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Entry
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- *604774 - ANGIOPOIETIN-LIKE 3; ANGPTL3
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*604774</span>
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<br />
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<strong>Table of Contents</strong>
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<li role="presentation">
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604774">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000132855;t=ENST00000371129" 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=27329" 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=604774" 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 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=ENSG00000132855;t=ENST00000371129" 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_014495" 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_014495" 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=604774" 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=10381&isoform_id=10381_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/ANGPTL3" 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/4929790,7656888,25008126,34849467,37181666,45505203,117938824,119626988,158259875,189054867,239740416" 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/Q9Y5C1" 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=27329" 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=ENSG00000132855;t=ENST00000371129" 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=ANGPTL3" 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=ANGPTL3" 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+27329" 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/ANGPTL3" 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:27329" 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/27329" 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=chr1&hgg_gene=ENST00000371129.4&hgg_start=62597520&hgg_end=62606313&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:491" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:491" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604774[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=604774[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000132855" 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=ANGPTL3" 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=ANGPTL3" 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=ANGPTL3" 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=ANGPTL3&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/PA24796" 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:491" 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://flybase.org/reports/FBgn0003326.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1353627" 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/ANGPTL3#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:1353627" 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/27329/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=27329" 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=WBGene00017013;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-010817-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:27329" 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=ANGPTL3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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604774
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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ANGIOPOIETIN-LIKE 3; ANGPTL3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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ANGIOPOIETIN 5; ANGPT5
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ANGPTL3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ANGPTL3</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/1/675?start=-3&limit=10&highlight=675">1p31.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:62597520-62606313&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'})">1:62,597,520-62,606,313</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/1/675?start=-3&limit=10&highlight=675">
|
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1p31.3
|
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</a>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Hypobetalipoproteinemia, familial, 2
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/605019"> 605019 </a>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604774" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604774" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
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</span>
|
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</span>
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</h4>
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<div>
|
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<a id="cloning" class="mim-anchor"></a>
|
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<p>The angiopoietins are a family of growth factors that are specific for vascular endothelium. By searching an EST database for signal sequences and amphipathic helices, <a href="#3" class="mim-tip-reference" title="Conklin, D., Gilbertson, D., Taft, D. W., Maurer, M. F., Whitmore, T. E., Smith, D. L., Walker, K. M., Chen, L. H., Wattler, S., Nehls, M., Lewis, K. B. <strong>Identification of a mammalian angiopoietin-related protein expressed specifically in liver.