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Entry
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- *604214 - KRIT1 ANKYRIN REPEAT-CONTAINING PROTEIN 1; KRIT1
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- OMIM
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<p>
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<span class="h4">*604214</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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<a href="#text"><strong>Text</strong></a>
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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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<a href="#geneFunction">Gene Function</a>
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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="#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/604214">Table View</a>
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<a href="#references"><strong>References</strong></a>
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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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<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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<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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</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=ENSG00000001631;t=ENST00000394505" 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=889" 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=604214" 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=ENSG00000001631;t=ENST00000394505" 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_001013406,NM_001350669,NM_001350670,NM_001350671,NM_001350672,NM_001350673,NM_001350674,NM_001350675,NM_001350676,NM_001350677,NM_001350678,NM_001350679,NM_001350680,NM_001350681,NM_001350682,NM_001350683,NM_001350684,NM_001350685,NM_001350686,NM_001350687,NM_001350688,NM_001350689,NM_001350690,NM_001350691,NM_001350692,NM_001350693,NM_001350694,NM_001350695,NM_001350696,NM_001350697,NM_004912,NM_194454,NM_194455,NM_194456" 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_194454" 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=604214" 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=05020&isoform_id=05020_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/KRIT1" 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/2149602,2832226,9998950,11544636,12044278,20339623,31581522,37221182,37221184,37221187,37577187,37577189,37577191,37577193,41471985,51094907,61742817,63014373,63014375,66267176,77432385,119597260,119597261,193786214,193786458,1183596616,1183596618,1183596620,1183596629,1183596631,1183596639,1183596641,1183596643,1183596649,1183596653,1183596657,1183596659,1183596667,1183596671,1183596673,1183596675,1183596679,1183596690,1183596692,1183596694,1183596696,1183596698,1183596702,1183596704,1183596706,1183596708,1184495025,1184495035,1184495057" 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/O00522" 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=889" 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=ENSG00000001631;t=ENST00000394505" 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=KRIT1" 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=KRIT1" 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+889" 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/KRIT1" 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:889" 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/889" 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=ENST00000458493.6&hgg_start=92198969&hgg_end=92246100&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>
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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/krit1" 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=604214[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=604214[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://www.deciphergenomics.org/gene/KRIT1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000001631" 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=KRIT1" 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=KRIT1" 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=KRIT1" 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=KRIT1&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/PA26144" 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:1573" 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:1930618" 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/KRIT1#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:1930618" 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/889/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=889" 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://wormbase.org/db/gene/gene?name=WBGene00013955;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-555" 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">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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|
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<div style="display: table-cell;">Cellular Pathways</div>
|
|
</div>
|
|
</a>
|
|
</span>
|
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</span>
|
|
</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:889" 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=KRIT1&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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|
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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>
|
|
<div class="text-right">
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</div>
|
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
604214
|
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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>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
KRIT1 ANKYRIN REPEAT-CONTAINING PROTEIN 1; KRIT1
|
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|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
|
|
<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
KREV INTERACTION TRAPPED 1<br />
|
|
CCM1 GENE; CCM1
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
|
|
|
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</div>
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|
|
<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KRIT1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KRIT1</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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|
|
|
|
|
|
|
|
<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/7/406?start=-3&limit=10&highlight=406">7q21.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:92198969-92246100&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'})">7:92,198,969-92,246,100</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/7/406?start=-3&limit=10&highlight=406">
|
|
7q21.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cavernous malformations of CNS and retina
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/116860"> 116860 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Cerebral cavernous malformations-1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/116860"> 116860 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/116860"> 116860 </a>
|
|
|
|
</span>
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<p>The CCM complex, which includes CCM1, CCM2 (<a href="/entry/607929">607929</a>), 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 2-hybrid screen of a HeLa cell cDNA library designed to identify KREV1 (RAP1A; <a href="/entry/179520">179520</a>) activity, <a href="#26" class="mim-tip-reference" title="Serebriiskii, I., Estojak, J., Sonoda, G., Testa, J. R., Golemis, E. A. <strong>Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22.</strong> Oncogene 15: 1043-1049, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285558</a>] [<a href="https://doi.org/10.1038/sj.onc.1201268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285558">Serebriiskii et al. (1997)</a> isolated a novel cDNA, called KRIT1 for 'Krev interaction trapped-1.' The deduced 529-amino acid KRIT1 protein contains an N-terminal ankyrin repeat domain and a novel C-terminal domain required for association with KREV1. KRIT1 mRNA was expressed endogenously at low levels, with tissue-specific variation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9285558" 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="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> detected a KRIT1 transcript of 5 to 6 kb in all tissues, although it was less abundant in brain, kidney, and lung. A 3.5-kb band was also observed in heart, skeletal muscle, and pancreas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508515" 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="#24" class="mim-tip-reference" title="Sahoo, T., Goenaga-Diaz, E., Serebriiskii, I. G., Thomas, J. W., Kotova, E., Cuellar, J. G., Peloquin, J. M., Golemis, E., Beitinjaneh, F., Green, E. D., Johnson, E. W., Marchuk, D. A. <strong>Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene.</strong> Genomics 71: 123-126, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161805</a>] [<a href="https://doi.org/10.1006/geno.2000.6426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161805">Sahoo et al. (2001)</a> extended the N terminus of the KRIT1 protein by 207 amino acids. The deduced full-length 736-amino acid protein has a calculated molecular mass of about 81 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161805" 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="#34" class="mim-tip-reference" title="Zhang, J., Clatterbuck, R. E., Rigamonti, D., Dietz, H. C. <strong>Cloning of the murine Krit1 cDNA reveals novel mammalian 5-prime coding exons.</strong> Genomics 70: 392-395, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161791</a>] [<a href="https://doi.org/10.1006/geno.2000.6410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161791">Zhang et al. (2000)</a> cloned mouse Krit1. The deduced 736-amino acid protein contains an ankyrin repeat, FERM motifs, and 2 potential nuclear localization signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161791" 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="#22" class="mim-tip-reference" title="Retta, S. F., Avolio, M., Francalanci, F., Procida, S., Balzac, F., Degani, S., Tarone, G., Silengo, L. <strong>Identification of Krit1B: a novel alternative splicing isoform of cerebral cavernous malformation gene-1.</strong> Gene 325: 63-78, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14697511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14697511</a>] [<a href="https://doi.org/10.1016/j.gene.2003.09.046" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14697511">Retta et al. (2004)</a> identified Krit1b, a splice variant of mouse Krit1 that lacks exon 15. Compared with the full-length protein, which the authors called Krit1a, the deduced 697-amino acid Krit1b protein has a 39-amino acid deletion in a C-terminal region required for association with Rap1a. RT-PCR detected strongest Krit1b expression in thymus and brain and weaker expression in several other mouse tissues. KRIT1B was expressed at a low level in some human cell lines, but it was not detected in any adult or fetal human tissues examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14697511" 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="#26" class="mim-tip-reference" title="Serebriiskii, I., Estojak, J., Sonoda, G., Testa, J. R., Golemis, E. A. <strong>Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22.</strong> Oncogene 15: 1043-1049, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285558</a>] [<a href="https://doi.org/10.1038/sj.onc.1201268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285558">Serebriiskii et al. (1997)</a> found that KRIT1 interacted strongly with KREV1 but only weakly with Ras (see <a href="/entry/190020">190020</a>), suggesting that KRIT1 might specifically regulate KREV1 activities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9285558" 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 2-hybrid analysis and coimmunoprecipitation, <a href="#33" class="mim-tip-reference" title="Zhang, J., Clatterbuck, R. E., Rigamonti, D., Chang, D. D., Dietz, H. C. <strong>Interaction between krit1 and icap1-alpha infers perturbation of integrin beta-1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation.</strong> Hum. Molec. Genet. 10: 2953-2960, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741838</a>] [<a href="https://doi.org/10.1093/hmg/10.25.2953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11741838">Zhang et al. (2001)</a> found that full-length KRIT1 failed to interact with KREV1/RAP1A but showed strong interaction with integrin cytoplasmic domain-associated protein-1 (ICAP1; <a href="/entry/607153">607153</a>). ICAP1 binds to an NPXY (asn-pro-X-tyr, where X is any amino acid) sequence motif in the cytoplasmic domain of beta-1 integrin (ITGB1; <a href="/entry/135630">135630</a>) and participates in beta-1-mediated cell adhesion and migration. The novel N terminus of KRIT1 also contains an NPXY motif that was found to be required for ICAP1 interaction. Like ITGB1, KRIT1 interacted with the 200-amino acid isoform of ICAP1 (ICAP1-alpha), but not a 150-amino acid form that results from alternative splicing (ICAP1-beta). In a competition assay, induced expression of KRIT1 diminished the interaction between ICAP1A and ITGB1. The authors hypothesized that ITGB1 and KRIT1 may compete for the same site on ICAP1A, perhaps constituting a regulatory mechanism. Loss-of-function KRIT1 mutations, as observed in cerebral cavernous malformation-1 (CCM1; <a href="/entry/116860">116860</a>), may shift the balance with predicted consequences for endothelial cell performance during ITGB1-dependent angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741838" 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="#31" class="mim-tip-reference" title="Zawistowski, J. S., Serebriiskii, I. G., Lee, M. F., Golemis, E. A., Marchuk, D. A. <strong>KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis.</strong> Hum. Molec. Genet. 11: 389-396, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854171</a>] [<a href="https://doi.org/10.1093/hmg/11.4.389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11854171">Zawistowski et al. (2002)</a> confirmed the interaction of KRIT1 and ICAP1 using a yeast 2-hybrid screen. Mutagenesis of the N-terminal KRIT1 NPXY sequence completely abrogated the KRIT1-ICAP1 interaction. The authors hypothesized that KRIT1 may be involved in bidirectional signaling between integrin molecules and the cytoskeleton, and that KRIT1 may affect cell adhesion processes via integrin signaling in CCM1 pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854171" 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>To study the biologic functions of KRIT1, <a href="#10" class="mim-tip-reference" title="Gunel, M., Laurans, M. S. H., Shin, D., DiLuna, M. L., Voorhees, J., Choate, K., Nelson-Williams, C., Lifton, R. P. <strong>KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.</strong> Proc. Nat. Acad. Sci. 99: 10677-10682, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140362</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12140362[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/10.1073/pnas.122354499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140362">Gunel et al. (2002)</a> investigated KRIT1 expression in endothelial cells with the use of specific anti-KRIT1 antibodies. By both microscopy and coimmunoprecipitation, they showed that KRIT1 colocalizes with microtubules. In interphase cells, KRIT1 was found along the length of microtubules. During metaphase, KRIT1 was located on spindle pole bodies and the mitotic spindle. During late phases of mitosis, KRIT1 localized in a pattern indicative of association with microtubule plus ends. In anaphase, the plus ends of the interpolar microtubules showed strong KRIT1 staining and, in late telophase, KRIT1 stained the midbody remnant most strongly; this is the site of cytokinesis where plus ends of microtubules from dividing cells overlap. These results established that KRIT1 is a microtubule-associated protein; its location at plus ends in mitosis suggested a possible role in microtubule targeting. These findings, coupled with evidence of interaction of KRIT1 with KREV1 and ICAP1A, suggested that KRIT1 may help determine endothelial cell shape and function in response to cell-cell and cell-matrix interactions by guiding cytoskeletal structure. <a href="#10" class="mim-tip-reference" title="Gunel, M., Laurans, M. S. H., Shin, D., DiLuna, M. L., Voorhees, J., Choate, K., Nelson-Williams, C., Lifton, R. P. <strong>KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.