphorylation of myosin light chain-2 (MLC2; see <a href="/entry/160781">160781</a>). <a href="#3" class="mim-tip-reference" title="Borikova, A. L., Dibble, C. F., Sciaky, N., Welch, C. M., Abell, A. N., Bencharit, S., Johnson, G. L. <strong>Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype.</strong> J. Biol. Chem. 285: 11760-11764, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20181950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20181950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20181950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.C109.097220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20181950">Borikova et al. (2010)</a> concluded that the CCM protein complex regulates RhoA activation and cytoskeletal dynamics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20181950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using short interfering RNA, <a href="#17" class="mim-tip-reference" title="Renz, M., Otten, C., Faurobert, E., Rudolph, F., Zhu, Y., Boulday, G., Duchene, J., Mickoleit, M., Dietrich, A.-C., Ramspacher, C., Steed, E., Manet-Dupe, S., and 9 others. <strong>Regulation of beta-1 integrin-Klf2-mediated angiogenesis by CCM proteins.</strong> Dev. Cell 32: 181-190, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25625207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25625207</a>] [<a href="https://doi.org/10.1016/j.devcel.2014.12.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25625207">Renz et al. (2015)</a> found that silencing CCM2 elevated expression of KLF2 (<a href="/entry/602016">602016</a>) mRNA in human umbilical vein endothelial cells. Elevated expression of KLF2 in CCM2-knockdown cells required activation of cell surface beta-1 integrin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25625207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By studying the role of ECs in genetic risk for coronary artery disease (CAD), <a href="#18" class="mim-tip-reference" title="Schnitzler, G. R., Kang, H., Fang, S., Angom, R. S., Lee-Kim, V. S., Ma, X. R., Zhou, R., Zeng, T., Guo, K., Taylor, M. S., Vellarikkal, S. K., Barry, A. E., and 15 others. <strong>Convergence of coronary artery disease genes onto endothelial cell programs.</strong> Nature 626: 799-807, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38326615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38326615</a>] [<a href="https://doi.org/10.1038/s41586-024-07022-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38326615">Schnitzler et al. (2024)</a> identified CCM2 and TLNRD1 (<a href="/entry/615466">615466</a>) as regulators in the CCM signaling pathway that may be linked to CAD risk. Knockdown of CCM2 or TLNRD1 perturbed expression of genes in the CCM signaling pathway in human aortic ECs and led to changes in gene expression that might be protective in CAD. CCM2 and TLNRD1 interacted directly, mediated by the C-terminal helix of CCM2 and the 9-helix bundle of TLNRD1. Through their interaction, TLNRD1 and CCM2 regulated the CCM signaling pathway and EC phenotypes relevant to CAD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38326615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> screened a cohort of 37 probands with cerebral cavernous malformations for KRIT1 mutations and found mutations of this gene in 10 (see CCM1, <a href="/entry/116860">116860</a>). Among the panel of 27 probands without a KRIT1 mutation, they detected 8 different mutations in the MGC4607 gene (see CCM2, <a href="/entry/603284">603284</a>). One mutation, a 4-bp deletion (<a href="#0004">607929.0004</a>), was found in 2 separate families which, as suggested by a further investigation into ethnic background, may be distantly related. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. <strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 74: 326-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14740320">Denier et al. (2004)</a> likewise identified the MGC4607 gene as the gene mutated in CCM2. They narrowed the CCM2 linkage interval from 22 cM to 7.5 cM. They then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions such as tuberous sclerosis (<a href="/entry/191100">191100</a>) and neurofibromatosis (<a href="/entry/162200">162200</a>). They performed a high density microsatellite genotyping of this 7.5-cM interval in search of putative null alleles in 30 unrelated families. In this way, they identified null alleles that were the result of deletions within a 350-kb interval in 2 families. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these 2 distinct deletions overlapped and that both of them deleted the first exon of MGC4607. In both families, 1 of the 2 MGC4607 transcripts was not detected. They then identified 8 additional point mutations within MGC4607 in 8 of the remaining families. One of them led to the alteration of the initiation codon and 5 of them to a premature termination, including 1 nonsense, 1 frameshift, and 3 splice-site mutations. The findings in cerebral cavernous malformations strongly suggest that MGC4607 has a role in vascular morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A. <strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong> Am. J. Hum. Genet. 80: 69-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160895">Liquori et al. (2007)</a> commented that DNA sequence analysis of the genes CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) in a cohort of 63 CCM-affected families showed that 40% of these lacked any identifiable mutation. The data suggested either that another CCM gene exists or that a significant fraction of CCM mutations are not found by routine DNA sequence analysis. Potential mutations that would be undetected by sequence analysis included mutations within regulatory regions not included in routine sequencing, as well as larger genomic insertions, deletions, or duplications. <a href="#14" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A. <strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong> Am. J. Hum. Genet. 80: 69-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160895">Liquori et al. (2007)</a> used multiplex ligation-dependent probe analysis to screen 25 probands who were negative for CCM1, -2, and -3 mutations for potential deletions or duplications within these 3 genes. They identified 15 deletions: 1 in the CCM1 gene, none in the CCM3 gene, and 14 in the CCM2 gene. In this cohort, mutation screening that included sequence and deletion analyses gave disease-gene frequencies of 40% for CCM1, 38% for CCM2, 6% for CCM3, and 16% with no mutation detected. The data indicated that the prevalence of CCM2 is much higher than previously predicted, nearly equal to CCM1, and that large genomic deletions in the CCM2 gene represent a major component of this disorder. A common 77.6-kb deletion spanning CCM2 exons 2 through 10 was identified, which was present in 13% of the entire CCM cohort (<a href="#0009">607929.0009</a>). <a href="#14" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A. <strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong> Am. J. Hum. Genet. 80: 69-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160895">Liquori et al. (2007)</a> hypothesized that these deletions occurred in a hypermutable region because of surrounding repetitive sequence elements and may catalyze the formation of intragenic deletions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 (14%) of 14 unrelated patients with sporadic CCM and multiple lesions, <a href="#8" class="mim-tip-reference" title="Felbor, U., Gaetzner, S., Verlaan, D. J., Vijzelaar, R., Rouleau, G. A., Siegel, A. M. <strong>Large germline deletions and duplication in isolated cerebral cavernous malformation patients.</strong> Neurogenetics 8: 149-153, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17211633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17211633</a>] [<a href="https://doi.org/10.1007/s10048-006-0076-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17211633">Felbor et al. (2007)</a> identified a respective deletion in the CCM2 gene using multiplex ligation-dependent probe amplification. One of the deletions involved the entire coding region of the CCM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17211633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 24 Italian families with CCM, <a href="#15" class="mim-tip-reference" title="Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F. <strong>Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.</strong> Neurogenetics 9: 25-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18060436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18060436</a>] [<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18060436">Liquori et al. (2008)</a> identified 4 deletions and 1 duplication in the CCM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18060436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For each of the 3 CCM genes, <a href="#16" class="mim-tip-reference" title="Pagenstecher, A., Stahl, S., Sure, U., Felbor, U. <strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong> Hum. Molec. Genet. 18: 911-918, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088124">Pagenstecher et al. (2009)</a> showed complete localized loss of either KRIT1, CCM2/malcavernin, or PDCD10 protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient, normal brain endothelium from a CCM2 patient, and capillary endothelial cells of vessels in a revascularized thrombosed cavern from a CCM3 patient stained positively for KRIT1, CCM2/malcavernin, and PDCD10 respectively. <a href="#16" class="mim-tip-reference" title="Pagenstecher, A., Stahl, S., Sure, U., Felbor, U. <strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong> Hum. Molec. Genet. 18: 911-918, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088124</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088124[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088124">Pagenstecher et al. (2009)</a> suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By use of repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, <a href="#1" class="mim-tip-reference" title="Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. <strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong> Hum. Molec. Genet. 18: 919-930, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088123">Akers et al. (2009)</a> identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. <a href="#1" class="mim-tip-reference" title="Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. <strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong> Hum. Molec. Genet. 18: 919-930, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn430" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19088123">Akers et al. (2009)</a> suggested that CCM lesion genesis may require complete loss of function for one of the CCM genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A. <strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong> Genet. Med. 13: 662-666, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21543988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21543988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21543988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/GIM.0b013e318211ff8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21543988">Gallione et al. (2011)</a> identified a founder mutation in the Ashkenazi Jewish population that affects mRNA splicing of the CCM2 gene causing cerebral cavernous malformations (<a href="#0010">607929.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21543988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 27 unrelated patients with CCM and heterozygosity for the 77.6-kb deletion (<a href="#0009">607929.0009</a>) encompassing exons 2-10 the CCM2 gene, <a href="#9" class="mim-tip-reference" title="Gallione, C. J., Detter, M. R., Sheline, A., Christmas, H. M., Lee, C., Marchuk, D. A. <strong>Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.</strong> Hum. Genet. 