</strong> Genomics 62: 477-482, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644446</a>] [<a href="https://doi.org/10.1006/geno.1999.6041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644446">Conklin et al. (1999)</a> identified the ANGPTL3 gene. They isolated a full-length ANGPTL3 cDNA from a human fetal liver/spleen cDNA library. The deduced 460-amino acid ANGPTL3 protein has the characteristic structure of angiopoietins: a signal peptide, an extended helical domain predicted to form dimeric or trimeric coiled-coils, a short linker peptide, and a globular fibrinogen homology domain (FHD). ANGPTL3 contains the 4 conserved cysteine residues implicated in the intramolecular disulfide bonds within the FHD, but it does not contain 2 other cysteines that are found within the FHDs of ANGPT1 (<a href="/entry/601667">601667</a>), ANGPT2 (<a href="/entry/601922">601922</a>), and ANGPT4 (<a href="/entry/603705">603705</a>). ANGPTL3 also does not contain the characteristic calcium-binding motif found in other angiopoietins. The authors found that ANGPTL3 is glycosylated at 1 of 2 potential N-glycosylation sites. Human ANGPTL3 shares 76% amino acid sequence identity with mouse Angptl3, which <a href="#3" class="mim-tip-reference" title="Conklin, D., Gilbertson, D., Taft, D. W., Maurer, M. F., Whitmore, T. E., Smith, D. L., Walker, K. M., Chen, L. H., Wattler, S., Nehls, M., Lewis, K. B. <strong>Identification of a mammalian angiopoietin-related protein expressed specifically in liver.</strong> Genomics 62: 477-482, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644446</a>] [<a href="https://doi.org/10.1006/geno.1999.6041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644446">Conklin et al. (1999)</a> also cloned. Northern blot analysis of human tissues showed 4 ANGPTL3 transcripts of approximately 4.5, 3.0, 2.8, and 1.7 kb in liver; the 1.7-kb transcript was also weakly expressed in kidney. No ANGPTL3 expression was detected in the other tissues examined, namely heart, brain, placenta, lung, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, stomach, thyroid, spinal cord, lymph node, trachea, adrenal gland, and bone marrow. Mouse Angptl3 expression was observed in 15- and 17-day embryos, but not in 7- or 11-day embryos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. <strong>Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans.</strong> J. Clin. Invest. 119: 70-79, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075393[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/10.1172/JCI37118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19075393">Romeo et al. (2009)</a> examined levels of ANGPTL3 mRNA in 48 human tissues and found that expression was largely restricted to the liver. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19075393" 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="#12" class="mim-tip-reference" title="Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., Hobbs, H. H. <strong>Atypical angiopoietin-like protein that regulates ANGPTL3.</strong> Proc. Nat. Acad. Sci. 109: 19751-19756, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150577[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.1217552109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150577">Quagliarini et al. (2012)</a> reported that the ANGPTL3 gene contains 7 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23150577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By radiation hybrid mapping and the use of surrounding genes, <a href="#3" class="mim-tip-reference" title="Conklin, D., Gilbertson, D., Taft, D. W., Maurer, M. F., Whitmore, T. E., Smith, D. L., Walker, K. M., Chen, L. H., Wattler, S., Nehls, M., Lewis, K. B. <strong>Identification of a mammalian angiopoietin-related protein expressed specifically in liver.</strong> Genomics 62: 477-482, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644446</a>] [<a href="https://doi.org/10.1006/geno.1999.6041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10644446">Conklin et al. (1999)</a> mapped the ANGPTL3 gene to chromosome 1p31. They mapped the mouse Angptl3 gene to a region in chromosome 4 that shows homology of synteny with human 1p31. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644446" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., Hobbs, H. H. <strong>Atypical angiopoietin-like protein that regulates ANGPTL3.</strong> Proc. Nat. Acad. Sci. 109: 19751-19756, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150577[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.1217552109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150577">Quagliarini et al. (2012)</a> noted that the ANGPTL3 gene resides within an intron of the DOCK7 gene (<a href="/entry/615730">615730</a>) on the opposite strand of chromosome 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23150577" 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="#2" class="mim-tip-reference" title="Camenisch, G, Pisabarro, M. T., Sherman, D., Kowalski, J., Nagel, M., Hass, P, Xie, M.-H., Gurney, A., Bodary, S., Liang, X. H., Clark, K., Beresini, M, Ferrara, N., Gerber, H.-P. <strong>ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha-v-beta-3 and induces blood vessel formation in vivo.</strong> J. Biol. Chem. 277: 17281-17290, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11877390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11877390</a>] [<a href="https://doi.org/10.1074/jbc.M109768200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11877390">Camenisch et al. (2002)</a> determined that ANGPTL3 binds to human vascular endothelial cells; however, it does not bind to the Tie2 receptor (TEK; <a href="/entry/600221">600221</a>), which is utilized by other members of the angiopoietin family to regulate blood vessel formation. Crystallographic studies and sequence analysis revealed that the fibrinogen-like domain of ANGPTL3 shares significant similarity with the C terminus of the gamma chain of human fibrinogen (<a href="/entry/134850">134850</a>), suggesting that ANGPTL3 may bind integrins. Using a panel of integrin subunits expressed in 293 cells, they determined that cells expressing alpha-5/beta-3 integrins (<a href="/entry/135620">135620</a>, <a href="/entry/173470">173470</a>) adhered to ANGPTL3-coated dishes. Binding induced integrin alpha-5/beta-3-dependent haptotactic endothelial cell adhesion and migration, and stimulated signal transduction pathways characteristic for integrin activation. ANGPTL3 also induced angiogenesis in the rat corneal assay. The C-terminal fibrinogen-like domain alone was sufficient to induce endothelial cell adhesion and in vivo angiogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11877390" 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 microarray analysis, <a href="#15" class="mim-tip-reference" title="Zhang, C. C., Kaba, M., Ge, G., Xie, K., Tong, W., Hug, C., Lodish, H. F. <strong>Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells.</strong> Nature Med. 12: 240-245, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16429146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16429146</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16429146[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/nm1342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16429146">Zhang et al. (2006)</a> showed that mouse hematopoietic stem cell (HSC)-supportive fetal liver Cd3 (see <a href="/entry/186830">186830</a>)-positive cells expressed Angptl2 (<a href="/entry/605001">605001</a>) and Angptl3. Long-term HSC expansion occurred when HSCs were cultured in the presence of Angptl2 and Angptl3 together with saturating levels of other growth factors. Several other angiopoietin-like proteins, though not all, also supported HSC growth. <a href="#15" class="mim-tip-reference" title="Zhang, C. C., Kaba, M., Ge, G., Xie, K., Tong, W., Hug, C., Lodish, H. F. <strong>Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells.</strong> Nature Med. 12: 240-245, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16429146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16429146</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16429146[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/nm1342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16429146">Zhang et al. (2006)</a> concluded that angiopoietin-like proteins can be potent stimulators of ex vivo expansion of HSCs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16429146" 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="#16" class="mim-tip-reference" title="Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Canto, A. P., Chen, S.-H., Wang, H.-Y., Ward, E. S., Zhang, C. C. <strong>Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.</strong> Nature 485: 656-660, 2012. Note: Erratum: Nature 488: 684 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22660330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22660330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22660330[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/nature11095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22660330">Zheng et al. (2012)</a> showed that the human immune inhibitory receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; <a href="/entry/604815">604815</a>) and its mouse ortholog paired immunoglobulin-like receptor (PIRB) are receptors for several angiopoietin-like proteins, including ANGPTL3. LILRB2 and PIRB are expressed on human and mouse hematopoietic stem cells, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of hematopoietic stem cells. In mouse transplantation acute myeloid leukemia models, a deficiency in intracellular signaling of PIRB resulted in increased differentiation of leukemia cells, revealing that PIRB supports leukemia development. <a href="#16" class="mim-tip-reference" title="Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Canto, A. P., Chen, S.-H., Wang, H.-Y., Ward, E. S., Zhang, C. C. <strong>Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.</strong> Nature 485: 656-660, 2012. Note: Erratum: Nature 488: 684 only, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22660330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22660330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22660330[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/nature11095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22660330">Zheng et al. (2012)</a> concluded that their study indicated an unexpected functional significance of classical immune inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22660330" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using immunoprecipitation analysis, <a href="#12" class="mim-tip-reference" title="Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., Hobbs, H. H. <strong>Atypical angiopoietin-like protein that regulates ANGPTL3.</strong> Proc. Nat. Acad. Sci. 109: 19751-19756, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150577[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.1217552109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150577">Quagliarini et al. (2012)</a> found that human ANGPTL8 (C19ORF80; <a href="/entry/616223">616223</a>) interacted with full-length ANGPTL3 and the isolated N-terminal fragment of ANGPTL3. Expression of ANGPTL8 increased plasma levels of triglycerides and nonesterified fatty acids in wildtype mice, but not in Angptl3 -/- mice. Infection of mice with both ANGPTL8 and ANGPTL3 dramatically increased plasma triglyceride and fatty acid levels. In cultured HepG2 hepatocytes, ANGPTL8 promoted cleavage and secretion of the functional ANGPTL3 N-terminal fragment. Serum ALGPTL8 levels were low after a 12-hour fast in humans and increased significantly within 3 hours of feeding. <a href="#12" class="mim-tip-reference" title="Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., Hobbs, H. H. <strong>Atypical angiopoietin-like protein that regulates ANGPTL3.