</strong> Proc. Nat. Acad. Sci. 99: 10677-10682, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140362</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12140362[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/10.1073/pnas.122354499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12140362">Gunel et al. (2002)</a> proposed that the loss of this targeting function leads to abnormal endothelial tube formation, thereby explaining the mechanism of formation of cerebral cavernous malformation lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12140362" 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>Hereditary hemorrhagic telangiectasia (see <a href="/entry/187300">187300</a>) and cerebral cavernous malformations (see <a href="/entry/116860">116860</a>) are disorders involving disruption of normal vascular morphogenesis. The autosomal dominant mode of inheritance in both of these disorders suggested to <a href="#18" class="mim-tip-reference" title="Marchuk, D. A., Srinivasan, S., Squire, T. L., Zawistowski, J. S. <strong>Vascular morphogenesis: tales of two syndromes.</strong> Hum. Molec. Genet. 12: R97-R112, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668602</a>] [<a href="https://doi.org/10.1093/hmg/ddg103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12668602">Marchuk et al. (2003)</a> that their underlying genes might regulate critical aspects of vascular morphogenesis. The authors summarized the roles of these genes, KRIT1, endoglin (<a href="/entry/131195">131195</a>), and ALK1 (<a href="/entry/601284">601284</a>), in the genetic control of angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668602" 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="#32" 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 the CCM2 gene (<a href="/entry/607929">607929</a>) product, malcavernin. Analogous to the established interactions of KRIT1/ITGB1 and KRIT1/ICAP1, the KRIT1/CCM2 association was dependent upon phosphotyrosine-binding (PTB) domain of CCM2. A familial CCM2 L198R mutation (<a href="/entry/607929#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 (<a href="/entry/600289">600289</a>) signaling module by demonstrating that KRIT1 associated with CCM2 and MEKK3 (<a href="/entry/602539">602539</a>) in a ternary complex. <a href="#32" 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><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 (<a href="/entry/165390">165390</a>) 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 (<a href="/entry/604002">604002</a>) 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><a href="#17" class="mim-tip-reference" title="Maddaluno, L., Rudini, N., Cuttano, R., Bravi, L., Giampietro, C., Corada, M., Ferrarini, L., Orsenigo, F., Papa, E., Boulday, G., Tournier-Lasserve, E., Chapon, F., Richichi, C., Retta, S. F., Lampugnani, M. G., Dejana, E. <strong>EndMT contributes to the onset and progression of cerebral cavernous malformations.</strong> Nature 498: 492-496, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23748444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23748444</a>] [<a href="https://doi.org/10.1038/nature12207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23748444">Maddaluno et al. (2013)</a> demonstrated that endothelial-specific disruption of the KRIT1 gene in mice induces endothelial-to-mesenchymal transition, which contributes to the development of vascular malformations. Endothelial-to-mesenchymal transition in KRIT1-ablated endothelial cells is mediated by the upregulation of endogenous bone morphogenetic protein-6 (BMP6; <a href="/entry/112266">112266</a>) that, in turn, activates the transforming growth factor-beta (TGF-beta; <a href="/entry/190180">190180</a>) and BMP signaling pathway. Inhibitors of the TGF-beta and BMP pathway prevented endothelial-to-mesenchymal transition both in vitro and in vivo and reduced the number and size of vascular lesions in KRIT1-deficient mice. Thus, increased TGF-beta and BMP signaling, and the consequent endothelial-to-mesenchymal transition of KRIT1-null endothelial cells, are crucial events in the onset and progression of cerebral cavernous malformation disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23748444" 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="#20" class="mim-tip-reference" title="Mleynek, T. M., Chan, A. C., Redd, M., Gibson, C. C., Davis, C. T., Shi, D. S., Chen, T., Carter, K. L., Ling, J., Blanco, R., Gerhardt, H., Whitehead, K., Li, D. Y. <strong>Lack of CCM1 induces hypersprouting and impairs response to flow.</strong> Hum. Molec. Genet. 23: 6223-6234, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990152[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/ddu342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990152">Mleynek et al. (2014)</a> used small interfering RNA to suppress CCM1 expression in human umbilical vein endothelial cells (HUVECs) and exposed the cells to laminar shear stress to simulate arterial shear. Unlike wildtype HUVECs, cells depleted of CCM1 failed to align with the direction of flow in the medium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24990152" 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="#14" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> identified 12 exons in the KRIT1 gene. <a href="#24" class="mim-tip-reference" title="Sahoo, T., Goenaga-Diaz, E., Serebriiskii, I. G., Thomas, J. W., Kotova, E., Cuellar, J. G., Peloquin, J. M., Golemis, E., Beitinjaneh, F., Green, E. D., Johnson, E. W., Marchuk, D. A. <strong>Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene.</strong> Genomics 71: 123-126, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161805</a>] [<a href="https://doi.org/10.1006/geno.2000.6426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161805">Sahoo et al. (2001)</a> determined that the KRIT1 gene has 19 exons, the first 3 of which are noncoding. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11161805+10508515" 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="#26" class="mim-tip-reference" title="Serebriiskii, I., Estojak, J., Sonoda, G., Testa, J. R., Golemis, E. A. <strong>Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22.</strong> Oncogene 15: 1043-1049, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285558</a>] [<a href="https://doi.org/10.1038/sj.onc.1201268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9285558">Serebriiskii et al. (1997)</a> mapped the KRIT1 gene to 7q21-q22 by FISH. The authors noted that this region is frequently deleted or amplified in multiple forms of cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9285558" 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="#34" class="mim-tip-reference" title="Zhang, J., Clatterbuck, R. E., Rigamonti, D., Dietz, H. C. <strong>Cloning of the murine Krit1 cDNA reveals novel mammalian 5-prime coding exons.</strong> Genomics 70: 392-395, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161791</a>] [<a href="https://doi.org/10.1006/geno.2000.6410" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161791">Zhang et al. (2000)</a> mapped the mouse Krit1 gene to a region of chromosome 5 that shares homology of synteny with human chromosome 7q21-q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161791" 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 12 of 20 pedigrees with cerebral cavernous malformations-1 (CCM1; <a href="/entry/116860">116860</a>), <a href="#14" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> identified mutations in the CCM1 gene (see, e.g., <a href="#0001">604214.0001</a>) that segregated with the affected phenotype. <a href="#14" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> suggested that the mutations in the CCM1 gene might result in a dominant-negative effect or a loss of function; they favored the second hypothesis. Sporadic forms of cavernous angiomas manifest as unique lesions and familial forms as multiple lesions, which evokes a Knudson double-hit mechanism and would be consistent with the need for a complete loss of CCM1 function for the appearance of cavernous angiomas. All the mutations they reported predicted truncated CCM1 proteins completely or partially devoid of the putative RAP1A-interacting region. The data suggested the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508515" 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="#25" class="mim-tip-reference" title="Sahoo, T., Johnson, E. W., Thomas, J. W., Kuehl, P. M., Jones, T. L., Dokken, C. G., Touchman, J. W., Gallione, C. J., Lee-Lin, S.-Q., Kosofsky, B., Kurth, J. H., Louis, D. N., Mettler, G., Morrison, L., Gil-Nagel, A., Rich, S. S., Zabramski, J. M., Boguski, M. S., Green, E. D., Marchuk, D. A. <strong>Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).</strong> Hum. Molec. Genet. 8: 2325-2333, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10545614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10545614</a>] [<a href="https://doi.org/10.1093/hmg/8.12.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10545614">Sahoo et al. (1999)</a> observed that 7 different KRIT1 mutations had been identified in 23 distinct CCM1 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10545614" 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 29 families and 5 sporadic cases with CCM, <a href="#7" class="mim-tip-reference" title="Davenport, W. J., Siegel, A. M., Dichgans, J., Drigo, P., Mammi, I., Pereda, P., Wood, N. W., Rouleau, G. A. <strong>CCM1 gene mutations in families segregating cerebral cavernous malformations.</strong> Neurology 56: 540-543, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11222804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11222804</a>] [<a href="https://doi.org/10.1212/wnl.56.4.540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11222804">Davenport et al. (2001)</a> identified 10 novel mutations and 1 previously described mutation in the KRIT1 gene (see, e.g., <a href="#0008">604214.0008</a>). The high frequency of loss-of-function mutations suggested loss of a tumor suppressor mechanism. In a follow-up study, <a href="#28" class="mim-tip-reference" title="Verlaan, D. J., Davenport, W. J., Stefan, H., Sure, U., Siegel, A. M., Rouleau, G. A. <strong>Cerebral cavernous malformations: mutations in Krit1.</strong> Neurology 58: 853-857, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11914398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11914398</a>] [<a href="https://doi.org/10.1212/wnl.58.6.853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11914398">Verlaan et al. (2002)</a> reported 7 additional novel mutations and 1 previously described mutation in the KRIT1 gene in families with CCM. In combination with the previous study, <a href="#28" class="mim-tip-reference" title="Verlaan, D. J., Davenport, W. J., Stefan, H., Sure, U., Siegel, A. M., Rouleau, G. A. <strong>Cerebral cavernous malformations: mutations in Krit1.</strong> Neurology 58: 853-857, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11914398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11914398</a>] [<a href="https://doi.org/10.1212/wnl.58.6.853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11914398">Verlaan et al. (2002)</a> found that approximately 47% of CCM families harbor KRIT1 mutations. The authors noted that the majority of mutations in the KRIT1 gene lead to a substantial alteration of the gene product, supporting a loss-of-function mechanism consistent with a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11222804+11914398" 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="#24" class="mim-tip-reference" title="Sahoo, T., Goenaga-Diaz, E., Serebriiskii, I. G., Thomas, J. W., Kotova, E., Cuellar, J. G., Peloquin, J. M., Golemis, E., Beitinjaneh, F., Green, E. D., Johnson, E. W., Marchuk, D. A. <strong>Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene.</strong> Genomics 71: 123-126, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161805</a>] [<a href="https://doi.org/10.1006/geno.2000.6426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161805">Sahoo et al. (2001)</a> identified several novel frameshift mutations in the KRIT1 gene in patients with CCM1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161805" 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="#6" class="mim-tip-reference" title="Cave-Riant, F., Denier, C., Labauge, P., Cecillon, M., Maciazek, J., Joutel, A., Laberge-le Couteulx, S., Tournier-Lasserve, E., Societe Francaise de Neurochirurgie. <strong>Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations.</strong> Europ. J. Hum. Genet. 10: 733-740, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404106</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200870" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404106">Cave-Riant et al. (2002)</a> screened the KRIT1 gene in 121 unrelated CCM probands having at least 1 affected relative and/or showing multiple lesions on cerebral MRI. Fifty-two individuals (43%) were shown to have a KRIT1 mutation, and 42 distinct mutations were identified. Three-quarters of the mutations were located in the C-terminal half of the gene, primarily within exons 13, 15, and 17. All of them were predicted to result in premature stop codons. <a href="#6" class="mim-tip-reference" title="Cave-Riant, F., Denier, C., Labauge, P., Cecillon, M., Maciazek, J., Joutel, A., Laberge-le Couteulx, S., Tournier-Lasserve, E., Societe Francaise de Neurochirurgie. <strong>Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations.</strong> Europ. J. Hum. Genet. 10: 733-740, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404106</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200870" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12404106">Cave-Riant et al. (2002)</a> concluded that the underlying mechanism of CCM may be KRIT1 mRNA decay due to the presence of premature stop codons and KRIT1 haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404106" 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>Almost all KRIT1 mutations causing CCM lead to a premature stop codon, and severe impairment of KRIT1 protein functions is likely to be involved in the pathogenesis of the disorder. In 20 patients with CCM, <a href="#19" class="mim-tip-reference" title="Marini, V., Ferrera, L., Pigatto, F., Origone, P., Garre, C., Dorcaratto, A., Viale, G., Alberti, F., Mareni, C. <strong>Search for loss of heterozygosity and mutation analysis of KRIT1 gene in CCM patients. (Letter)</strong> Am. J. Med. Genet. 130A: 98-101, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15368504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15368504</a>] [<a href="https://doi.org/10.1002/ajmg.a.30122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15368504">Marini et al. (2004)</a> failed to find loss of heterozygosity (LOH) in cavernous angiomas, validating the hypothesis that KRIT1 haploinsufficiency is the underlying mechanism of CCM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15368504" 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="#29" class="mim-tip-reference" title="Verlaan, D. J., Laurent, S. B., Sure, U., Bertalanffy, H., Andermann, E., Andermann, F., Rouleau, G. A., Siegel, A. M. <strong>CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.