141: 1761-1769, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35488064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35488064</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35488064[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1007/s00439-022-02458-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35488064">Gallione et al. (2022)</a> sequenced 10 kb upstream and downstream of the deletion to evaluate for a shared haplotype. SNP analysis demonstrated a shared haplotype among all 27 patients. The deletion was shown to be due to a recombination event between an AluSx sequence and an AluSg sequence, which, while highly homologous, are not identical. Genealogy studies showed that 5 of the families may share a single common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35488064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified 6 heterozygous mutations in the CCM gene (<a href="#0007">607929.0007</a>; <a href="#0011">607929.0011</a>-<a href="#0015">607929.0015</a>) in 7 unrelated patients with CCM. The mutations were identified by sequencing of 3 genes associated with cerebral cavernous malformations. Coimmunoprecipitation studies with each of the mutations resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Hogan, B. M., Bussmann, J., Wolburg, H., Schulte-Merker, S. <strong>ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish.</strong> Hum. Molec. Genet. 17: 2424-2432, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469344</a>] [<a href="https://doi.org/10.1093/hmg/ddn142" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469344">Hogan et al. (2008)</a> found that deletion of Ccm1 in zebrafish caused dilation of embryonic vessels. Vascular dilation was associated with progressive spreading of endothelial cells and thinning of vessel walls. Determination of cell fate, cell number, and endothelial cell-cell contacts appeared normal. Ccm1 mutants, Ccm2 mutants, and Ccm1/Ccm2 double mutants had indistinguishable vascular phenotypes, suggesting conservation of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Boulday, G., Rudini, N., Maddaluno, L., Blecon, A., Arnould, M., Gaudric, A., Chapon, F., Adams, R. H., Dejana, E., Tournier-Lasserve, E. <strong>Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice.</strong> J. Exp. Med. 208: 1835-1847, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21859843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21859843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21859843[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20110571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21859843">Boulday et al. (2011)</a> noted that deletion of Ccm1, Ccm2, or Ccm3 in mice is embryonic lethal. They generated mice with an endothelial-specific Ccm2 deletion at postnatal day 1, which resulted in vascular lesions mimicking human CCM lesions. Deletion of Ccm1 or Ccm3 at postnatal day 1 resulted in similar cerebellar and retinal lesions. Ccm2 lesion development was restricted to the venous bed. <a href="#4" class="mim-tip-reference" title="Boulday, G., Rudini, N., Maddaluno, L., Blecon, A., Arnould, M., Gaudric, A., Chapon, F., Adams, R. H., Dejana, E., Tournier-Lasserve, E. <strong>Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice.</strong> J. Exp. Med. 208: 1835-1847, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21859843/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21859843</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21859843[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20110571" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21859843">Boulday et al. (2011)</a> concluded that the consequences of Ccm2 deletion depend on the developmental timing of the ablation and are associated with a developmental stage with intense angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21859843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using zebrafish mutants and morpholino-mediated knockdown of genes in zebrafish embryos, <a href="#17" class="mim-tip-reference" title="Renz, M., Otten, C., Faurobert, E., Rudolph, F., Zhu, Y., Boulday, G., Duchene, J., Mickoleit, M., Dietrich, A.-C., Ramspacher, C., Steed, E., Manet-Dupe, S., and 9 others. <strong>Regulation of beta-1 integrin-Klf2-mediated angiogenesis by CCM proteins.</strong> Dev. Cell 32: 181-190, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25625207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25625207</a>] [<a href="https://doi.org/10.1016/j.devcel.2014.12.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25625207">Renz et al. (2015)</a> identified a proangiogenic signaling pathway that involved activation of beta-1 integrin, followed by elevated expression of klf2a, klf2b, egfl7 (<a href="/entry/608582">608582</a>), and vegf (VEGFA; <a href="/entry/192240">192240</a>). Ccm2 negatively regulated this pathway. Loss of ccm2 elevated expression of several genes related to angiogenesis, including klf2a and klf2b, and resulted in significant cardiovascular malformations. These defects occurred in the absence of blood flow and did not require mir126a or mir126b (see <a href="/entry/611767">611767</a>), the latter of which is located within the egfl7 gene. Knockdown of beta-1 integrin reversed the cardiovascular defects in ccm2 mutant embryos. Knockout of Ccm2 in mice also resulted in elevated Klf2 expression and cardiovascular defects. <a href="#17" class="mim-tip-reference" title="Renz, M., Otten, C., Faurobert, E., Rudolph, F., Zhu, Y., Boulday, G., Duchene, J., Mickoleit, M., Dietrich, A.-C., Ramspacher, C., Steed, E., Manet-Dupe, S., and 9 others. <strong>Regulation of beta-1 integrin-Klf2-mediated angiogenesis by CCM proteins.</strong> Dev. Cell 32: 181-190, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25625207/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25625207</a>] [<a href="https://doi.org/10.1016/j.devcel.2014.12.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25625207">Renz et al. (2015)</a> concluded that the beta-1 integrin-KLF2-EGFL7 pathway is tightly regulated by CCM2 and that this regulation prevents angiogenic overgrowth and ensures quiescence in endothelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25625207" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562848466 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562848466;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1562848466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1562848466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family (family 2626) in which 4 members had type 2 cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> found a heterozygous 1-bp deletion in exon 1 of the CCM2 gene (23delG), causing a frameshift at amino acid 23 and premature termination at amino acid 22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852841 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852841;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002800 OR RCV000289897" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002800, RCV000289897" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002800...</a>
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<p>In a family (family IFCAS-14) in which 2 members had type 2 cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> found a heterozygous 319C-T transition in exon 4 of the CCM2 gene, resulting in a gln107-to-ter (Q107X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562913873 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562913873;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1562913873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1562913873" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002801 OR RCV000721788" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002801, RCV000721788" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002801...</a>
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<p>In a family (family 2030) in which 5 members had type 2 cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> found a heterozygous splice junction mutation (610-1G-A), involving the invariant G residue at the splice acceptor site adjacent to exon 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562882045 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562882045;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1562882045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1562882045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000721772 OR RCV001849084" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000721772, RCV001849084" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000721772...</a>
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<p>In 1 family (family 70) with 5 affected individuals and a second family (family IFCAS-1) with 4 affected individuals, <a href="#13" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A. <strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 73: 1459-1464, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14624391/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14624391</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14624391[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/380314" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14624391">Liquori et al. (2003)</a> found that type 2 cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>) was associated with a heterozygous 4-bp deletion in exon 2 of the CCM2 gene (169-172delAGAC). The deletion caused a frameshift at amino acid 57 with a premature stop at amino acid 58. The 2 families were thought to be distantly related because they came from the same ethnic background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14624391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852842 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852842;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002803 OR RCV000517211" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002803, RCV000517211" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002803...</a>
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<p>In affected members of a family (family C038) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#7" class="mim-tip-reference" title="Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. <strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 74: 326-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14740320">Denier et al. (2004)</a> found a heterozygous mutation in the initiating ATG codon of the CCM2 gene, changing nucleotide 1 from A to G (c.1A-G, NM_031443). In this family, 2 sisters and the daughter of 1 of them were affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4>
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<strong>.0006 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562906981 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562906981;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1562906981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1562906981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002804" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002804" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002804</a>