</strong> Proc. Nat. Acad. Sci. 109: 19751-19756, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150577[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.1217552109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23150577">Quagliarini et al. (2012)</a> concluded that ANGPTL8 regulates postprandial triacylglycerol and fatty acid metabolism by activating ANGPTL3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23150577" 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="#1" class="mim-tip-reference" title="Arca, M., Minicocci, I., Maranghi, M. <strong>The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism.</strong> Curr. Opin. Lipidol. 24: 313-320, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23839332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23839332</a>] [<a href="https://doi.org/10.1097/MOL.0b013e3283630cf0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23839332">Arca et al. (2013)</a> reviewed the role of liver-derived ANGPTL3 in metabolic processes and concluded that ANGPTL3 modulates the metabolism of triglyceride-rich lipoproteins mainly by inhibiting the activity of lipoprotein lipase (LPL; <a href="/entry/609708">609708</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23839332" 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="#8" class="mim-tip-reference" title="Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., Fennell, T., Banks, E., and 15 others. <strong>Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.</strong> New Eng. J. Med. 363: 2220-2227, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20942659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20942659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20942659[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/10.1056/NEJMoa1002926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20942659">Musunuru et al. (2010)</a> performed whole-genome exome sequencing in 2 affected sibs from a 4-generation family with hypobetalipoproteinemia (FHLB2; <a href="/entry/605019">605019</a>), previously reported by <a href="#11" class="mim-tip-reference" title="Pulai, J. I., Neuman, R. J., Groenewegen, A. W., Wu, J., Schonfeld, G. <strong>Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the ApoB gene in Caucasian families.</strong> Am. J. Med. Genet. 76: 79-86, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9508071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9508071</a>]" pmid="9508071">Pulai et al. (1998)</a> as family 'F' in which linkage to the APOB gene (<a href="/entry/107730">107730</a>) was excluded. Only the ANGPTL3 gene harbored novel variants in both alleles in both sibs, who were compound heterozygous for 2 nonsense mutations (<a href="#0001">604774.0001</a>)-(<a href="#0002">604774.0002</a>). Genomewide linkage analysis ruled out significant linkage elsewhere in the genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9508071+20942659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. <strong>Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans.</strong> J. Clin. Invest. 119: 70-79, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075393[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/10.1172/JCI37118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19075393">Romeo et al. (2009)</a> sequenced the ANGPTL3, ANGPTL5 (<a href="/entry/607666">607666</a>), and ANGPTL6 (<a href="/entry/609336">609336</a>) genes in a large multiethnic population and identified multiple rare nonsynonymous sequence variations (see, e.g., <a href="#0003">604774.0003</a> and <a href="#0005">604774.0005</a>) that were associated with low plasma triglyceride (TG) levels but not other metabolic phenotypes. Functional studies showed that all mutant alleles of ANGPTL3 that were associated with low plasma TG levels interfered either with the synthesis or secretion of the protein, or with the ability of the ANGPTL protein to inhibit LPL. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19075393" 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 4 affected members of 3 kindreds with hypobetalipoproteinemia, who were negative for mutation in 6 genes known to be associated with lipid disorders, <a href="#10" class="mim-tip-reference" title="Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S. <strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong> Circ. Cardiovasc. Genet. 5: 42-50, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.111.960674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22062970">Pisciotta et al. (2012)</a> identified homozygosity for a splice site mutation (<a href="#0003">604774.0003</a>) in 1 family and compound heterozygosity for a 1-bp and a 4-bp deletion in the other 2 families (<a href="#0004">604774.0004</a> and <a href="#0005">604774.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22062970" 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 4 unrelated Spanish patients with severe hypolipidemia who were negative for mutation in the APOB gene, <a href="#6" class="mim-tip-reference" title="Martin-Campos, J. M., Roig, R., Mayoral, C., Martinez, S., Marti, G., Arroyo, J. A., Julve, J., Blanco-Vaca, F. <strong>Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation.</strong> Clin. Chim. Acta 413: 552-555, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22155345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22155345</a>] [<a href="https://doi.org/10.1016/j.cca.2011.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22155345">Martin-Campos et al. (2012)</a> analyzed ANGPTL3 and identified homozygosity for a 5-bp deletion in 2 of the patients (<a href="#0006">604774.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22155345" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a cohort of 78 patients with low total, LDL, and HDL cholesterol and TG levels, who were negative for mutation in the APOB, PCSK9 (<a href="/entry/607786">607786</a>), and MTP (<a href="/entry/157147">157147</a>) genes, <a href="#9" class="mim-tip-reference" title="Noto, D., Cefalu, A. B., Valenti, V., Fayer, F., Pinotti, E., Ditta, M., Spina, R., Vigna, G., Yue, P., Kathiresan, S., Tarugi, P., Averna, M. R. <strong>Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia.</strong> Arterioscler. Thromb. Vasc. Biol. 32: 805-809, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22247256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22247256</a>] [<a href="https://doi.org/10.1161/ATVBAHA.111.238766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22247256">Noto et al. (2012)</a> sequenced the ANGPTL3 gene and identified homozygous or compound heterozygous mutations in 4 patients (see, e.g., <a href="#0005">604774.0005</a> and <a href="#0007">604774.0007</a>) as well as heterozygous mutations in 4 patients. Compared to ANGPTL3 mutation-negative individuals from the cohort, ANGPTL3 heterozygotes had lower TG levels but similar levels of total, LDL, and HDL cholesterol, suggesting that gene dosage affects only the TG plasma levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22247256" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a small town in Italy, <a href="#7" class="mim-tip-reference" title="Minicocci, I., Montali, A., Robciuc, M. R., Quagliarini, F., Censi, V., Labbadia, G., Gabiati, C., Pigna, G., Sepe, M. L., Pannozzo, F., Lutjohann, D., Fazio, S., Jauhiainen, M., Ehnholm, C., Arca, M. <strong>Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.</strong> J. Clin. Endocr. Metab. 97: E1266-E1275, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22659251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22659251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22659251[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/10.1210/jc.2012-1298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22659251">Minicocci et al. (2012)</a> identified homozygosity or heterozygosity for the ANGPTL3 S17X mutation (<a href="#0001">604774.0001</a>) in the probands of 9 hypocholesterolemic families and 20 affected family members, as well as 32 individuals from the community; in addition, heterozygosity for a 2-bp deletion and a 3-bp deletion in ANGPTL3 were identified in 2 hypocholesterolemic individuals, respectively. The prevalence of ANGPTL3 variants in the whole population sample was 9.4%; in hypocholesterolemic individuals, prevalence was 15.2%. Homozygotes for S17X had no circulating ANGPTL3 and a marked reduction of all plasma lipids, whereas heterozygotes had 42% reduction in ANGPTL3 compared with noncarriers, but a significant reduction of only total cholesterol and HDL cholesterol. No differences were observed in plasma noncholesterol sterols between carriers and noncarriers, and there was no association detected between familial combined hypolipidemia and the risk of hepatic or cardiovascular disease. <a href="#7" class="mim-tip-reference" title="Minicocci, I., Montali, A., Robciuc, M. R., Quagliarini, F., Censi, V., Labbadia, G., Gabiati, C., Pigna, G., Sepe, M. L., Pannozzo, F., Lutjohann, D., Fazio, S., Jauhiainen, M., Ehnholm, C., Arca, M. <strong>Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.</strong> J. Clin. Endocr. Metab. 97: E1266-E1275, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22659251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22659251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22659251[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/10.1210/jc.2012-1298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22659251">Minicocci et al. (2012)</a> concluded that hypobetalipoproteinemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22659251" 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="Dewey, F. E., Gusarova, V., Dunbar, R. L., O'Dushlaine, C., Schurmann, C., Gottesman, O., McCarthy, S., Van Hout, C. V., Bruse, S., Dansky, H. M., Leader, J. B., Murray, M. F., and 45 others. <strong>Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.</strong> New Eng. J. Med. 377: 211-221, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28538136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28538136</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28538136[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/10.1056/NEJMoa1612790" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28538136">Dewey et al. (2017)</a> sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. They identified 13 different loss-of-function variants in 43 (0.33%) patients with coronary artery disease and in 183 (0.45%) controls (adjusted OR, 0.59; 95% CI, 0.41 to 0.85; p = 0.004). They then performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from 4 population studies. In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. The results were confirmed in the follow-up studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28538136" 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>The KK mouse is moderately obese and has abnormally high levels of plasma insulin, glucose, and lipids. This is a multigenic syndrome that resembles type 2 diabetes in humans. <a href="#5" class="mim-tip-reference" title="Koishi, R., Ando, Y., Ono, M., Shimamura, M., Yasumo, H., Fujiwara, T., Horikoshi, H., Furukawa, H. <strong>Angptl3 regulates lipid metabolism in mice.</strong> Nature Genet. 