</strong> Neurology 62: 1213-1215, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15079030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15079030</a>] [<a href="https://doi.org/10.1212/01.wnl.0000118299.55857.bb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15079030">Verlaan et al. (2004)</a> identified a pathogenic mutation in the KRIT1 gene in 4 (29%) of 14 unrelated patients with sporadic CCM and multiple malformations. None of 21 unrelated sporadic patients with a single malformation had a KRIT1 mutation. <a href="#29" class="mim-tip-reference" title="Verlaan, D. J., Laurent, S. B., Sure, U., Bertalanffy, H., Andermann, E., Andermann, F., Rouleau, G. A., Siegel, A. M. <strong>CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.</strong> Neurology 62: 1213-1215, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15079030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15079030</a>] [<a href="https://doi.org/10.1212/01.wnl.0000118299.55857.bb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15079030">Verlaan et al. (2004)</a> concluded that genetic analysis is warranted in sporadic cases of CCM with multiple malformations. In 2 additional patients of the 14 sporadic CCM patients reported by <a href="#29" class="mim-tip-reference" title="Verlaan, D. J., Laurent, S. B., Sure, U., Bertalanffy, H., Andermann, E., Andermann, F., Rouleau, G. A., Siegel, A. M. <strong>CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.</strong> Neurology 62: 1213-1215, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15079030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15079030</a>] [<a href="https://doi.org/10.1212/01.wnl.0000118299.55857.bb" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15079030">Verlaan et al. (2004)</a>, <a href="#9" 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> used multiplex ligation-dependent probe amplification to detect a large duplication and a large deletion, respectively, within the KRIT1 gene. Thus, 6 (42%) of the 14 sporadic patients had KRIT1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17211633+15079030" 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="Battistini, S., Rocchi, R., Cerase, A., Citterio, A., Tassi, L., Lando, G., Patrosso, M. C., Galli, R., Brunori, P., Sgro, D. L., Pitillo, G., Russo, G. L., Marocchi, A., Penco, S. <strong>Clinical, magnetic resonance imaging, and genetic study of 5 families with cerebral cavernous malformation.</strong> Arch. Neurol. 64: 843-848, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17562932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17562932</a>] [<a href="https://doi.org/10.1001/archneur.64.6.843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17562932">Battistini et al. (2007)</a> identified 5 different heterozygous KRIT1 mutations (see, e.g., <a href="#0009">604214.0009</a>) in affected individuals from 5 unrelated families with CCM1. The families included 33 mutation carriers, 57.6% of whom had no symptoms. Brain MRI revealed lesions in 82.3% of symptom-free mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17562932" 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 5 with deletions in the CCM1 gene, including 1 complete deletion of the 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="#21" 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 (<a href="/entry/609118">609118</a>) 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="#21" 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>Through 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 1 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="#5" class="mim-tip-reference" title="Cau, M., Loi, M., Melis, M., Congiu, R., Loi, A., Meloni, C., Serrenti, M., Addis, M., Melis, M. A. <strong>C329X in KRIT1 is a founder mutation among CCM patients in Sardinia.</strong> Europ. J. Med. Genet. 52: 344-348, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19454328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19454328</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19454328">Cau et al. (2009)</a> identified 2 different mutations in the KRIT1 gene (see, e.g., C329X; <a href="#0011">604214.0011</a>) in 5 (71%) of 7 Sardinian families with CCM. Haplotype analysis of patients from 4 of the affected families indicated a founder effect for the C329X mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19454328" 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>By examining the initial stages of vascular lesion development in conditional Ccm1-knockout mice and in ccm1-morphant zebrafish, <a href="#20" class="mim-tip-reference" title="Mleynek, T. M., Chan, A. C., Redd, M., Gibson, C. C., Davis, C. T., Shi, D. S., Chen, T., Carter, K. L., Ling, J., Blanco, R., Gerhardt, H., Whitehead, K., Li, D. Y. <strong>Lack of CCM1 induces hypersprouting and impairs response to flow.</strong> Hum. Molec. Genet. 23: 6223-6234, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990152[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/ddu342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990152">Mleynek et al. (2014)</a> found that loss of Ccm1 resulted in vasculature that exhibited stereotypic hypersprouting prior to dilation. The authors observed that this sprouting behavior was similar to that seen in troponin T2 (TNNT2; <a href="/entry/191045">191045</a>)-morphant zebrafish, which have a nonbeating heart and completely lack blood flow. <a href="#20" class="mim-tip-reference" title="Mleynek, T. M., Chan, A. C., Redd, M., Gibson, C. C., Davis, C. T., Shi, D. S., Chen, T., Carter, K. L., Ling, J., Blanco, R., Gerhardt, H., Whitehead, K., Li, D. Y. <strong>Lack of CCM1 induces hypersprouting and impairs response to flow.</strong> Hum. Molec. Genet. 23: 6223-6234, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990152[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/ddu342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990152">Mleynek et al. (2014)</a> hypothesized that CCM1 is required for endothelial cells to sense blood flow. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24990152" 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>To study the requirement for endothelial TLR4 in spontaneous CCM formation, <a href="#27" class="mim-tip-reference" title="Tang, A. T., Choi, J. P., Kotzin, J. J., Yang, Y., Hong, C. C., Hobson, N., Girard, R., Zeineddine, H. A., Lightle, R., Moore, T., Cao, Y., Shenkar, R., and 18 others. <strong>Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.</strong> Nature 545: 305-310, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489816[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/nature22075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28489816">Tang et al. (2017)</a> bred mice with floxed Tlr4 and Krit1 alleles using mice from the CCM-susceptible Krit1(ECKO) colony (endothelial-specific deletion of Krit1). <a href="#27" class="mim-tip-reference" title="Tang, A. T., Choi, J. P., Kotzin, J. J., Yang, Y., Hong, C. C., Hobson, N., Girard, R., Zeineddine, H. A., Lightle, R., Moore, T., Cao, Y., Shenkar, R., and 18 others. <strong>Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.</strong> Nature 545: 305-310, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489816[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/nature22075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28489816">Tang et al. (2017)</a> observed that loss of a single endothelial Tlr4 allele resulted in an approximately 75% reduction in CCM lesion burden at postnatal day 10, whereas loss of both alleles resulted in virtually complete prevention of CCM lesion formation. Although less complete, global loss of Cd14, a soluble TLR4 coreceptor that binds lipopolysaccharide and facilitates TLR4 signaling, also prevented CCM formation in susceptible Krit1(ECKO) mice. Seven of 8 Krit1(ECKO) neonates who had been delivered and raised in a germ-free environment did not develop any CCM lesions. In contrast, all Krit1(ECKO) neonates who had been delivered in a germ-free environment but raised by conventional mothers exhibited robust CCM formation at postnatal day 10. <a href="#27" class="mim-tip-reference" title="Tang, A. T., Choi, J. P., Kotzin, J. J., Yang, Y., Hong, C. C., Hobson, N., Girard, R., Zeineddine, H. A., Lightle, R., Moore, T., Cao, Y., Shenkar, R., and 18 others. <strong>Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.</strong> Nature 545: 305-310, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489816[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/nature22075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28489816">Tang et al. (2017)</a> found that CCM susceptibility associated with gram-negative bacteria, and that either Tlr4 blockade or altering the microbiome prevented CCM formation in susceptible mice. They concluded that while KRIT1 mutation predisposes to the formation of cerebral cavernous malformations, endothelial TLR4 and the microbiome drive their development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28489816" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604214[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<p>In 3 probands with cerebral cavernous malformations-1 (CCM1; <a href="/entry/116860">116860</a>), <a href="#14" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> found nonsense stop codons in the CCM1 gene, one of which was a C-to-T transition in nucleotide 1283. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508515" 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">rs2131308132 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2131308132;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=rs2131308132" 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=rs2131308132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 5 probands with cerebral cavernous malformations-1 (CCM1; <a href="/entry/116860">116860</a>), <a href="#14" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> found deletions causing frameshifts resulting in premature stop codons in CCM1 gene. One of these was a 1-bp deletion involving nucleotide 1342. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508515" 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 2 probands with cerebral cavernous malformations-1 (CCM1; <a href="/entry/116860">116860</a>), <a href="#14" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E. <strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong> Nature Genet. 23: 189-193, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>] [<a href="https://doi.org/10.1038/13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10508515">Laberge-Le Couteulx et al. (1999)</a> found, in the CCM1 gene, insertions leading to frameshift and premature termination, one of which was insertion of a cytosine after nucleotide 1271 in one pedigree. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508515" 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"><span class="text-primary">●</span> rs267607203 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607203;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267607203?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607203" 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=rs267607203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 16 of 21 Mexican American families with cerebral cavernous malformations (CCM1; <a href="/entry/116860">116860</a>) analyzed, <a href="#25" class="mim-tip-reference" title="Sahoo, T., Johnson, E. W., Thomas, J. W., Kuehl, P. M., Jones, T. L., Dokken, C. G., Touchman, J. W., Gallione, C. J., Lee-Lin, S.-Q., Kosofsky, B., Kurth, J. H., Louis, D. N., Mettler, G., Morrison, L., Gil-Nagel, A., Rich, S. S., Zabramski, J. M., Boguski, M. S., Green, E. D., Marchuk, D. A. <strong>Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).</strong> Hum. Molec. Genet. 8: 2325-2333, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10545614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10545614</a>] [<a href="https://doi.org/10.1093/hmg/8.12.2325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10545614">Sahoo et al. (1999)</a> found that the KRIT1 gene harbored a 1-bp transition (742C-T), changing a gln to a premature termination codon (Q248X). Distinct mutations in KRIT1 were identified in other Mexican American families, as well as in non-Hispanic Caucasian families. The apparently high frequency of cerebral cavernous malformations in Mexican Americans had been noted by <a href="#23" class="mim-tip-reference" title="Rigamonti, D., Hadley, M. N., Drayer, B. P., Johnson, P. C., Hoenig-Rigamonti, K., Knight, J. T., Spetzler, R. F. <strong>Cerebral cavernous malformations: incidence and familial occurrence.</strong> New Eng. J. Med. 319: 343-347, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3393196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3393196</a>] [<a href="https://doi.org/10.1056/NEJM198808113190605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3393196">Rigamonti et al. (1988)</a> and <a href="#12" class="mim-tip-reference" title="Kattapong, V. J., Hart, B. L., Davis, L. E. <strong>Familial cerebral cavernous angiomas: clinical and radiologic studies.</strong> Neurology 45: 492-497, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898703</a>] [<a href="https://doi.org/10.1212/wnl.45.3.492" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7898703">Kattapong et al. (1995)</a>. The finding of a common disease haplotype in affected kindreds from this population had suggested a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3393196+7898703+10545614" 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>Due to numbering differences, this mutation is also known as gln455 to ter (Q455X, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607203;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs267607203</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">rs2131660732 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2131660732;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=rs2131660732" 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=rs2131660732" 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=RCV001665312 OR RCV001807487" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001665312, RCV001807487" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001665312...</a>
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<p><a href="#8" class="mim-tip-reference" title="Eerola, I., Plate, K. H., Spiegel, R., Boon, L. M., Mulliken, J. B., Vikkula, M. <strong>KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation.</strong> Hum. Molec. Genet. 9: 1351-1355, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814716</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814716">Eerola et al. (2000)</a> reported 2 of 4 individuals in a family with inherited cerebral capillary malformations who also manifested hyperkeratotic cutaneous capillary-venous malformations (see <a href="/entry/116860">116860</a>). The latter are distinguished by extension into dermis and hypodermis, and have hyperkeratosis of overlying skin. All 4 affected individuals were heterozygous for a 1-bp deletion of a G in exon 1 of the KRIT1 gene that resulted in a frameshift after amino acid 26 and a premature stop at codon 37. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814716" 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">rs1563302930 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1563302930;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=rs1563302930" 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=rs1563302930" 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=RCV000006077 OR RCV003444193" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006077, RCV003444193" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006077...</a>