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<p>In a family (family C039) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#7" class="mim-tip-reference" title="Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. <strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 74: 326-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14740320">Denier et al. (2004)</a> identified a heterozygous donor splice site mutation within intron 3, c.288+1G-A (c.288+1G-A, NM-031443) of the CCM2 gene, leading to a transcript in which exon 3 was deleted. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852843 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852843;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs137852843" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family (family C002) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#7" class="mim-tip-reference" title="Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. <strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 74: 326-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14740320">Denier et al. (2004)</a> found that affected individuals had a heterozygous c.593T-G transversion (c.593T-G, NM_031443) in exon 5 of the CCM2 gene, resulting in a leu198-to-arg (L198R) substitution. In this family, a brother and sister were affected as well as a daughter and son. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient (family 7) with CCM2, <a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified heterozygosity for the L198R mutation in the PTB domain of the CCM2 gene. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L198R mutation in CCM2 resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562921605 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562921605;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1562921605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1562921605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a family (family C047) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>) in 3 successive generations, <a href="#7" class="mim-tip-reference" title="Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others. <strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong> Am. J. Hum. Genet. 74: 326-337, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14740320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14740320</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14740320[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/381718" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14740320">Denier et al. (2004)</a> found a heterozygous deletion of 2 nucleotides, c.1248_1249delAG (c.1248_1249delAG, NM_031443), in exon 10 of the CCM2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14740320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Among a cohort of 63 families with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#14" class="mim-tip-reference" title="Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A. <strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong> Am. J. Hum. Genet. 80: 69-75, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17160895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/510439" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160895">Liquori et al. (2007)</a> identified a heterozygous 77.6-kb deletion in the CCM2 gene in 8 probands (13%). The deletion encompassed exons 2 through 10, with the proximal breakpoint within an AluSx repeat in intron 1 and the distal breakpoint within an AluSg repeat distal to exon 10. Haplotype analysis suggested that this deletion may have occurred independently at least twice in their cohort, although the evidence was not conclusive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F. <strong>Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts.</strong> Neurogenetics 9: 25-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18060436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18060436</a>] [<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18060436">Liquori et al. (2008)</a> reported 6 additional CCM families from the United States with the 77.6-kb CCM2 deletion. Haplotype analysis, which included the previously reported families with this deletion, indicated a founder effect. This deletion was not present in 24 Italian families with CCM, indicating that it is specific to a certain cohort of patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18060436" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044623 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044623;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs797044623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs797044623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 7 apparently unrelated probands from 10 different kindreds of Ashkenazi Jewish descent segregating CCM2 (CCM2; <a href="/entry/603284">603284</a>), <a href="#10" class="mim-tip-reference" title="Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A. <strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong> Genet. Med. 13: 662-666, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21543988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21543988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21543988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/GIM.0b013e318211ff8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21543988">Gallione et al. (2011)</a> identified a heterozygous 2-bp change in the CCM2 gene caused by deletion of a GC pair and insertion of a TT pair near the splice donor site of exon 1 (30+5_6delinsTT). The 2-bp change segregated with affected status in the study families. Transcripts arising from the normal and mutant alleles were examined by RT-PCR from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization. The 2-bp change, when tested in this in vitro synthetic splicing system, altered splice donor site utilization. RT-PCR revealed loss of the transcript allele that was in phase with the mutation. <a href="#10" class="mim-tip-reference" title="Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A. <strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong> Genet. Med. 13: 662-666, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21543988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21543988</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21543988[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1097/GIM.0b013e318211ff8b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21543988">Gallione et al. (2011)</a> concluded that this 2-bp change in CCM2 disrupted proper splice donor utilization leading to a degraded transcript. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common SNP haplotype in affected individuals that demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21543988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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CCM2, LEU113PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003319556 OR RCV004593261" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003319556, RCV004593261" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003319556...</a>
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<p>In 2 unrelated patients (families 1 and 2) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified heterozygosity for a c.338T-C transition (c.338T-C, NM_031443.3) in the CCM2 gene, resulting in a leu113-to-pro (L113P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L113P mutation resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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CCM2, LEU198PRO
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003319557" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003319557" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003319557</a>
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<p>In a patient (family 6) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified heterozygosity for a c.593T-C transition (c.593T-C, NM_031443.3) in the CCM2 gene, resulting in a leu198-to-pro (L198P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L198P mutation resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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CCM2, SER116PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1562907616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1562907616;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1562907616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1562907616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000690574" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000690574" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000690574</a>
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<span class="mim-text-font">
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<p>In a patient (family 3) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified heterozygosity for a c.346T-C transition (c.346T-C, NM_031443.3) in the CCM2 gene, resulting in a ser116-to-pro (S116P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the S116P mutation resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0014 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</h4>
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CCM2, LEU122ARG
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003319558" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003319558" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003319558</a>
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</span>
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<span class="mim-text-font">
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<p>In a patient (family 4) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified heterozygosity for a c.365T-G transversion (c.365T-G, NM_031443.3) in the CCM2 gene, resulting in a leu122-to-arg (L122R) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L122R mutation resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</div>
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<div>
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<div>
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<a id="0015" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0015 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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CCM2, ALA123PRO
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003319559" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003319559" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003319559</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a patient (family 5) with cerebral cavernous malformations (CCM2; <a href="/entry/603284">603284</a>), <a href="#2" class="mim-tip-reference" title="Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F. <strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong> J. Med. Genet. 57: 400-404, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>] [<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31937560">Bergametti et al. (2020)</a> identified heterozygosity for a c.367G-C transversion (c.367G-C, NM_031443.3) in the CCM2 gene, resulting in an ala123-to-pro (A123P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the A123P mutation resulted in loss of interaction between CCM1 and CCM2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</span>
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<a id="1" class="mim-anchor"></a>
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<a id="Akers2009" class="mim-anchor"></a>
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<div class="">
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Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A.
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<strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong>
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Hum. Molec. Genet. 18: 919-930, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19088123/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19088123</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19088123[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19088123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn430" target="_blank">Full Text</a>]
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<a id="Bergametti2020" class="mim-anchor"></a>
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Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F.
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|
<strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong>
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J. Med. Genet. 57: 400-404, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31937560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31937560</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31937560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmedgenet-2019-106401" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Borikova2010" class="mim-anchor"></a>
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<div class="">
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Borikova, A. L., Dibble, C. F., Sciaky, N., Welch, C. M., Abell, A. N., Bencharit, S., Johnson, G. L.