30: 151-157, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11788823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11788823</a>] [<a href="https://doi.org/10.1038/ng814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11788823">Koishi et al. (2002)</a> observed 1 strain, KK/San, that showed abnormally low plasma lipid levels (hypolipidemia) inherited as a mendelian recessive. They mapped the hypolipidemia locus (hypl) to the middle of mouse chromosome 4 and by positional cloning identified the gene carrying the mutation responsible for the hypolipidemia. They found that the hypl locus encodes a unique angiopoietin-like lipoprotein modulator, which they named Allm1. It was found to be identical to angiopoietin-like protein-3, encoded by Angptl3, and had a highly conserved counterpart in humans. Overexpression of Angptl3 or intravenous injection of the purified protein in KK/San mice elicited an increase in circulating plasma lipid levels. This increase was also observed in normal C57BL/6J mice. Taken together, these data suggested that Angptl3 regulates lipid metabolism in animals. The authors suggested the possibility that genetic variation in ANGPTL3 contributes to atherosclerosis, coronary artery disease, and diabetes mellitus and stated that animal studies demonstrated that an Angptl3 mutation reduces atherosclerosis in mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11788823" 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 characterizing the KK/San mouse model, <a href="#14" class="mim-tip-reference" title="Shimizugawa, T., Ono, M, Shimamura, M, Yoshida, K., Ando, Y., Koishi, R., Ueda, K., Inaba, T, Minekura, H, Kohama, T., Furukawa, H. <strong>ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase.</strong> J. Biol. Chem. 277: 33742-33748, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12097324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12097324</a>] [<a href="https://doi.org/10.1074/jbc.M203215200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12097324">Shimizugawa et al. (2002)</a> determined that overexpression of Angptl3 in KK/San mice results in a marked increase of triglyceride-enriched very low density lipoprotein (VLDL). In vivo studies revealed that there is no significant difference between mutant and wildtype KK mice in the hepatic VLDL triglyceride secretion rate. However, turnover studies using radiolabeled VLDL revealed that the clearance of 3H-triglyceride-labeled VLDL was significantly enhanced in KK/San mice, whereas the clearance of 125I-labeled protein from VLDL was only slightly enhanced. In vitro analysis of recombinant protein revealed that Angptl3 directly inhibits lipoprotein lipase (LPL) activity. From these data, <a href="#14" class="mim-tip-reference" title="Shimizugawa, T., Ono, M, Shimamura, M, Yoshida, K., Ando, Y., Koishi, R., Ueda, K., Inaba, T, Minekura, H, Kohama, T., Furukawa, H. <strong>ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase.</strong> J. Biol. Chem. 277: 33742-33748, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12097324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12097324</a>] [<a href="https://doi.org/10.1074/jbc.M203215200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12097324">Shimizugawa et al. (2002)</a> concluded that Angptl3 regulates VLDL triglyceride levels through the inhibition of LPL activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12097324" 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">rs267606655 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606655;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=rs267606655" 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=rs267606655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 affected sibs from a 4-generation family with hypobetalipoproteinemia (FHLB2; <a href="/entry/605019">605019</a>), originally studied by <a href="#11" class="mim-tip-reference" title="Pulai, J. I., Neuman, R. J., Groenewegen, A. W., Wu, J., Schonfeld, G. <strong>Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the ApoB gene in Caucasian families.</strong> Am. J. Med. Genet. 76: 79-86, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9508071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9508071</a>]" pmid="9508071">Pulai et al. (1998)</a> (family 'F'), <a href="#8" class="mim-tip-reference" title="Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., Fennell, T., Banks, E., and 15 others. <strong>Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.</strong> New Eng. J. Med. 363: 2220-2227, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20942659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20942659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20942659[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/10.1056/NEJMoa1002926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20942659">Musunuru et al. (2010)</a> performed whole-genome exome sequencing and identified compound heterozygosity for a CC-to-GA double transversion at nucleotide 62,835,875 to 62,835,876 in exon 1 of the ANGPTL3 gene, resulting in a ser17-to-ter (S17X) substitution, and a G-T transversion at nucleotide 62,836,210 in exon 1 of the ANGPTL3 gene, resulting in a glu129-to-ter (E129X) substitution (<a href="#0002">604774.0002</a>). The 2 sibs had a clinical syndrome of combined hypolipidemia, consisting of extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Family members who were heterozygous for either mutation had plasma levels of LDL cholesterol and triglycerides that were intermediate between the levels in persons with neither mutation and those with both mutations, findings consistent with a codominant mode of inheritance for the LDL cholesterol and triglyceride phenotypes. In contrast, the level of HDL cholesterol appeared to segregate as a recessive trait: family members who carried both nonsense alleles had significantly lower plasma HDL cholesterol levels than members with 1 or no mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9508071+20942659" 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 the probands of 9 hypocholesterolemic families from a small town in Italy, <a href="#7" class="mim-tip-reference" title="Minicocci, I., Montali, A., Robciuc, M. R., Quagliarini, F., Censi, V., Labbadia, G., Gabiati, C., Pigna, G., Sepe, M. L., Pannozzo, F., Lutjohann, D., Fazio, S., Jauhiainen, M., Ehnholm, C., Arca, M. <strong>Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.</strong> J. Clin. Endocr. Metab. 