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<p><a href="#8" class="mim-tip-reference" title="Eerola, I., Plate, K. H., Spiegel, R., Boon, L. M., Mulliken, J. B., Vikkula, M. <strong>KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation.</strong> Hum. Molec. Genet. 9: 1351-1355, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814716</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814716">Eerola et al. (2000)</a> reported a 3-generation family with cerebral cavernous malformations (CCM1; <a href="/entry/116860">116860</a>) in which affected members were heterozygous for a T-to-C transition in the splice donor site of intron 2 of the KRIT1 gene. RT-PCR analysis of lymphoblastoid cells from affected individuals yielded aberrant cDNA products from the mutant allele that lacked either exon 2 or both exons 2 and 3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814716" 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"><span class="text-primary">●</span> rs1180476377 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1180476377;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1180476377?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1180476377" 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=rs1180476377" 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=RCV000552882 OR RCV000721835 OR RCV001807642" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000552882, RCV000721835, RCV001807642" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000552882...</a>
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<p><a href="#16" class="mim-tip-reference" title="Lucas, M., Costa, A. F., Montori, M., Solano, F., Zayas, M. D., Izquierdo, G. <strong>Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.</strong> Ann. Neurol. 49: 529-532, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310633</a>]" pmid="11310633">Lucas et al. (2001)</a> investigated the possibility that de novo mutations in CCM1 cause cavernous angioma (<a href="/entry/116860">116860</a>). They described a patient with 2 cerebral malformations who carried a heterozygous 2-bp deletion (741delTC) in exon 6 of the CCM1 gene. The deletion initiated a frameshift that produced a TAA stop triplet 23 amino acids downstream, replacing a CAT triplet of histidine in exon 7 (H271X). MRI of the parents were normal, and neither parent carried the 741delTC mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310633" 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">rs137853139 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853139;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=rs137853139" 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=rs137853139" 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=RCV000006079 OR RCV001822994" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006079, RCV001822994" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006079...</a>
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<p><a href="#30" class="mim-tip-reference" title="Verlaan, D. J., Siegel, A. M., Rouleau, G. A. <strong>Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.</strong> Am. J. Hum. Genet. 70: 1564-1567, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11941540[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/10.1086/340604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941540">Verlaan et al. (2002)</a> pointed out that all KRIT1 mutations causing cerebral cavernous malformations (CCM1; <a href="/entry/116860">116860</a>) identified to that time, except for 2, asp137 to gly (D137G) and gln201 to glu (Q201E; <a href="#0009">604214.0009</a>), led to a truncated and presumably inactive protein. They reinvestigated these 2 cases, originally reported by <a href="#7" class="mim-tip-reference" title="Davenport, W. J., Siegel, A. M., Dichgans, J., Drigo, P., Mammi, I., Pereda, P., Wood, N. W., Rouleau, G. A. <strong>CCM1 gene mutations in families segregating cerebral cavernous malformations.</strong> Neurology 56: 540-543, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11222804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11222804</a>] [<a href="https://doi.org/10.1212/wnl.56.4.540" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11222804">Davenport et al. (2001)</a> and <a href="#28" class="mim-tip-reference" title="Verlaan, D. J., Davenport, W. J., Stefan, H., Sure, U., Siegel, A. M., Rouleau, G. A. <strong>Cerebral cavernous malformations: mutations in Krit1.</strong> Neurology 58: 853-857, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11914398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11914398</a>] [<a href="https://doi.org/10.1212/wnl.58.6.853" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11914398">Verlaan et al. (2002)</a>, and found that, in fact, both point mutations activated cryptic splice donor sites, causing aberrant splicing and leading to a frameshift and protein truncation. Thus, no simple missense mutation had been detected in KRIT1. In the family in which the change was interpreted as a D137G missense mutation, affected members were heterozygous for an A-to-G substitution in exon 7 at nucleotide position 410 of the coding sequence. The migration pattern of the cDNA showed that affected individuals had 2 different-sized alleles, whereas the unaffected individual was homozygous for the larger allele. Sequencing of the different cDNA alleles showed that alternative splicing had occurred in the mutated allele. The A-to-G shift created an alternative splice site, which, when used, resulted in premature splicing of exon 7 and in splicing of exon 8 at the correct position but in an incorrect reading frame. This resulted in a frameshift, leading to a truncated protein of 138 amino acids that had 2 novel amino acids and contained no structural domains of KRIT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11222804+11941540+11914398" 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 href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006080 OR RCV000522732 OR RCV003522917" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006080, RCV000522732, RCV003522917" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006080...</a>
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<p>The second case of apparent missense mutation causing cerebral cavernous malformations (CCM1; <a href="/entry/116860">116860</a>), shown by <a href="#30" class="mim-tip-reference" title="Verlaan, D. J., Siegel, A. M., Rouleau, G. A. <strong>Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.</strong> Am. J. Hum. Genet. 70: 1564-1567, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11941540[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/10.1086/340604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11941540">Verlaan et al. (2002)</a>, in fact, to be an instance of splicing error, was found to have, in members of the family, heterozygosity for a C-to-G substitution in exon 8 at nucleotide position 601 of the coding sequence. As in the other case, affected individuals had 2 different-sized alleles, and sequencing of the different cDNA alleles showed alternative splicing resulting in premature splicing of exon 8 and splicing of exon 9 at the correct position but in an incorrect reading frame. This resulted in a frameshift, which was predicted to lead to a truncated protein of 201 amino acids that had a novel amino acid and contained only the NPXY motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11941540" 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="Battistini, S., Rocchi, R., Cerase, A., Citterio, A., Tassi, L., Lando, G., Patrosso, M. C., Galli, R., Brunori, P., Sgro, D. L., Pitillo, G., Russo, G. L., Marocchi, A., Penco, S. <strong>Clinical, magnetic resonance imaging, and genetic study of 5 families with cerebral cavernous malformation.</strong> Arch. Neurol. 64: 843-848, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17562932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17562932</a>] [<a href="https://doi.org/10.1001/archneur.64.6.843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17562932">Battistini et al. (2007)</a> identified a heterozygous Q201E mutation in 3 members of an Italian family with CCM1. The proband developed seizures at age 20 years, whereas her affected mother, aged 79 years, and her daughter were symptom-free. However, brain MRI showed lesions in both the unaffected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17562932" 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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KRIT1, 1-BP INS, 1374C
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006081" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006081" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006081</a>
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<p>In a family in which 5 individuals had both retinal and cerebral cavernous angiomas (see <a href="/entry/116860">116860</a>), <a href="#13" class="mim-tip-reference" title="Laberge-Le Couteulx, S., Brezin, A. P., Fontaine, B., Tournier-Lasserve, E., Labauge, P. <strong>A novel KRIT/CCM1 truncating mutation in a patient with cerebral and retinal cavernous angiomas.</strong> Arch. Ophthal. 120: 217-218, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11831930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11831930</a>]" pmid="11831930">Laberge-Le Couteulx et al. (2002)</a> identified a heterozygous insertion of cytosine after nucleotide 1374 in exon 10 of the KRIT1 gene, causing a frameshift that led to a premature stop codon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11831930" 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">rs267607204 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607204;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=rs267607204" 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=rs267607204" 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=RCV000006082 OR RCV000239438" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006082, RCV000239438" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006082...</a>
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<p>In 7 affected individuals from 4 Sardinian families with cerebral cavernous malformations (CCM1; <a href="/entry/116860">116860</a>), <a href="#5" class="mim-tip-reference" title="Cau, M., Loi, M., Melis, M., Congiu, R., Loi, A., Meloni, C., Serrenti, M., Addis, M., Melis, M. A. <strong>C329X in KRIT1 is a founder mutation among CCM patients in Sardinia.</strong> Europ. J. Med. Genet. 52: 344-348, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19454328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19454328</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.05.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19454328">Cau et al. (2009)</a> identified a heterozygous 987C-A transversion in exon 10 of the KRIT1 gene, resulting in a cys329-to-ter (C329X) substitution. Two asymptomatic individuals also carried the mutation. Haplotype analysis indicated a founder effect. Clinical features of those affected included seizures, headache, diplopia, and hearing loss. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19454328" 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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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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Battistini, S., Rocchi, R., Cerase, A., Citterio, A., Tassi, L., Lando, G., Patrosso, M. C., Galli, R., Brunori, P., Sgro, D. L., Pitillo, G., Russo, G. L., Marocchi, A., Penco, S.
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<strong>Clinical, magnetic resonance imaging, and genetic study of 5 families with cerebral cavernous malformation.</strong>
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Arch. Neurol. 64: 843-848, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17562932/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17562932</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17562932" 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/10.1001/archneur.64.6.843" target="_blank">Full Text</a>]
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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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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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J. Exp. Med. 208: 1835-1847, 2011.
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[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://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'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1084/jem.20110571" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Cau2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cau, M., Loi, M., Melis, M., Congiu, R., Loi, A., Meloni, C., Serrenti, M., Addis, M., Melis, M. A.
|
|
<strong>C329X in KRIT1 is a founder mutation among CCM patients in Sardinia.</strong>
|
|
Europ. J. Med. Genet. 52: 344-348, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19454328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19454328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19454328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.ejmg.2009.05.002" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Cave-Riant2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cave-Riant, F., Denier, C., Labauge, P., Cecillon, M., Maciazek, J., Joutel, A., Laberge-le Couteulx, S., Tournier-Lasserve, E., Societe Francaise de Neurochirurgie.
|
|
<strong>Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations.</strong>
|
|
Europ. J. Hum. Genet. 10: 733-740, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12404106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12404106</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12404106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/sj.ejhg.5200870" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Davenport2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Davenport, W. J., Siegel, A. M., Dichgans, J., Drigo, P., Mammi, I., Pereda, P., Wood, N. W., Rouleau, G. A.
|
|
<strong>CCM1 gene mutations in families segregating cerebral cavernous malformations.</strong>
|
|
Neurology 56: 540-543, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11222804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11222804</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11222804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1212/wnl.56.4.540" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Eerola2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Eerola, I., Plate, K. H., Spiegel, R., Boon, L. M., Mulliken, J. B., Vikkula, M.
|
|
<strong>KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation.</strong>
|
|
Hum. Molec. Genet. 9: 1351-1355, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814716/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814716</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814716" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/9.9.1351" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Felbor2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
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://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'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s10048-006-0076-7" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Gunel2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gunel, M., Laurans, M. S. H., Shin, D., DiLuna, M. L., Voorhees, J., Choate, K., Nelson-Williams, C., Lifton, R. P.
|
|
<strong>KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 10677-10682, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12140362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12140362</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12140362[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=12140362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1073/pnas.122354499" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Hogan2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
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://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'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddn142" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Kattapong1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kattapong, V. J., Hart, B. L., Davis, L. E.