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<strong>Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype.</strong>
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J. Biol. Chem. 285: 11760-11764, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20181950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20181950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20181950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20181950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.C109.097220" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Boulday2011" class="mim-anchor"></a>
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Boulday, G., Rudini, N., Maddaluno, L., Blecon, A., Arnould, M., Gaudric, A., Chapon, F., Adams, R. H., Dejana, E., Tournier-Lasserve, E.
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<strong>Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice.</strong>
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[<a href="https://doi.org/10.1084/jem.20110571" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/7.12.1851" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.C900009200" target="_blank">Full Text</a>]
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<strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong>
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[<a href="https://doi.org/10.1086/381718" target="_blank">Full Text</a>]
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<strong>Large germline deletions and duplication in isolated cerebral cavernous malformation patients.</strong>
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[<a href="https://doi.org/10.1007/s10048-006-0076-7" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-022-02458-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1097/GIM.0b013e318211ff8b" target="_blank">Full Text</a>]
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<strong>ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish.</strong>
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[<a href="https://doi.org/10.1093/hmg/ddn142" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nm.1918" target="_blank">Full Text</a>]
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Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A.
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<strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong>
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[<a href="https://doi.org/10.1086/380314" target="_blank">Full Text</a>]
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<strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong>
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[<a href="https://doi.org/10.1086/510439" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2014.12.016" target="_blank">Full Text</a>]
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<a id="Schnitzler2024" class="mim-anchor"></a>
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Schnitzler, G. R., Kang, H., Fang, S., Angom, R. S., Lee-Kim, V. S., Ma, X. R., Zhou, R., Zeng, T., Guo, K., Taylor, M. S., Vellarikkal, S. K., Barry, A. E., and 15 others.
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[<a href="https://doi.org/10.1038/s41586-024-07022-x" target="_blank">Full Text</a>]
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Uhlik, M. T., Abell, A. N., Johnson, N. L., Sun, W., Cuevas, B. D., Lobel-Rice, K. E., Horne, E. A., Dell'Acqua, M. L., Johnson, G. L.
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<strong>Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock.</strong>
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Nature Cell Biol. 5: 1104-1110, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14634666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14634666</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14634666" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ncb1071" target="_blank">Full Text</a>]
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<a id="Voss2007" class="mim-anchor"></a>
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Voss, K., Stahl, S., Schleider, E., Ullrich, S., Nickel, J., Mueller, T. D., Felbor, U.
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<strong>CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations.</strong>
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Neurogenetics 8: 249-256, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17657516/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17657516</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17657516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-007-0098-9" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Zawistowski2005" class="mim-anchor"></a>
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Zawistowski, J. S., Stalheim, L., Uhlik, M. T., Abell, A. N., Ancrile, B. B., Johnson, G. L., Marchuk, D. A.
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<strong>CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis.</strong>
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Hum. Molec. Genet. 14: 2521-2531, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16037064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16037064</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16037064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi256" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 07/18/2024
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/04/2023<br>Patricia A. Hartz - updated : 09/13/2016<br>Paul J. Converse - updated : 1/11/2012<br>Ada Hamosh - updated : 8/24/2011<br>Patricia A. Hartz - updated : 5/26/2011<br>Patricia A. Hartz - updated : 12/20/2010<br>Matthew B. Gross - updated : 11/2/2009<br>Patricia A. Hartz - updated : 11/2/2009<br>George E. Tiller - updated : 8/12/2009<br>Patricia A. Hartz - updated : 2/23/2009<br>George E. Tiller - updated : 1/23/2009<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 11/27/2007<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Victor A. McKusick - updated : 1/2/2007<br>Victor A. McKusick - updated : 1/30/2004
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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Victor A. McKusick : 12/22/2003
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mgross : 07/18/2024
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carol : 08/07/2023<br>carol : 08/04/2023<br>carol : 06/09/2023<br>carol : 06/08/2023<br>alopez : 06/07/2023<br>carol : 03/10/2021<br>carol : 03/09/2021<br>mgross : 09/13/2016<br>mgross : 09/13/2016<br>mgross : 01/20/2012<br>terry : 1/11/2012<br>alopez : 8/24/2011<br>mgross : 8/19/2011<br>terry : 5/26/2011<br>mgross : 1/5/2011<br>terry : 12/20/2010<br>mgross : 11/2/2009<br>mgross : 11/2/2009<br>wwang : 8/26/2009<br>terry : 8/12/2009<br>mgross : 2/24/2009<br>mgross : 2/24/2009<br>terry : 2/23/2009<br>joanna : 2/2/2009<br>wwang : 1/23/2009<br>wwang : 4/15/2008<br>ckniffin : 3/18/2008<br>wwang : 12/3/2007<br>ckniffin : 11/27/2007<br>wwang : 5/11/2007<br>ckniffin : 5/4/2007<br>carol : 2/28/2007<br>alopez : 1/4/2007<br>terry : 1/2/2007<br>wwang : 4/12/2006<br>alopez : 2/5/2004<br>cwells : 1/30/2004<br>joanna : 1/15/2004<br>cwells : 12/22/2003
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<span class="mim-font">
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<strong>*</strong> 607929
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CCM2 SCAFFOLD PROTEIN; CCM2
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<em>Alternative titles; symbols</em>
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CCM2 GENE<br />
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MALCAVERNIN<br />
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CHROMOSOME 7 OPEN READING FRAME 22; C7ORF22<br />
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OSMOSENSING SCAFFOLD FOR MEKK3; OSM<br />
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MGC4607
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: CCM2</em></strong>
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Cytogenetic location: 7p13
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:44,999,746-45,076,470 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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7p13
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Cerebral cavernous malformations-2
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<span class="mim-font">
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603284
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The CCM complex, which includes CCM1 (KRIT1; 604214), CCM2, and CCM3 (PDCD10; 609118), is associated with cytoskeletal elements, signal transduction components, and cell junctions (Hogan et al., 2008). </p>
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<strong>Cloning and Expression</strong>