|
|
<strong>Familial cerebral cavernous angiomas: clinical and radiologic studies.</strong>
|
|
Neurology 45: 492-497, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7898703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7898703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7898703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1212/wnl.45.3.492" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Laberge-Le Couteulx2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Laberge-Le Couteulx, S., Brezin, A. P., Fontaine, B., Tournier-Lasserve, E., Labauge, P.
|
|
<strong>A novel KRIT/CCM1 truncating mutation in a patient with cerebral and retinal cavernous angiomas.</strong>
|
|
Arch. Ophthal. 120: 217-218, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11831930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11831930</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11831930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Laberge-Le Couteulx1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E.
|
|
<strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong>
|
|
Nature Genet. 23: 189-193, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10508515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10508515</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10508515" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/13815" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Liquori2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
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://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'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s10048-007-0109-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Lucas2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Lucas, M., Costa, A. F., Montori, M., Solano, F., Zayas, M. D., Izquierdo, G.
|
|
<strong>Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.</strong>
|
|
Ann. Neurol. 49: 529-532, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11310633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11310633</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11310633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Maddaluno2013" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Maddaluno, L., Rudini, N., Cuttano, R., Bravi, L., Giampietro, C., Corada, M., Ferrarini, L., Orsenigo, F., Papa, E., Boulday, G., Tournier-Lasserve, E., Chapon, F., Richichi, C., Retta, S. F., Lampugnani, M. G., Dejana, E.
|
|
<strong>EndMT contributes to the onset and progression of cerebral cavernous malformations.</strong>
|
|
Nature 498: 492-496, 2013.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23748444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23748444</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23748444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature12207" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Marchuk2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Marchuk, D. A., Srinivasan, S., Squire, T. L., Zawistowski, J. S.
|
|
<strong>Vascular morphogenesis: tales of two syndromes.</strong>
|
|
Hum. Molec. Genet. 12: R97-R112, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12668602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12668602</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12668602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddg103" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Marini2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Marini, V., Ferrera, L., Pigatto, F., Origone, P., Garre, C., Dorcaratto, A., Viale, G., Alberti, F., Mareni, C.
|
|
<strong>Search for loss of heterozygosity and mutation analysis of KRIT1 gene in CCM patients. (Letter)</strong>
|
|
Am. J. Med. Genet. 130A: 98-101, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15368504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15368504</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15368504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.30122" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Mleynek2014" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mleynek, T. M., Chan, A. C., Redd, M., Gibson, C. C., Davis, C. T., Shi, D. S., Chen, T., Carter, K. L., Ling, J., Blanco, R., Gerhardt, H., Whitehead, K., Li, D. Y.
|
|
<strong>Lack of CCM1 induces hypersprouting and impairs response to flow.</strong>
|
|
Hum. Molec. Genet. 23: 6223-6234, 2014.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990152</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990152[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=24990152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddu342" target="_blank">Full Text</a>]
|
|
|
|
|
|
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|
|
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|
|
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|
|
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://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'})">related citations</a>]
|
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|
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[<a href="https://doi.org/10.1093/hmg/ddn420" target="_blank">Full Text</a>]
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|
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|
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|
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|
|
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|
|
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|
|
Retta, S. F., Avolio, M., Francalanci, F., Procida, S., Balzac, F., Degani, S., Tarone, G., Silengo, L.
|
|
<strong>Identification of Krit1B: a novel alternative splicing isoform of cerebral cavernous malformation gene-1.</strong>
|
|
Gene 325: 63-78, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14697511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14697511</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14697511" 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/10.1016/j.gene.2003.09.046" target="_blank">Full Text</a>]
|
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|
|
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|
|
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|
|
|
|
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|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Rigamonti1988" class="mim-anchor"></a>
|
|
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|
|
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|
|
Rigamonti, D., Hadley, M. N., Drayer, B. P., Johnson, P. C., Hoenig-Rigamonti, K., Knight, J. T., Spetzler, R. F.
|
|
<strong>Cerebral cavernous malformations: incidence and familial occurrence.</strong>
|
|
New Eng. J. Med. 319: 343-347, 1988.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3393196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3393196</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3393196" 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/10.1056/NEJM198808113190605" target="_blank">Full Text</a>]
|
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|
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|
|
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|
|
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|
|
|
|
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|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Sahoo2001" class="mim-anchor"></a>
|
|
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|
|
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|
|
Sahoo, T., Goenaga-Diaz, E., Serebriiskii, I. G., Thomas, J. W., Kotova, E., Cuellar, J. G., Peloquin, J. M., Golemis, E., Beitinjaneh, F., Green, E. D., Johnson, E. W., Marchuk, D. A.
|
|
<strong>Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene.</strong>
|
|
Genomics 71: 123-126, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161805</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161805" 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/10.1006/geno.2000.6426" target="_blank">Full Text</a>]
|
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|
|
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|
|
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|
|
|
|
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|
|
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|
|
<a id="Sahoo1999" class="mim-anchor"></a>
|
|
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|
|
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|
|
Sahoo, T., Johnson, E. W., Thomas, J. W., Kuehl, P. M., Jones, T. L., Dokken, C. G., Touchman, J. W., Gallione, C. J., Lee-Lin, S.-Q., Kosofsky, B., Kurth, J. H., Louis, D. N., Mettler, G., Morrison, L., Gil-Nagel, A., Rich, S. S., Zabramski, J. M., Boguski, M. S., Green, E. D., Marchuk, D. A.
|
|
<strong>Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).</strong>
|
|
Hum. Molec. Genet. 8: 2325-2333, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10545614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10545614</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10545614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
|
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[<a href="https://doi.org/10.1093/hmg/8.12.2325" target="_blank">Full Text</a>]
|
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</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Serebriiskii1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Serebriiskii, I., Estojak, J., Sonoda, G., Testa, J. R., Golemis, E. A.
|
|
<strong>Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22.</strong>
|
|
Oncogene 15: 1043-1049, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9285558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9285558</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9285558" 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/sj.onc.1201268" target="_blank">Full Text</a>]
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|
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|
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|
</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
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|
|
<a id="Tang2017" class="mim-anchor"></a>
|
|
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|
|
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|
|
Tang, A. T., Choi, J. P., Kotzin, J. J., Yang, Y., Hong, C. C., Hobson, N., Girard, R., Zeineddine, H. A., Lightle, R., Moore, T., Cao, Y., Shenkar, R., and 18 others.
|
|
<strong>Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.</strong>
|
|
Nature 545: 305-310, 2017.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28489816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28489816</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28489816[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=28489816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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[<a href="https://doi.org/10.1038/nature22075" target="_blank">Full Text</a>]
|
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|
|
|
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|
|
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|
|
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|
|
|
|
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|
|
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|
|
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|
|
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|
|
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|
|
Verlaan, D. J., Davenport, W. J., Stefan, H., Sure, U., Siegel, A. M., Rouleau, G. A.
|
|
<strong>Cerebral cavernous malformations: mutations in Krit1.</strong>
|
|
Neurology 58: 853-857, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11914398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11914398</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11914398" 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/10.1212/wnl.58.6.853" target="_blank">Full Text</a>]
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|
|
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|
|
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|
|
|
|
<li>
|
|
<a id="29" class="mim-anchor"></a>
|
|
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|
|
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|
|
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|
|
Verlaan, D. J., Laurent, S. B., Sure, U., Bertalanffy, H., Andermann, E., Andermann, F., Rouleau, G. A., Siegel, A. M.
|
|
<strong>CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.</strong>
|
|
Neurology 62: 1213-1215, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15079030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15079030</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15079030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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[<a href="https://doi.org/10.1212/01.wnl.0000118299.55857.bb" target="_blank">Full Text</a>]
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|
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|
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|
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|
|
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|
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|
|
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|
|
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|
|
Verlaan, D. J., Siegel, A. M., Rouleau, G. A.
|
|
<strong>Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.</strong>
|
|
Am. J. Hum. Genet. 70: 1564-1567, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11941540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11941540</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11941540[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=11941540" 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/10.1086/340604" target="_blank">Full Text</a>]
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|
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|
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|
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|
|
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|
|
Zawistowski, J. S., Serebriiskii, I. G., Lee, M. F., Golemis, E. A., Marchuk, D. A.
|
|
<strong>KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis.</strong>
|
|
Hum. Molec. Genet. 11: 389-396, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11854171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11854171</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11854171" 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/11.4.389" target="_blank">Full Text</a>]
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|
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|
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|
|
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://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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Zhang, J., Clatterbuck, R. E., Rigamonti, D., Chang, D. D., Dietz, H. C.
|
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<strong>Interaction between krit1 and icap1-alpha infers perturbation of integrin beta-1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation.</strong>
|
|
Hum. Molec. Genet. 10: 2953-2960, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11741838/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11741838</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11741838" 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/10.25.2953" target="_blank">Full Text</a>]
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Zhang, J., Clatterbuck, R. E., Rigamonti, D., Dietz, H. C.