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<p>In a study of cerebral cavernous malformations type 2 (CCM2; 603284), Liquori et al. (2003) performed mutational analysis on a positional candidate gene, MGC4607 (CCM2), located in the critical linkage region in the UCSC human genome assembly. The gene was chosen because its translation product contains a putative PTP domain. The same domain had been found in ICAP1-alpha (607153), a binding partner of the CCM1 product KRIT1 (604214), which is mutant in cerebral cavernous malformations type 1 (116860). </p><p>Liquori et al. (2003) named the novel protein encoded by the CCM2 gene malcavernin. They suggested that it may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation. Liquori et al. (2003) found, from Northern blot analysis of human tissues, using the entire cDNA as a probe, that MCG4607 is most highly expressed in skeletal muscle, heart, and liver, with minimal or no expression in the colon and lung. MGC4607 is also expressed in the brain. </p><p>Using Western blot analysis, Uhlik et al. (2003) found that CCM2, which they called OSM, was expressed in the majority of mouse and human cell types tested. Northern blot and in situ hybridization of mouse tissues showed highest Osm expression in nervous system and lymphoid tissues. </p>
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<strong>Gene Structure</strong>
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<p>Liquori et al. (2003) determined that the CCM2 gene contains 10 exons and spans 77.6 kb. It contains LINE and SINE elements, including Alu sequences, within intron 1 and the 3-prime region distal to exon 10. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>By linkage analysis, Craig et al. (1998) mapped the CCM2 gene to chromosome 7p15-p13. </p>
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<h4>
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<strong>Gene Function</strong>
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<p>By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al. (2003) showed that a C-terminal fragment of mouse Osm interacted with Mekk3 (MAP3K3; 602539), a p38 (MAPK14; 600289) activator that responds to sorbitol-induced hyperosmotic conditions. Mekk3 and Osm colocalized in the cytoplasmic compartment of cotransfected cells, and the Mekk3-Osm complex was recruited to Rac1 (602048)- and cytoskeletal actin (see 102560)-containing membrane ruffles in response to sorbitol treatment. Protein interaction assays showed that Osm interacted directly with the Mekk3 substrate Mkk3 (MAP2K3; 602315), with actin, and with both GDP- and GTP-loaded Rac1. Uhlik et al. (2003) concluded that the RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity in response to osmotic shock. </p><p>Zawistowski et al. (2005) used coimmunoprecipitation, fluorescence resonance energy transfer, and subcellular localization strategies to show that KRIT1 interacted with CCM2. Analogous to the established interactions of KRIT1/ITGB1 (135630) and KRIT1/ICAP1, the KRIT1/CCM2 association was dependent upon phosphotyrosine-binding (PTB) domain of CCM2. A familial CCM2 L198R mutation (607929.0007) abrogated the KRIT1/CCM2 interaction, suggesting that loss of this interaction may be critical in CCM pathogenesis. CCM2 and ICAP1, when bound to KRIT1 via their respective PTB domains, differentially influenced KRIT1 subcellular localization. The authors expanded upon the established involvement of CCM2 in the p38 MAPK signaling module by demonstrating that KRIT1 associated with CCM2 and MEKK3 in a ternary complex. Zawistowski et al. (2005) proposed that the genetic heterogeneity observed in familial CCM may reflect mutation of different molecular members of a coordinated signaling complex. </p><p>By GST pull-down and coimmunoprecipitation analysis, Voss et al. (2007) demonstrated that CCM2 coprecipitated and colocalized with CCM3 (PDCD10; 609118). Yeast 2-hybrid analysis showed that CCM3 directly bound to STK25 (602255) and the phosphatase domain of FAP1 (600267). CCM3 was phosphorylated by STK25, whereas the C-terminal domain of FAP1 dephosphorylated CCM3. Further experiments showed that STK25 and CCM2 formed a protein complex. The findings linked CCM3 and STK25 with CCM2, which is part of signaling pathways that are essential for vascular development. Voss et al. (2007) hypothesized that CCM3 is part of the KRIT1/CCM2 protein complex through its interaction with CCM2, and therefore may participate in CCM1-dependent modulation of ITGB1 signaling. </p><p>Using RNA interference, Crose et al. (2009) showed that knockdown of Ccm2 in mouse brain endothelial cells led to increased monolayer permeability, decreased tubule formation, and reduced cell migration following wounding. These effects were associated with elevated levels of RhoA (165390), a small GTPase necessary for cytoskeletal turnover and migration. Coimmunoprecipitation analysis revealed that both Ccm2 and Mekk3 directly bound the RhoA ubiquitin ligase Smurf1 (605568). Domain analysis revealed that the PTB domain of Ccm2 directly bound the HECT domain of Smurf1, and the interaction targeted Smurf1 to Ccm2 complexes localized primarily at the cell periphery. Coexpression of Ccm2 and Smurf1 led to cell rounding, likely due to loss of RhoA. Crose et al. (2009) concluded that CCM2 contributes to endothelial cell integrity by regulating SMURF1-directed RHOA degradation </p><p>Kleaveland et al. (2009) showed that knockdown of CCM2 in human umbilical vein endothelial cells (HUVECs) via small hairpin RNA had no effect on cell size, proliferation, migration, or formation of branching structures. However, branched cords formed by CCM2-knockdown HUVECs often lacked visible lumens, suggesting a defect in endothelial tube formation. Using mice and zebrafish lacking Ccm2 and/or Heg1 (614182) and CCM2-knockdown HUVECs, Kleaveland et al. (2009) showed that CCM2-HEG1 signaling regulated endothelial tube formation and endothelial junction formation. Coimmunoprecipitation experiments and pull-down assays in transfected HEK293T cells suggested a model in which HEG1 coupled with CCM2 primarily through interaction with KRIT1 at endothelial cell-cell junctions. </p><p>Borikova et al. (2010) showed that knockdown of Ccm1, Ccm2, or Ccm3 in mouse embryonic endothelial cells induced RhoA overexpression and persistent RhoA activity at the cell edge, as well as in the cytoplasm and nucleus. RhoA activation was especially pronounced following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited formation of vessel-like tubes and invasion of extracellular matrix. Knockdown or inhibition of Rock2 countered these effects and was associated with inhibition of RhoA-stimulated phosphorylation of myosin light chain-2 (MLC2; see 160781). Borikova et al. (2010) concluded that the CCM protein complex regulates RhoA activation and cytoskeletal dynamics. </p><p>Using short interfering RNA, Renz et al. (2015) found that silencing CCM2 elevated expression of KLF2 (602016) mRNA in human umbilical vein endothelial cells. Elevated expression of KLF2 in CCM2-knockdown cells required activation of cell surface beta-1 integrin. </p><p>By studying the role of ECs in genetic risk for coronary artery disease (CAD), Schnitzler et al. (2024) identified CCM2 and TLNRD1 (615466) as regulators in the CCM signaling pathway that may be linked to CAD risk. Knockdown of CCM2 or TLNRD1 perturbed expression of genes in the CCM signaling pathway in human aortic ECs and led to changes in gene expression that might be protective in CAD. CCM2 and TLNRD1 interacted directly, mediated by the C-terminal helix of CCM2 and the 9-helix bundle of TLNRD1. Through their interaction, TLNRD1 and CCM2 regulated the CCM signaling pathway and EC phenotypes relevant to CAD. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Liquori et al. (2003) screened a cohort of 37 probands with cerebral cavernous malformations for KRIT1 mutations and found mutations of this gene in 10 (see CCM1, 116860). Among the panel of 27 probands without a KRIT1 mutation, they detected 8 different mutations in the MGC4607 gene (see CCM2, 603284). One mutation, a 4-bp deletion (607929.0004), was found in 2 separate families which, as suggested by a further investigation into ethnic background, may be distantly related. </p><p>Denier et al. (2004) likewise identified the MGC4607 gene as the gene mutated in CCM2. They narrowed the CCM2 linkage interval from 22 cM to 7.5 cM. They then hypothesized that large deletions might be involved in the disorder, as already reported in other hamartomatous conditions such as tuberous sclerosis (191100) and neurofibromatosis (162200). They performed a high density microsatellite genotyping of this 7.5-cM interval in search of putative null alleles in 30 unrelated families. In this way, they identified null alleles that were the result of deletions within a 350-kb interval in 2 families. Additional microsatellite and single-nucleotide polymorphism genotyping showed that these 2 distinct deletions overlapped and that both of them deleted the first exon of MGC4607. In both families, 1 of the 2 MGC4607 transcripts was not detected. They then identified 8 additional point mutations within MGC4607 in 8 of the remaining families. One of them led to the alteration of the initiation codon and 5 of them to a premature termination, including 1 nonsense, 1 frameshift, and 3 splice-site mutations. The findings in cerebral cavernous malformations strongly suggest that MGC4607 has a role in vascular morphogenesis. </p><p>Liquori et al. (2007) commented that DNA sequence analysis of the genes CCM1 (KRIT1), CCM2, and CCM3 (PDCD10) in a cohort of 63 CCM-affected families showed that 40% of these lacked any identifiable mutation. The data suggested either that another CCM gene exists or that a significant fraction of CCM mutations are not found by routine DNA sequence analysis. Potential mutations that would be undetected by sequence analysis included mutations within regulatory regions not included in routine sequencing, as well as larger genomic insertions, deletions, or duplications. Liquori et al. (2007) used multiplex ligation-dependent probe analysis to screen 25 probands who were negative for CCM1, -2, and -3 mutations for potential deletions or duplications within these 3 genes. They identified 15 deletions: 1 in the CCM1 gene, none in the CCM3 gene, and 14 in the CCM2 gene. In this cohort, mutation screening that included sequence and deletion analyses gave disease-gene frequencies of 40% for CCM1, 38% for CCM2, 6% for CCM3, and 16% with no mutation detected. The data indicated that the prevalence of CCM2 is much higher than previously predicted, nearly equal to CCM1, and that large genomic deletions in the CCM2 gene represent a major component of this disorder. A common 77.6-kb deletion spanning CCM2 exons 2 through 10 was identified, which was present in 13% of the entire CCM cohort (607929.0009). Liquori et al. (2007) hypothesized that these deletions occurred in a hypermutable region because of surrounding repetitive sequence elements and may catalyze the formation of intragenic deletions. </p><p>In 2 (14%) of 14 unrelated patients with sporadic CCM and multiple lesions, Felbor et al. (2007) identified a respective deletion in the CCM2 gene using multiplex ligation-dependent probe amplification. One of the deletions involved the entire coding region of the CCM2 gene. </p><p>Among 24 Italian families with CCM, Liquori et al. (2008) identified 4 deletions and 1 duplication in the CCM2 gene. </p><p>For each of the 3 CCM genes, Pagenstecher et al. (2009) showed complete localized loss of either KRIT1, CCM2/malcavernin, or PDCD10 protein expression depending on the respective inherited mutation. Cavernous but not adjacent normal or reactive endothelial cells of known germline mutation carriers displayed immunohistochemical negativity only for the corresponding CCM protein, but stained positively for the 2 other proteins. Immunohistochemical studies demonstrated endothelial cell mosaicism as neoangiogenic vessels within caverns from a CCM1 patient, normal brain endothelium from a CCM2 patient, and capillary endothelial cells of vessels in a revascularized thrombosed cavern from a CCM3 patient stained positively for KRIT1, CCM2/malcavernin, and PDCD10 respectively. Pagenstecher et al. (2009) suggested that complete lack of CCM protein in affected endothelial cells from CCM germline mutation carriers supports a 2-hit mechanism for CCM formation. </p><p>By use of repeated cycles of amplification, subcloning, and sequencing of multiple clones per amplicon, Akers et al. (2009) identified somatic mutations that were otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all 3 forms of inherited CCMs. The somatic mutations were found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. Although widely expressed in the different cell types of the brain, the authors also suggested a unique role for the CCM proteins in endothelial cell biology. Akers et al. (2009) suggested that CCM lesion genesis may require complete loss of function for one of the CCM genes. </p><p>Gallione et al. (2011) identified a founder mutation in the Ashkenazi Jewish population that affects mRNA splicing of the CCM2 gene causing cerebral cavernous malformations (607929.0010). </p><p>In 27 unrelated patients with CCM and heterozygosity for the 77.6-kb deletion (607929.0009) encompassing exons 2-10 the CCM2 gene, Gallione et al. (2022) sequenced 10 kb upstream and downstream of the deletion to evaluate for a shared haplotype. SNP analysis demonstrated a shared haplotype among all 27 patients. The deletion was shown to be due to a recombination event between an AluSx sequence and an AluSg sequence, which, while highly homologous, are not identical. Genealogy studies showed that 5 of the families may share a single common ancestor. </p><p>Bergametti et al. (2020) identified 6 heterozygous mutations in the CCM gene (607929.0007; 607929.0011-607929.0015) in 7 unrelated patients with CCM. The mutations were identified by sequencing of 3 genes associated with cerebral cavernous malformations. Coimmunoprecipitation studies with each of the mutations resulted in loss of interaction between CCM1 and CCM2. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hogan et al. (2008) found that deletion of Ccm1 in zebrafish caused dilation of embryonic vessels. Vascular dilation was associated with progressive spreading of endothelial cells and thinning of vessel walls. Determination of cell fate, cell number, and endothelial cell-cell contacts appeared normal. Ccm1 mutants, Ccm2 mutants, and Ccm1/Ccm2 double mutants had indistinguishable vascular phenotypes, suggesting conservation of function. </p><p>Boulday et al. (2011) noted that deletion of Ccm1, Ccm2, or Ccm3 in mice is embryonic lethal. They generated mice with an endothelial-specific Ccm2 deletion at postnatal day 1, which resulted in vascular lesions mimicking human CCM lesions. Deletion of Ccm1 or Ccm3 at postnatal day 1 resulted in similar cerebellar and retinal lesions. Ccm2 lesion development was restricted to the venous bed. Boulday et al. (2011) concluded that the consequences of Ccm2 deletion depend on the developmental timing of the ablation and are associated with a developmental stage with intense angiogenesis. </p><p>Using zebrafish mutants and morpholino-mediated knockdown of genes in zebrafish embryos, Renz et al. (2015) identified a proangiogenic signaling pathway that involved activation of beta-1 integrin, followed by elevated expression of klf2a, klf2b, egfl7 (608582), and vegf (VEGFA; 192240). Ccm2 negatively regulated this pathway. Loss of ccm2 elevated expression of several genes related to angiogenesis, including klf2a and klf2b, and resulted in significant cardiovascular malformations. These defects occurred in the absence of blood flow and did not require mir126a or mir126b (see 611767), the latter of which is located within the egfl7 gene. Knockdown of beta-1 integrin reversed the cardiovascular defects in ccm2 mutant embryos. Knockout of Ccm2 in mice also resulted in elevated Klf2 expression and cardiovascular defects. Renz et al. (2015) concluded that the beta-1 integrin-KLF2-EGFL7 pathway is tightly regulated by CCM2 and that this regulation prevents angiogenic overgrowth and ensures quiescence in endothelial cells. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>15 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, 1-BP DEL, 23G
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<br />
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SNP: rs1562848466,
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ClinVar: RCV000002799
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family (family 2626) in which 4 members had type 2 cerebral cavernous malformations (CCM2; 603284), Liquori et al. (2003) found a heterozygous 1-bp deletion in exon 1 of the CCM2 gene (23delG), causing a frameshift at amino acid 23 and premature termination at amino acid 22. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, GLN107TER
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<br />
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SNP: rs137852841,
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ClinVar: RCV000002800, RCV000289897
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family (family IFCAS-14) in which 2 members had type 2 cerebral cavernous malformations (CCM2; 603284), Liquori et al. (2003) found a heterozygous 319C-T transition in exon 4 of the CCM2 gene, resulting in a gln107-to-ter (Q107X) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, IVS5AS, G-A, -1
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<br />
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SNP: rs1562913873,
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ClinVar: RCV000002801, RCV000721788
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family (family 2030) in which 5 members had type 2 cerebral cavernous malformations (CCM2; 603284), Liquori et al. (2003) found a heterozygous splice junction mutation (610-1G-A), involving the invariant G residue at the splice acceptor site adjacent to exon 6. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, 4-BP DEL, NT169
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<br />
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SNP: rs1562882045,
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ClinVar: RCV000721772, RCV001849084
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 1 family (family 70) with 5 affected individuals and a second family (family IFCAS-1) with 4 affected individuals, Liquori et al. (2003) found that type 2 cerebral cavernous malformations (CCM2; 603284) was associated with a heterozygous 4-bp deletion in exon 2 of the CCM2 gene (169-172delAGAC). The deletion caused a frameshift at amino acid 57 with a premature stop at amino acid 58. The 2 families were thought to be distantly related because they came from the same ethnic background. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, MET1VAL
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<br />
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SNP: rs137852842,
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ClinVar: RCV000002803, RCV000517211
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family (family C038) with cerebral cavernous malformations (CCM2; 603284), Denier et al. (2004) found a heterozygous mutation in the initiating ATG codon of the CCM2 gene, changing nucleotide 1 from A to G (c.1A-G, NM_031443). In this family, 2 sisters and the daughter of 1 of them were affected. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, IVS3DS, G-A, +1