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<strong>Cloning of the murine Krit1 cDNA reveals novel mammalian 5-prime coding exons.</strong>
|
|
Genomics 70: 392-395, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161791</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161791" 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/10.1006/geno.2000.6410" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Ada Hamosh - updated : 03/21/2019
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 1/16/2015<br>Ada Hamosh - updated : 9/3/2013<br>Paul J. Converse - updated : 1/11/2012<br>Patricia A. Hartz - updated : 12/20/2010<br>Cassandra L. Kniffin - updated : 9/21/2010<br>Matthew B. Gross - updated : 11/2/2009<br>Patricia A. Hartz - updated : 10/12/2009<br>George E. Tiller - updated : 8/12/2009<br>George E. Tiller - updated : 1/23/2009<br>Cassandra L. Kniffin - updated : 5/23/2008<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Patricia A. Hartz - updated : 4/7/2006<br>George E. Tiller - updated : 3/3/2005<br>Victor A. McKusick - updated : 12/1/2004<br>Marla J. F. O'Neill - updated : 3/24/2004<br>Cassandra L. Kniffin - reorganized : 6/6/2003<br>Cassandra L. Kniffin - updated : 6/3/2003<br>Jane Kelly - updated : 11/6/2002<br>Victor A. McKusick - updated : 9/27/2002<br>George E. Tiller - updated : 8/23/2002<br>George E. Tiller - updated : 8/16/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Victor A. McKusick - updated : 2/22/2002<br>George E. Tiller - updated : 8/7/2000<br>Victor A. McKusick - updated : 11/19/1999
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 10/6/1999
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 06/08/2023
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carol : 06/01/2022<br>alopez : 03/21/2019<br>carol : 10/18/2016<br>carol : 02/17/2015<br>carol : 2/16/2015<br>mgross : 1/20/2015<br>mcolton : 1/16/2015<br>alopez : 9/3/2013<br>mgross : 1/20/2012<br>terry : 1/11/2012<br>mgross : 1/5/2011<br>mgross : 1/5/2011<br>terry : 12/20/2010<br>wwang : 9/21/2010<br>ckniffin : 9/21/2010<br>mgross : 11/2/2009<br>mgross : 11/2/2009<br>terry : 10/12/2009<br>wwang : 8/26/2009<br>terry : 8/12/2009<br>wwang : 1/23/2009<br>wwang : 5/29/2008<br>ckniffin : 5/23/2008<br>wwang : 4/15/2008<br>ckniffin : 3/18/2008<br>wwang : 5/11/2007<br>ckniffin : 5/4/2007<br>wwang : 9/7/2006<br>mgross : 6/13/2006<br>wwang : 4/12/2006<br>terry : 4/7/2006<br>alopez : 3/3/2005<br>alopez : 3/3/2005<br>tkritzer : 12/2/2004<br>terry : 12/1/2004<br>tkritzer : 3/25/2004<br>terry : 3/24/2004<br>carol : 6/6/2003<br>ckniffin : 6/3/2003<br>carol : 11/6/2002<br>cwells : 10/2/2002<br>carol : 9/27/2002<br>mgross : 9/16/2002<br>mgross : 8/23/2002<br>mgross : 8/23/2002<br>cwells : 8/20/2002<br>cwells : 8/16/2002<br>alopez : 6/14/2002<br>terry : 6/12/2002<br>cwells : 3/11/2002<br>cwells : 3/6/2002<br>terry : 2/22/2002<br>alopez : 8/7/2000<br>alopez : 2/22/2000<br>alopez : 12/2/1999<br>terry : 11/24/1999<br>terry : 11/19/1999<br>alopez : 11/10/1999<br>alopez : 10/25/1999<br>joanna : 10/25/1999<br>alopez : 10/23/1999<br>alopez : 10/7/1999
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<span class="mim-font">
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<strong>*</strong> 604214
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<h3>
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KRIT1 ANKYRIN REPEAT-CONTAINING PROTEIN 1; KRIT1
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<em>Alternative titles; symbols</em>
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<span class="mim-font">
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KREV INTERACTION TRAPPED 1<br />
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CCM1 GENE; CCM1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KRIT1</em></strong>
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<strong>
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<em>
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Cytogenetic location: 7q21.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:92,198,969-92,246,100 </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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<table class="table table-bordered table-condensed small mim-table-padding">
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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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<span class="mim-font">
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7q21.2
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Cavernous malformations of CNS and retina
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<span class="mim-font">
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116860
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Cerebral cavernous malformations-1
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<span class="mim-font">
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116860
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations
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<span class="mim-font">
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116860
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<span class="mim-font">
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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, CCM2 (607929), 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 2-hybrid screen of a HeLa cell cDNA library designed to identify KREV1 (RAP1A; 179520) activity, Serebriiskii et al. (1997) isolated a novel cDNA, called KRIT1 for 'Krev interaction trapped-1.' The deduced 529-amino acid KRIT1 protein contains an N-terminal ankyrin repeat domain and a novel C-terminal domain required for association with KREV1. KRIT1 mRNA was expressed endogenously at low levels, with tissue-specific variation. </p><p>Laberge-Le Couteulx et al. (1999) detected a KRIT1 transcript of 5 to 6 kb in all tissues, although it was less abundant in brain, kidney, and lung. A 3.5-kb band was also observed in heart, skeletal muscle, and pancreas. </p><p>Sahoo et al. (2001) extended the N terminus of the KRIT1 protein by 207 amino acids. The deduced full-length 736-amino acid protein has a calculated molecular mass of about 81 kD. </p><p>Zhang et al. (2000) cloned mouse Krit1. The deduced 736-amino acid protein contains an ankyrin repeat, FERM motifs, and 2 potential nuclear localization signals. </p><p>Retta et al. (2004) identified Krit1b, a splice variant of mouse Krit1 that lacks exon 15. Compared with the full-length protein, which the authors called Krit1a, the deduced 697-amino acid Krit1b protein has a 39-amino acid deletion in a C-terminal region required for association with Rap1a. RT-PCR detected strongest Krit1b expression in thymus and brain and weaker expression in several other mouse tissues. KRIT1B was expressed at a low level in some human cell lines, but it was not detected in any adult or fetal human tissues examined. </p>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Serebriiskii et al. (1997) found that KRIT1 interacted strongly with KREV1 but only weakly with Ras (see 190020), suggesting that KRIT1 might specifically regulate KREV1 activities. </p><p>By 2-hybrid analysis and coimmunoprecipitation, Zhang et al. (2001) found that full-length KRIT1 failed to interact with KREV1/RAP1A but showed strong interaction with integrin cytoplasmic domain-associated protein-1 (ICAP1; 607153). ICAP1 binds to an NPXY (asn-pro-X-tyr, where X is any amino acid) sequence motif in the cytoplasmic domain of beta-1 integrin (ITGB1; 135630) and participates in beta-1-mediated cell adhesion and migration. The novel N terminus of KRIT1 also contains an NPXY motif that was found to be required for ICAP1 interaction. Like ITGB1, KRIT1 interacted with the 200-amino acid isoform of ICAP1 (ICAP1-alpha), but not a 150-amino acid form that results from alternative splicing (ICAP1-beta). In a competition assay, induced expression of KRIT1 diminished the interaction between ICAP1A and ITGB1. The authors hypothesized that ITGB1 and KRIT1 may compete for the same site on ICAP1A, perhaps constituting a regulatory mechanism. Loss-of-function KRIT1 mutations, as observed in cerebral cavernous malformation-1 (CCM1; 116860), may shift the balance with predicted consequences for endothelial cell performance during ITGB1-dependent angiogenesis. </p><p>Zawistowski et al. (2002) confirmed the interaction of KRIT1 and ICAP1 using a yeast 2-hybrid screen. Mutagenesis of the N-terminal KRIT1 NPXY sequence completely abrogated the KRIT1-ICAP1 interaction. The authors hypothesized that KRIT1 may be involved in bidirectional signaling between integrin molecules and the cytoskeleton, and that KRIT1 may affect cell adhesion processes via integrin signaling in CCM1 pathogenesis. </p><p>To study the biologic functions of KRIT1, Gunel et al. (2002) investigated KRIT1 expression in endothelial cells with the use of specific anti-KRIT1 antibodies. By both microscopy and coimmunoprecipitation, they showed that KRIT1 colocalizes with microtubules. In interphase cells, KRIT1 was found along the length of microtubules. During metaphase, KRIT1 was located on spindle pole bodies and the mitotic spindle. During late phases of mitosis, KRIT1 localized in a pattern indicative of association with microtubule plus ends. In anaphase, the plus ends of the interpolar microtubules showed strong KRIT1 staining and, in late telophase, KRIT1 stained the midbody remnant most strongly; this is the site of cytokinesis where plus ends of microtubules from dividing cells overlap. These results established that KRIT1 is a microtubule-associated protein; its location at plus ends in mitosis suggested a possible role in microtubule targeting. These findings, coupled with evidence of interaction of KRIT1 with KREV1 and ICAP1A, suggested that KRIT1 may help determine endothelial cell shape and function in response to cell-cell and cell-matrix interactions by guiding cytoskeletal structure. Gunel et al. (2002) proposed that the loss of this targeting function leads to abnormal endothelial tube formation, thereby explaining the mechanism of formation of cerebral cavernous malformation lesions. </p><p>Hereditary hemorrhagic telangiectasia (see 187300) and cerebral cavernous malformations (see 116860) are disorders involving disruption of normal vascular morphogenesis. The autosomal dominant mode of inheritance in both of these disorders suggested to Marchuk et al. (2003) that their underlying genes might regulate critical aspects of vascular morphogenesis. The authors summarized the roles of these genes, KRIT1, endoglin (131195), and ALK1 (601284), in the genetic control of angiogenesis. </p><p>Zawistowski et al. (2005) used coimmunoprecipitation, fluorescence resonance energy transfer, and subcellular localization strategies to show that KRIT1 interacted with the CCM2 gene (607929) product, malcavernin. Analogous to the established interactions of KRIT1/ITGB1 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 (600289) signaling module by demonstrating that KRIT1 associated with CCM2 and MEKK3 (602539) 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>Borikova et al. (2010) showed that knockdown of Ccm1, Ccm2, or Ccm3 in mouse embryonic endothelial cells induced RhoA (165390) 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 (604002) 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>Maddaluno et al. (2013) demonstrated that endothelial-specific disruption of the KRIT1 gene in mice induces endothelial-to-mesenchymal transition, which contributes to the development of vascular malformations. Endothelial-to-mesenchymal transition in KRIT1-ablated endothelial cells is mediated by the upregulation of endogenous bone morphogenetic protein-6 (BMP6; 112266) that, in turn, activates the transforming growth factor-beta (TGF-beta; 190180) and BMP signaling pathway. Inhibitors of the TGF-beta and BMP pathway prevented endothelial-to-mesenchymal transition both in vitro and in vivo and reduced the number and size of vascular lesions in KRIT1-deficient mice. Thus, increased TGF-beta and BMP signaling, and the consequent endothelial-to-mesenchymal transition of KRIT1-null endothelial cells, are crucial events in the onset and progression of cerebral cavernous malformation disease. </p><p>Mleynek et al. (2014) used small interfering RNA to suppress CCM1 expression in human umbilical vein endothelial cells (HUVECs) and exposed the cells to laminar shear stress to simulate arterial shear. Unlike wildtype HUVECs, cells depleted of CCM1 failed to align with the direction of flow in the medium. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Laberge-Le Couteulx et al. (1999) identified 12 exons in the KRIT1 gene. Sahoo et al. (2001) determined that the KRIT1 gene has 19 exons, the first 3 of which are noncoding. </p>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>Serebriiskii et al. (1997) mapped the KRIT1 gene to 7q21-q22 by FISH. The authors noted that this region is frequently deleted or amplified in multiple forms of cancer. </p><p>Zhang et al. (2000) mapped the mouse Krit1 gene to a region of chromosome 5 that shares homology of synteny with human chromosome 7q21-q22. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>In 12 of 20 pedigrees with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) identified mutations in the CCM1 gene (see, e.g., 604214.0001) that segregated with the affected phenotype. Laberge-Le Couteulx et al. (1999) suggested that the mutations in the CCM1 gene might result in a dominant-negative effect or a loss of function; they favored the second hypothesis. Sporadic forms of cavernous angiomas manifest as unique lesions and familial forms as multiple lesions, which evokes a Knudson double-hit mechanism and would be consistent with the need for a complete loss of CCM1 function for the appearance of cavernous angiomas. All the mutations they reported predicted truncated CCM1 proteins completely or partially devoid of the putative RAP1A-interacting region. The data suggested the involvement of the RAP1A signal transduction pathway in vasculogenesis or angiogenesis. </p><p>Sahoo et al. (1999) observed that 7 different KRIT1 mutations had been identified in 23 distinct CCM1 families. </p><p>In 29 families and 5 sporadic cases with CCM, Davenport et al. (2001) identified 10 novel mutations and 1 previously described mutation in the KRIT1 gene (see, e.g., 604214.0008). The high frequency of loss-of-function mutations suggested loss of a tumor suppressor mechanism. In a follow-up study, Verlaan et al. (2002) reported 7 additional novel mutations and 1 previously described mutation in the KRIT1 gene in families with CCM. In combination with the previous study, Verlaan et al. (2002) found that approximately 47% of CCM families harbor KRIT1 mutations. The authors noted that the majority of mutations in the KRIT1 gene lead to a substantial alteration of the gene product, supporting a loss-of-function mechanism consistent with a tumor suppressor gene. </p><p>Sahoo et al. (2001) identified several novel frameshift mutations in the KRIT1 gene in patients with CCM1. </p><p>Cave-Riant et al. (2002) screened the KRIT1 gene in 121 unrelated CCM probands having at least 1 affected relative and/or showing multiple lesions on cerebral MRI. Fifty-two individuals (43%) were shown to have a KRIT1 mutation, and 42 distinct mutations were identified. Three-quarters of the mutations were located in the C-terminal half of the gene, primarily within exons 13, 15, and 17. All of them were predicted to result in premature stop codons. Cave-Riant et al. (2002) concluded that the underlying mechanism of CCM may be KRIT1 mRNA decay due to the presence of premature stop codons and KRIT1 haploinsufficiency. </p><p>Almost all KRIT1 mutations causing CCM lead to a premature stop codon, and severe impairment of KRIT1 protein functions is likely to be involved in the pathogenesis of the disorder. In 20 patients with CCM, Marini et al. (2004) failed to find loss of heterozygosity (LOH) in cavernous angiomas, validating the hypothesis that KRIT1 haploinsufficiency is the underlying mechanism of CCM. </p><p>Verlaan et al. (2004) identified a pathogenic mutation in the KRIT1 gene in 4 (29%) of 14 unrelated patients with sporadic CCM and multiple malformations. None of 21 unrelated sporadic patients with a single malformation had a KRIT1 mutation. Verlaan et al. (2004) concluded that genetic analysis is warranted in sporadic cases of CCM with multiple malformations. In 2 additional patients of the 14 sporadic CCM patients reported by Verlaan et al. (2004), Felbor et al. (2007) used multiplex ligation-dependent probe amplification to detect a large duplication and a large deletion, respectively, within the KRIT1 gene. Thus, 6 (42%) of the 14 sporadic patients had KRIT1 mutations. </p><p>Battistini et al. (2007) identified 5 different heterozygous KRIT1 mutations (see, e.g., 604214.0009) in affected individuals from 5 unrelated families with CCM1. The families included 33 mutation carriers, 57.6% of whom had no symptoms. Brain MRI revealed lesions in 82.3% of symptom-free mutation carriers. </p><p>Among 24 Italian families with CCM, Liquori et al. (2008) identified 5 with deletions in the CCM1 gene, including 1 complete deletion of the 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 (609118) 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>Through 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 1 of the CCM genes. </p><p>Cau et al. (2009) identified 2 different mutations in the KRIT1 gene (see, e.g., C329X; 604214.0011) in 5 (71%) of 7 Sardinian families with CCM. Haplotype analysis of patients from 4 of the affected families indicated a founder effect for the C329X mutation. </p>