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<br />
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SNP: rs1562906981,
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ClinVar: RCV000002804
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family (family C039) with cerebral cavernous malformations (CCM2; 603284), Denier et al. (2004) identified a heterozygous donor splice site mutation within intron 3, c.288+1G-A (c.288+1G-A, NM-031443) of the CCM2 gene, leading to a transcript in which exon 3 was deleted. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, LEU198ARG
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<br />
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SNP: rs137852843,
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ClinVar: RCV000002805
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family (family C002) with cerebral cavernous malformations (CCM2; 603284), Denier et al. (2004) found that affected individuals had a heterozygous c.593T-G transversion (c.593T-G, NM_031443) in exon 5 of the CCM2 gene, resulting in a leu198-to-arg (L198R) substitution. In this family, a brother and sister were affected as well as a daughter and son. </p><p>In a patient (family 7) with CCM2, Bergametti et al. (2020) identified heterozygosity for the L198R mutation in the PTB domain of the CCM2 gene. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L198R mutation in CCM2 resulted in loss of interaction between CCM1 and CCM2. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, 2-BP DEL, 1248AG
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<br />
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SNP: rs1562921605,
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ClinVar: RCV000002806, RCV000711047
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a family (family C047) with cerebral cavernous malformations (CCM2; 603284) in 3 successive generations, Denier et al. (2004) found a heterozygous deletion of 2 nucleotides, c.1248_1249delAG (c.1248_1249delAG, NM_031443), in exon 10 of the CCM2 gene. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0009 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, 77.6-KB DEL
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<br />
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ClinVar: RCV000002807
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>Among a cohort of 63 families with cerebral cavernous malformations (CCM2; 603284), Liquori et al. (2007) identified a heterozygous 77.6-kb deletion in the CCM2 gene in 8 probands (13%). The deletion encompassed exons 2 through 10, with the proximal breakpoint within an AluSx repeat in intron 1 and the distal breakpoint within an AluSg repeat distal to exon 10. Haplotype analysis suggested that this deletion may have occurred independently at least twice in their cohort, although the evidence was not conclusive. </p><p>Liquori et al. (2008) reported 6 additional CCM families from the United States with the 77.6-kb CCM2 deletion. Haplotype analysis, which included the previously reported families with this deletion, indicated a founder effect. This deletion was not present in 24 Italian families with CCM, indicating that it is specific to a certain cohort of patients. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, IVS1DS, GC-TT, +5
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<br />
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SNP: rs797044623,
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ClinVar: RCV000173535, RCV000339043, RCV004751328
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 7 apparently unrelated probands from 10 different kindreds of Ashkenazi Jewish descent segregating CCM2 (CCM2; 603284), Gallione et al. (2011) identified a heterozygous 2-bp change in the CCM2 gene caused by deletion of a GC pair and insertion of a TT pair near the splice donor site of exon 1 (30+5_6delinsTT). The 2-bp change segregated with affected status in the study families. Transcripts arising from the normal and mutant alleles were examined by RT-PCR from affected and unaffected Ashkenazi Jewish cerebral cavernous malformation family members. A synthetic splicing system using a chimeric exon was used to visualize the effects of the change on splice donor site utilization. The 2-bp change, when tested in this in vitro synthetic splicing system, altered splice donor site utilization. RT-PCR revealed loss of the transcript allele that was in phase with the mutation. Gallione et al. (2011) concluded that this 2-bp change in CCM2 disrupted proper splice donor utilization leading to a degraded transcript. Resequencing of the genomic region proximal and distal to the CCM2 gene mutation revealed a common SNP haplotype in affected individuals that demonstrated that this mutation was due to a founder in the Ashkenazi Jewish population. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, LEU113PRO
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<br />
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ClinVar: RCV003319556, RCV004593261
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients (families 1 and 2) with cerebral cavernous malformations (CCM2; 603284), Bergametti et al. (2020) identified heterozygosity for a c.338T-C transition (c.338T-C, NM_031443.3) in the CCM2 gene, resulting in a leu113-to-pro (L113P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L113P mutation resulted in loss of interaction between CCM1 and CCM2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, LEU198PRO
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<br />
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ClinVar: RCV003319557
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (family 6) with cerebral cavernous malformations (CCM2; 603284), Bergametti et al. (2020) identified heterozygosity for a c.593T-C transition (c.593T-C, NM_031443.3) in the CCM2 gene, resulting in a leu198-to-pro (L198P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L198P mutation resulted in loss of interaction between CCM1 and CCM2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, SER116PRO
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<br />
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SNP: rs1562907616,
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ClinVar: RCV000690574
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient (family 3) with cerebral cavernous malformations (CCM2; 603284), Bergametti et al. (2020) identified heterozygosity for a c.346T-C transition (c.346T-C, NM_031443.3) in the CCM2 gene, resulting in a ser116-to-pro (S116P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the S116P mutation resulted in loss of interaction between CCM1 and CCM2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, LEU122ARG
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<br />
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ClinVar: RCV003319558
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient (family 4) with cerebral cavernous malformations (CCM2; 603284), Bergametti et al. (2020) identified heterozygosity for a c.365T-G transversion (c.365T-G, NM_031443.3) in the CCM2 gene, resulting in a leu122-to-arg (L122R) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the L122R mutation resulted in loss of interaction between CCM1 and CCM2. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0015 CEREBRAL CAVERNOUS MALFORMATIONS 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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CCM2, ALA123PRO
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<br />
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ClinVar: RCV003319559
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|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a patient (family 5) with cerebral cavernous malformations (CCM2; 603284), Bergametti et al. (2020) identified heterozygosity for a c.367G-C transversion (c.367G-C, NM_031443.3) in the CCM2 gene, resulting in an ala123-to-pro (A123P) substitution in the PTB domain. The mutation was identified by sequencing of 3 genes associated with cerebral cavernous malformations. The variant was not present in the gnomAD database. Coimmunoprecipitation studies demonstrated that the A123P mutation resulted in loss of interaction between CCM1 and CCM2. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A.
|
|
<strong>Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis.</strong>
|
|
Hum. Molec. Genet. 18: 919-930, 2009.
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[PubMed: 19088123]
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[Full Text: https://doi.org/10.1093/hmg/ddn430]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Bergametti, F., Viot, G., Verny, C., Brechard, M. P., Denier, C., Labauge, P., Petit, P., Nouet, A., Viallet, F., Chaussenot, A., Herve, D., Tournier-Lasserve, E., Riant, F.
|
|
<strong>Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.</strong>
|
|
J. Med. Genet. 57: 400-404, 2020.
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[PubMed: 31937560]
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[Full Text: https://doi.org/10.1136/jmedgenet-2019-106401]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Borikova, A. L., Dibble, C. F., Sciaky, N., Welch, C. M., Abell, A. N., Bencharit, S., Johnson, G. L.
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<strong>Rho kinase inhibition rescues the endothelial cell cerebral cavernous malformation phenotype.</strong>
|
|
J. Biol. Chem. 285: 11760-11764, 2010.
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[PubMed: 20181950]
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[Full Text: https://doi.org/10.1074/jbc.C109.097220]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Boulday, G., Rudini, N., Maddaluno, L., Blecon, A., Arnould, M., Gaudric, A., Chapon, F., Adams, R. H., Dejana, E., Tournier-Lasserve, E.
|
|
<strong>Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice.</strong>
|
|
J. Exp. Med. 208: 1835-1847, 2011.
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[PubMed: 21859843]
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[Full Text: https://doi.org/10.1084/jem.20110571]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Craig, H. D., Gunel, M., Cepeda, O., Johnson, E. W., Ptacek, L., Steinberg, G. K., Ogilvy, C. S., Berg, M. J., Crawford, S. C., Scott, R. M., Steichen-Gersdorf, E., Sabroe, R., Kennedy, C. T., Mettler, G., Beis, M. J., Fryer, A., Awad, I. A., Lifton, R. P.
|
|
<strong>Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27.</strong>
|
|
Hum. Molec. Genet. 7: 1851-1858, 1998.
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[PubMed: 9811928]
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[Full Text: https://doi.org/10.1093/hmg/7.12.1851]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Crose, L. E. S., Hilder, T. L., Sciaky, N., Johnson, G. L.
|
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<strong>Cerebral cavernous malformation 2 protein promotes Smad ubiquitin regulatory factor 1-mediated RhoA degradation in endothelial cells.</strong>
|
|
J. Biol. Chem. 284: 13301-13305, 2009.
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[PubMed: 19318350]
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[Full Text: https://doi.org/10.1074/jbc.C900009200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Denier, C., Goutagny, S., Labauge, P., Krivosic, V., Arnoult, M., Cousin, A., Benabid, A. L., Comoy, J., Frerebeau, P., Gilbert, B., Houtteville, J. P., Jan, M., and 14 others.
|
|
<strong>Mutations within the MGC4607 gene cause cerebral cavernous malformations.</strong>
|
|
Am. J. Hum. Genet. 74: 326-337, 2004.
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[PubMed: 14740320]
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[Full Text: https://doi.org/10.1086/381718]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Felbor, U., Gaetzner, S., Verlaan, D. J., Vijzelaar, R., Rouleau, G. A., Siegel, A. M.
|
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<strong>Large germline deletions and duplication in isolated cerebral cavernous malformation patients.</strong>
|
|
Neurogenetics 8: 149-153, 2007.
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|
[PubMed: 17211633]
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[Full Text: https://doi.org/10.1007/s10048-006-0076-7]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Gallione, C. J., Detter, M. R., Sheline, A., Christmas, H. M., Lee, C., Marchuk, D. A.
|
|
<strong>Genetic genealogy uncovers a founder deletion mutation in the cerebral cavernous malformations 2 gene.</strong>
|
|
Hum. Genet. 141: 1761-1769, 2022.
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|
[PubMed: 35488064]
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[Full Text: https://doi.org/10.1007/s00439-022-02458-5]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Gallione, C. J., Solatycki, A., Awad, I. A., Weber, J. L., Marchuk, D. A.
|
|
<strong>A founder mutation in the Ashkenazi Jewish population affecting messenger RNA splicing of the CCM2 gene causes cerebral cavernous malformations.</strong>
|
|
Genet. Med. 13: 662-666, 2011.
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|
[PubMed: 21543988]
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[Full Text: https://doi.org/10.1097/GIM.0b013e318211ff8b]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hogan, B. M., Bussmann, J., Wolburg, H., Schulte-Merker, S.
|
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<strong>ccm1 cell autonomously regulates endothelial cellular morphogenesis and vascular tubulogenesis in zebrafish.</strong>
|
|
Hum. Molec. Genet. 17: 2424-2432, 2008.
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[PubMed: 18469344]
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[Full Text: https://doi.org/10.1093/hmg/ddn142]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Kleaveland, B., Zheng, X., Liu, J. J., Blum, Y., Tung, J. J., Zou, Z., Sweeney, S. M., Chen, M., Guo, L., Lu, M., Zhou, D., Kitajewski, J., Affolter, M., Ginsberg, M. H., Kahn, M. L.
|
|
<strong>Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway.</strong>
|
|
Nature Med. 15: 169-176, 2009. Note: Erratum: Nature Med. 15: 584 only, 2009.
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|
[PubMed: 19151727]
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[Full Text: https://doi.org/10.1038/nm.1918]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Liquori, C. L., Berg, M. J., Siegel, A. M., Huang, E., Zawistowski, J. S., Stoffer, T., Verlaan, D., Balogun, F., Hughes, L., Leedom, T. P., Plummer, N. W., Cannella, M., Maglione, V., Squitieri, F., Johnson, E. W., Rouleau, G. A., Ptacek, L., Marchuk, D. A.
|
|
<strong>Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations.</strong>
|
|
Am. J. Hum. Genet. 73: 1459-1464, 2003.
|
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|
[PubMed: 14624391]
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[Full Text: https://doi.org/10.1086/380314]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liquori, C. L., Berg, M. J., Squitieri, F., Leedom, T. P., Ptacek, L., Johnson, E. W., Marchuk, D. A.
|
|
<strong>Deletions in CCM2 are a common cause of cervical cavernous malformations.</strong>
|
|
Am. J. Hum. Genet. 80: 69-75, 2007.
|
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|
[PubMed: 17160895]
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[Full Text: https://doi.org/10.1086/510439]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Liquori, C. L., Penco, S., Gault, J., Leedom, T. P., Tassi, L., Esposito, T., Awad, I. A., Frati, L., Johnson, E. W., Squitieri, F., Marchuk, D. A., Gianfrancesco, F.
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<strong>A two-hit mechanism causes cerebral cavernous malformations: complete inactivation of CCM1, CCM2 or CCM3 in affected endothelial cells.</strong>
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Renz, M., Otten, C., Faurobert, E., Rudolph, F., Zhu, Y., Boulday, G., Duchene, J., Mickoleit, M., Dietrich, A.-C., Ramspacher, C., Steed, E., Manet-Dupe, S., and 9 others.
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<strong>Regulation of beta-1 integrin-Klf2-mediated angiogenesis by CCM proteins.</strong>
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Schnitzler, G. R., Kang, H., Fang, S., Angom, R. S., Lee-Kim, V. S., Ma, X. R., Zhou, R., Zeng, T., Guo, K., Taylor, M. S., Vellarikkal, S. K., Barry, A. E., and 15 others.
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Uhlik, M. T., Abell, A. N., Johnson, N. L., Sun, W., Cuevas, B. D., Lobel-Rice, K. E., Horne, E. A., Dell'Acqua, M. L., Johnson, G. L.
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<strong>CCM3 interacts with CCM2 indicating common pathogenesis for cerebral cavernous malformations.</strong>
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Bao Lige - updated : 07/18/2024<br>Hilary J. Vernon - updated : 08/04/2023<br>Patricia A. Hartz - updated : 09/13/2016<br>Paul J. Converse - updated : 1/11/2012<br>Ada Hamosh - updated : 8/24/2011<br>Patricia A. Hartz - updated : 5/26/2011<br>Patricia A. Hartz - updated : 12/20/2010<br>Matthew B. Gross - updated : 11/2/2009<br>Patricia A. Hartz - updated : 11/2/2009<br>George E. Tiller - updated : 8/12/2009<br>Patricia A. Hartz - updated : 2/23/2009<br>George E. Tiller - updated : 1/23/2009<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 11/27/2007<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Victor A. McKusick - updated : 1/2/2007<br>Victor A. McKusick - updated : 1/30/2004
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