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</span>
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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>By examining the initial stages of vascular lesion development in conditional Ccm1-knockout mice and in ccm1-morphant zebrafish, Mleynek et al. (2014) found that loss of Ccm1 resulted in vasculature that exhibited stereotypic hypersprouting prior to dilation. The authors observed that this sprouting behavior was similar to that seen in troponin T2 (TNNT2; 191045)-morphant zebrafish, which have a nonbeating heart and completely lack blood flow. Mleynek et al. (2014) hypothesized that CCM1 is required for endothelial cells to sense blood flow. </p><p>To study the requirement for endothelial TLR4 in spontaneous CCM formation, Tang et al. (2017) bred mice with floxed Tlr4 and Krit1 alleles using mice from the CCM-susceptible Krit1(ECKO) colony (endothelial-specific deletion of Krit1). Tang et al. (2017) observed that loss of a single endothelial Tlr4 allele resulted in an approximately 75% reduction in CCM lesion burden at postnatal day 10, whereas loss of both alleles resulted in virtually complete prevention of CCM lesion formation. Although less complete, global loss of Cd14, a soluble TLR4 coreceptor that binds lipopolysaccharide and facilitates TLR4 signaling, also prevented CCM formation in susceptible Krit1(ECKO) mice. Seven of 8 Krit1(ECKO) neonates who had been delivered and raised in a germ-free environment did not develop any CCM lesions. In contrast, all Krit1(ECKO) neonates who had been delivered in a germ-free environment but raised by conventional mothers exhibited robust CCM formation at postnatal day 10. Tang et al. (2017) found that CCM susceptibility associated with gram-negative bacteria, and that either Tlr4 blockade or altering the microbiome prevented CCM formation in susceptible mice. They concluded that while KRIT1 mutation predisposes to the formation of cerebral cavernous malformations, endothelial TLR4 and the microbiome drive their development. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>11 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 1</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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KRIT1, 1283C-T
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<br />
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SNP: rs2131309013,
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ClinVar: RCV000006072, RCV002512817
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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 3 probands with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) found nonsense stop codons in the CCM1 gene, one of which was a C-to-T transition in nucleotide 1283. </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 1</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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KRIT1, 1-BP DEL, 1342A
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<br />
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SNP: rs2131308132,
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ClinVar: RCV000006073
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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 5 probands with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) found deletions causing frameshifts resulting in premature stop codons in CCM1 gene. One of these was a 1-bp deletion involving nucleotide 1342. </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 1</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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KRIT1, 1-BP INS, 1271C
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<br />
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SNP: rs2131309179,
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ClinVar: RCV000006074
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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 probands with cerebral cavernous malformations-1 (CCM1; 116860), Laberge-Le Couteulx et al. (1999) found, in the CCM1 gene, insertions leading to frameshift and premature termination, one of which was insertion of a cytosine after nucleotide 1271 in one pedigree. </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 1</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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KRIT1, GLN248TER
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<br />
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SNP: rs267607203,
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gnomAD: rs267607203,
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ClinVar: RCV000006075, RCV000239441, RCV000256079, RCV000506458, RCV004547460
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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 16 of 21 Mexican American families with cerebral cavernous malformations (CCM1; 116860) analyzed, Sahoo et al. (1999) found that the KRIT1 gene harbored a 1-bp transition (742C-T), changing a gln to a premature termination codon (Q248X). Distinct mutations in KRIT1 were identified in other Mexican American families, as well as in non-Hispanic Caucasian families. The apparently high frequency of cerebral cavernous malformations in Mexican Americans had been noted by Rigamonti et al. (1988) and Kattapong et al. (1995). The finding of a common disease haplotype in affected kindreds from this population had suggested a founder effect. </p><p>Due to numbering differences, this mutation is also known as gln455 to ter (Q455X, rs267607203).</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 HYPERKERATOTIC CUTANEOUS CAPILLARY-VENOUS MALFORMATIONS ASSOCIATED WITH CEREBRAL CAPILLARY MALFORMATIONS</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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KRIT1, 1-BP DEL, 103G
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<br />
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SNP: rs2131660732,
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ClinVar: RCV001665312, RCV001807487
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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>Eerola et al. (2000) reported 2 of 4 individuals in a family with inherited cerebral capillary malformations who also manifested hyperkeratotic cutaneous capillary-venous malformations (see 116860). The latter are distinguished by extension into dermis and hypodermis, and have hyperkeratosis of overlying skin. All 4 affected individuals were heterozygous for a 1-bp deletion of a G in exon 1 of the KRIT1 gene that resulted in a frameshift after amino acid 26 and a premature stop at codon 37. </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 1</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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KRIT1, IVS2DS, T-C, +2
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<br />
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SNP: rs1563302930,
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ClinVar: RCV000006077, RCV003444193
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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>Eerola et al. (2000) reported a 3-generation family with cerebral cavernous malformations (CCM1; 116860) in which affected members were heterozygous for a T-to-C transition in the splice donor site of intron 2 of the KRIT1 gene. RT-PCR analysis of lymphoblastoid cells from affected individuals yielded aberrant cDNA products from the mutant allele that lacked either exon 2 or both exons 2 and 3. </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 1</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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KRIT1, 2-BP DEL, 741TC
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<br />
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SNP: rs1180476377,
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gnomAD: rs1180476377,
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ClinVar: RCV000552882, RCV000721835, RCV001807642
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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>Lucas et al. (2001) investigated the possibility that de novo mutations in CCM1 cause cavernous angioma (116860). They described a patient with 2 cerebral malformations who carried a heterozygous 2-bp deletion (741delTC) in exon 6 of the CCM1 gene. The deletion initiated a frameshift that produced a TAA stop triplet 23 amino acids downstream, replacing a CAT triplet of histidine in exon 7 (H271X). MRI of the parents were normal, and neither parent carried the 741delTC mutation. </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>.0008 CEREBRAL CAVERNOUS MALFORMATIONS 1</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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KRIT1, ASP137GLY
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<br />
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SNP: rs137853139,
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ClinVar: RCV000006079, RCV001822994
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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>Verlaan et al. (2002) pointed out that all KRIT1 mutations causing cerebral cavernous malformations (CCM1; 116860) identified to that time, except for 2, asp137 to gly (D137G) and gln201 to glu (Q201E; 604214.0009), led to a truncated and presumably inactive protein. They reinvestigated these 2 cases, originally reported by Davenport et al. (2001) and Verlaan et al. (2002), and found that, in fact, both point mutations activated cryptic splice donor sites, causing aberrant splicing and leading to a frameshift and protein truncation. Thus, no simple missense mutation had been detected in KRIT1. In the family in which the change was interpreted as a D137G missense mutation, affected members were heterozygous for an A-to-G substitution in exon 7 at nucleotide position 410 of the coding sequence. The migration pattern of the cDNA showed that affected individuals had 2 different-sized alleles, whereas the unaffected individual was homozygous for the larger allele. Sequencing of the different cDNA alleles showed that alternative splicing had occurred in the mutated allele. The A-to-G shift created an alternative splice site, which, when used, resulted in premature splicing of exon 7 and in splicing of exon 8 at the correct position but in an incorrect reading frame. This resulted in a frameshift, leading to a truncated protein of 138 amino acids that had 2 novel amino acids and contained no structural domains of KRIT1. </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 1</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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KRIT1, GLN201GLU
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<br />
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SNP: rs137853140,
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ClinVar: RCV000006080, RCV000522732, RCV003522917
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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>The second case of apparent missense mutation causing cerebral cavernous malformations (CCM1; 116860), shown by Verlaan et al. (2002), in fact, to be an instance of splicing error, was found to have, in members of the family, heterozygosity for a C-to-G substitution in exon 8 at nucleotide position 601 of the coding sequence. As in the other case, affected individuals had 2 different-sized alleles, and sequencing of the different cDNA alleles showed alternative splicing resulting in premature splicing of exon 8 and splicing of exon 9 at the correct position but in an incorrect reading frame. This resulted in a frameshift, which was predicted to lead to a truncated protein of 201 amino acids that had a novel amino acid and contained only the NPXY motif. </p><p>Battistini et al. (2007) identified a heterozygous Q201E mutation in 3 members of an Italian family with CCM1. The proband developed seizures at age 20 years, whereas her affected mother, aged 79 years, and her daughter were symptom-free. However, brain MRI showed lesions in both the unaffected individuals. </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 CAVERNOUS MALFORMATIONS OF CNS AND RETINA</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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KRIT1, 1-BP INS, 1374C
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<br />
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ClinVar: RCV000006081
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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 in which 5 individuals had both retinal and cerebral cavernous angiomas (see 116860), Laberge-Le Couteulx et al. (2002) identified a heterozygous insertion of cytosine after nucleotide 1374 in exon 10 of the KRIT1 gene, causing a frameshift that led to a premature stop codon. </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 1</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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KRIT1, CYS329TER
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<br />
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SNP: rs267607204,
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ClinVar: RCV000006082, RCV000239438
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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 affected individuals from 4 Sardinian families with cerebral cavernous malformations (CCM1; 116860), Cau et al. (2009) identified a heterozygous 987C-A transversion in exon 10 of the KRIT1 gene, resulting in a cys329-to-ter (C329X) substitution. Two asymptomatic individuals also carried the mutation. Haplotype analysis indicated a founder effect. Clinical features of those affected included seizures, headache, diplopia, and hearing loss. </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>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>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
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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: 19088123]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn430]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Battistini, S., Rocchi, R., Cerase, A., Citterio, A., Tassi, L., Lando, G., Patrosso, M. C., Galli, R., Brunori, P., Sgro, D. L., Pitillo, G., Russo, G. L., Marocchi, A., Penco, S.
|
|
<strong>Clinical, magnetic resonance imaging, and genetic study of 5 families with cerebral cavernous malformation.</strong>
|
|
Arch. Neurol. 64: 843-848, 2007.
|
|
|
|
|
|
[PubMed: 17562932]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1001/archneur.64.6.843]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 20181950]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.C109.097220]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 21859843]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1084/jem.20110571]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cau, M., Loi, M., Melis, M., Congiu, R., Loi, A., Meloni, C., Serrenti, M., Addis, M., Melis, M. A.
|
|
<strong>C329X in KRIT1 is a founder mutation among CCM patients in Sardinia.</strong>
|
|
Europ. J. Med. Genet. 52: 344-348, 2009.
|
|
|
|
|
|
[PubMed: 19454328]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.ejmg.2009.05.002]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cave-Riant, F., Denier, C., Labauge, P., Cecillon, M., Maciazek, J., Joutel, A., Laberge-le Couteulx, S., Tournier-Lasserve, E., Societe Francaise de Neurochirurgie.
|
|
<strong>Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations.</strong>
|
|
Europ. J. Hum. Genet. 10: 733-740, 2002.
|
|
|
|
|
|
[PubMed: 12404106]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5200870]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Davenport, W. J., Siegel, A. M., Dichgans, J., Drigo, P., Mammi, I., Pereda, P., Wood, N. W., Rouleau, G. A.
|
|
<strong>CCM1 gene mutations in families segregating cerebral cavernous malformations.</strong>
|
|
Neurology 56: 540-543, 2001.
|
|
|
|
|
|
[PubMed: 11222804]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.56.4.540]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Eerola, I., Plate, K. H., Spiegel, R., Boon, L. M., Mulliken, J. B., Vikkula, M.
|
|
<strong>KRIT1 is mutated in hyperkeratotic cutaneous capillary-venous malformation associated with cerebral capillary malformation.</strong>
|
|
Hum. Molec. Genet. 9: 1351-1355, 2000.
|
|
|
|
|
|
[PubMed: 10814716]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/9.9.1351]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 17211633]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10048-006-0076-7]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gunel, M., Laurans, M. S. H., Shin, D., DiLuna, M. L., Voorhees, J., Choate, K., Nelson-Williams, C., Lifton, R. P.
|
|
<strong>KRIT1, a gene mutated in cerebral cavernous malformation, encodes a microtubule-associated protein.</strong>
|
|
Proc. Nat. Acad. Sci. 99: 10677-10682, 2002.
|
|
|
|
|
|
[PubMed: 12140362]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.122354499]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 18469344]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn142]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kattapong, V. J., Hart, B. L., Davis, L. E.
|
|
<strong>Familial cerebral cavernous angiomas: clinical and radiologic studies.</strong>
|
|
Neurology 45: 492-497, 1995.
|
|
|
|
|
|
[PubMed: 7898703]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.45.3.492]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Laberge-Le Couteulx, S., Brezin, A. P., Fontaine, B., Tournier-Lasserve, E., Labauge, P.
|
|
<strong>A novel KRIT/CCM1 truncating mutation in a patient with cerebral and retinal cavernous angiomas.</strong>
|
|
Arch. Ophthal. 120: 217-218, 2002.
|
|
|
|
|
|
[PubMed: 11831930]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Laberge-Le Couteulx, S., Jung, H. H., Labauge, P., Houtteville, J.-P., Lescoat, C., Cecillon, M., Marechal, E., Joutel, A., Bach, J.-F., Tournier-Lasserve, E.
|
|
<strong>Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.</strong>
|
|
Nature Genet. 23: 189-193, 1999.
|
|
|
|
|
|
[PubMed: 10508515]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/13815]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 18060436]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10048-007-0109-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lucas, M., Costa, A. F., Montori, M., Solano, F., Zayas, M. D., Izquierdo, G.
|
|
<strong>Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations.</strong>
|
|
Ann. Neurol. 49: 529-532, 2001.
|
|
|
|
|
|
[PubMed: 11310633]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Maddaluno, L., Rudini, N., Cuttano, R., Bravi, L., Giampietro, C., Corada, M., Ferrarini, L., Orsenigo, F., Papa, E., Boulday, G., Tournier-Lasserve, E., Chapon, F., Richichi, C., Retta, S. F., Lampugnani, M. G., Dejana, E.
|
|
<strong>EndMT contributes to the onset and progression of cerebral cavernous malformations.</strong>
|
|
Nature 498: 492-496, 2013.
|
|
|
|
|
|
[PubMed: 23748444]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature12207]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Marchuk, D. A., Srinivasan, S., Squire, T. L., Zawistowski, J. S.
|
|
<strong>Vascular morphogenesis: tales of two syndromes.</strong>
|
|
Hum. Molec. Genet. 12: R97-R112, 2003.
|
|
|
|
|
|
[PubMed: 12668602]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg103]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Marini, V., Ferrera, L., Pigatto, F., Origone, P., Garre, C., Dorcaratto, A., Viale, G., Alberti, F., Mareni, C.
|
|
<strong>Search for loss of heterozygosity and mutation analysis of KRIT1 gene in CCM patients. (Letter)</strong>
|
|
Am. J. Med. Genet. 130A: 98-101, 2004.
|
|
|
|
|
|
[PubMed: 15368504]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.30122]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mleynek, T. M., Chan, A. C., Redd, M., Gibson, C. C., Davis, C. T., Shi, D. S., Chen, T., Carter, K. L., Ling, J., Blanco, R., Gerhardt, H., Whitehead, K., Li, D. Y.
|
|
<strong>Lack of CCM1 induces hypersprouting and impairs response to flow.</strong>
|
|
Hum. Molec. Genet. 23: 6223-6234, 2014.
|
|
|
|
|
|
[PubMed: 24990152]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddu342]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 19088124]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn420]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Retta, S. F., Avolio, M., Francalanci, F., Procida, S., Balzac, F., Degani, S., Tarone, G., Silengo, L.
|
|
<strong>Identification of Krit1B: a novel alternative splicing isoform of cerebral cavernous malformation gene-1.</strong>
|
|
Gene 325: 63-78, 2004.
|
|
|
|
|
|
[PubMed: 14697511]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.gene.2003.09.046]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rigamonti, D., Hadley, M. N., Drayer, B. P., Johnson, P. C., Hoenig-Rigamonti, K., Knight, J. T., Spetzler, R. F.
|
|
<strong>Cerebral cavernous malformations: incidence and familial occurrence.</strong>
|
|
New Eng. J. Med. 319: 343-347, 1988.
|
|
|
|
|
|
[PubMed: 3393196]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM198808113190605]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sahoo, T., Goenaga-Diaz, E., Serebriiskii, I. G., Thomas, J. W., Kotova, E., Cuellar, J. G., Peloquin, J. M., Golemis, E., Beitinjaneh, F., Green, E. D., Johnson, E. W., Marchuk, D. A.
|
|
<strong>Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene.</strong>
|
|
Genomics 71: 123-126, 2001.
|
|
|
|
|
|
[PubMed: 11161805]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1006/geno.2000.6426]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sahoo, T., Johnson, E. W., Thomas, J. W., Kuehl, P. M., Jones, T. L., Dokken, C. G., Touchman, J. W., Gallione, C. J., Lee-Lin, S.-Q., Kosofsky, B., Kurth, J. H., Louis, D. N., Mettler, G., Morrison, L., Gil-Nagel, A., Rich, S. S., Zabramski, J. M., Boguski, M. S., Green, E. D., Marchuk, D. A.
|
|
<strong>Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).</strong>
|
|
Hum. Molec. Genet. 8: 2325-2333, 1999.
|
|
|
|
|
|
[PubMed: 10545614]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.12.2325]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Serebriiskii, I., Estojak, J., Sonoda, G., Testa, J. R., Golemis, E. A.
|
|
<strong>Association of Krev-1/rap1a with Krit1, a novel ankyrin repeat-containing protein encoded by a gene mapping to 7q21-22.</strong>
|
|
Oncogene 15: 1043-1049, 1997.
|
|
|
|
|
|
[PubMed: 9285558]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.onc.1201268]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tang, A. T., Choi, J. P., Kotzin, J. J., Yang, Y., Hong, C. C., Hobson, N., Girard, R., Zeineddine, H. A., Lightle, R., Moore, T., Cao, Y., Shenkar, R., and 18 others.
|
|
<strong>Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.</strong>
|
|
Nature 545: 305-310, 2017.
|
|
|
|
|
|
[PubMed: 28489816]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature22075]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Verlaan, D. J., Davenport, W. J., Stefan, H., Sure, U., Siegel, A. M., Rouleau, G. A.
|
|
<strong>Cerebral cavernous malformations: mutations in Krit1.</strong>
|
|
Neurology 58: 853-857, 2002.
|
|
|
|
|
|
[PubMed: 11914398]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/wnl.58.6.853]
|
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|
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</p>
|
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|
|
|
|
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Verlaan, D. J., Laurent, S. B., Sure, U., Bertalanffy, H., Andermann, E., Andermann, F., Rouleau, G. A., Siegel, A. M.
|
|
<strong>CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.</strong>
|
|
Neurology 62: 1213-1215, 2004.
|
|
|
|
|
|
[PubMed: 15079030]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000118299.55857.bb]
|
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Verlaan, D. J., Siegel, A. M., Rouleau, G. A.
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<strong>Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation.</strong>
|
|
Am. J. Hum. Genet. 70: 1564-1567, 2002.
|
|
|
|
|
|
[PubMed: 11941540]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1086/340604]
|
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|
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Zawistowski, J. S., Serebriiskii, I. G., Lee, M. F., Golemis, E. A., Marchuk, D. A.
|
|
<strong>KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis.</strong>
|
|
Hum. Molec. Genet. 11: 389-396, 2002.
|
|
|
|
|
|
[PubMed: 11854171]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/11.4.389]
|
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</p>
|
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</li>
|
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|
|
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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: 16037064]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi256]
|
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</p>
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Zhang, J., Clatterbuck, R. E., Rigamonti, D., Chang, D. D., Dietz, H. C.
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<strong>Interaction between krit1 and icap1-alpha infers perturbation of integrin beta-1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation.</strong>
|
|
Hum. Molec. Genet. 10: 2953-2960, 2001.
|
|
|
|
|
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[PubMed: 11741838]
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[Full Text: https://doi.org/10.1093/hmg/10.25.2953]
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Zhang, J., Clatterbuck, R. E., Rigamonti, D., Dietz, H. C.
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<strong>Cloning of the murine Krit1 cDNA reveals novel mammalian 5-prime coding exons.</strong>
|
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Genomics 70: 392-395, 2000.
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|
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[PubMed: 11161791]
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[Full Text: https://doi.org/10.1006/geno.2000.6410]
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Ada Hamosh - updated : 03/21/2019<br>Patricia A. Hartz - updated : 1/16/2015<br>Ada Hamosh - updated : 9/3/2013<br>Paul J. Converse - updated : 1/11/2012<br>Patricia A. Hartz - updated : 12/20/2010<br>Cassandra L. Kniffin - updated : 9/21/2010<br>Matthew B. Gross - updated : 11/2/2009<br>Patricia A. Hartz - updated : 10/12/2009<br>George E. Tiller - updated : 8/12/2009<br>George E. Tiller - updated : 1/23/2009<br>Cassandra L. Kniffin - updated : 5/23/2008<br>Cassandra L. Kniffin - updated : 3/18/2008<br>Cassandra L. Kniffin - updated : 5/4/2007<br>Patricia A. Hartz - updated : 4/7/2006<br>George E. Tiller - updated : 3/3/2005<br>Victor A. McKusick - updated : 12/1/2004<br>Marla J. F. O'Neill - updated : 3/24/2004<br>Cassandra L. Kniffin - reorganized : 6/6/2003<br>Cassandra L. Kniffin - updated : 6/3/2003<br>Jane Kelly - updated : 11/6/2002<br>Victor A. McKusick - updated : 9/27/2002<br>George E. Tiller - updated : 8/23/2002<br>George E. Tiller - updated : 8/16/2002<br>Victor A. McKusick - updated : 6/12/2002<br>Victor A. McKusick - updated : 2/22/2002<br>George E. Tiller - updated : 8/7/2000<br>Victor A. McKusick - updated : 11/19/1999
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