97: E1266-E1275, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22659251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22659251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22659251[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/10.1210/jc.2012-1298" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22659251">Minicocci et al. (2012)</a> identified the S17X mutation in the ANGPTL3 gene, present in heterozygosity in 7 probands and in homozygosity in 2. Screening of family members revealed 20 additional individuals carrying the S17X mutation, 4 homozygotes and 16 heterozygotes; all but 3 heterozygous carriers showed a hypocholesterolemic phenotype. Only homozygous carriers showed comprehensive reduction of plasma lipoproteins; in heterozygous carriers, significant reduction was limited to total and HDL cholesterol levels. All of the S17X alleles shared the same haplotype, suggesting that the S17X mutation arose from a common ancestor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22659251" 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> rs200785483 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200785483;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/rs200785483?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=rs200785483" 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=rs200785483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the glu129-to-ter (E129X) mutation that was found in the ANGPTL3 gene in compound heterozygous state in 2 sibs with hypobetalipoproteinemia (FHLB2; <a href="/entry/605019">605019</a>) by <a href="#8" class="mim-tip-reference" title="Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., Fennell, T., Banks, E., and 15 others. <strong>Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.</strong> New Eng. J. Med. 363: 2220-2227, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20942659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20942659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20942659[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/10.1056/NEJMoa1002926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20942659">Musunuru et al. (2010)</a>, see <a href="#0001">604774.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20942659" 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 65-year-old Italian woman with very low plasma lipid levels (FHBL2; <a href="/entry/605019">605019</a>), <a href="#10" class="mim-tip-reference" title="Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S. <strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong> Circ. Cardiovasc. Genet. 5: 42-50, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.111.960674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22062970">Pisciotta et al. (2012)</a> identified homozygosity for a G-T transversion in intron 6 (c.1198+1G-T) of the ANGPTL3 gene, causing partial retention of intron 6 in mature mRNA and resulting in a frameshift and formation of a premature termination codon (Gly400ValfsTer5). The proband's clinically unaffected children were heterozygous carriers of the mutation; screening of 200 controls from the general Italian population identified 1 heterozygous carrier of the c.1198+1G-T mutation, a 36-year-old woman with low plasma ANGPTL3, moderately reduced LDL cholesterol, and normal HDL cholesterol. <a href="#10" class="mim-tip-reference" title="Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S. <strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong> Circ. Cardiovasc. Genet. 5: 42-50, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.111.960674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22062970">Pisciotta et al. (2012)</a> noted that this splice site mutation was previously found to be associated with low plasma TG levels in individuals from the large multiethnic population of the Dallas Heart Study by <a href="#13" class="mim-tip-reference" title="Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. <strong>Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans.</strong> J. Clin. Invest. 119: 70-79, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075393[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/10.1172/JCI37118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19075393">Romeo et al. (2009)</a>, who reported its occurrence at chr1:62,842,495. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22062970+19075393" 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">rs398122986 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122986;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=rs398122986" 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=rs398122986" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 59-year-old Italian man with low total, HDL, and LDL cholesterol and triglyceride levels (FHBL2; <a href="/entry/605019">605019</a>), <a href="#10" class="mim-tip-reference" title="Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S. <strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong> Circ. Cardiovasc. Genet. 5: 42-50, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.111.960674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22062970">Pisciotta et al. (2012)</a> identified compound heterozygosity for 2 mutations in the ANGPTL3 gene: a 1-bp deletion (c.55delA) in exon 1, resulting in a frameshift and a premature termination codon (Ile19LeufsTer22), and a 4-bp deletion in exon 1 (c.439_442delAACT; <a href="#0005">604774.0005</a>), also resulting in a frameshift and a premature termination codon (N147X). The proband's healthy brother, who had an identical lipid profile, was also compound heterozygous for the deletions; their mother and the brother's daughter were both heterozygous for the 1-bp deletion. A woman from an unrelated Italian kindred, who presented at 85 years of age with an acute respiratory tract infection and was found to have marked hypolipidemia, was also compound heterozygous for the 1-bp and 4-bp deletions; she died suddenly at 91 years of age. <a href="#10" class="mim-tip-reference" title="Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S. <strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong> Circ. Cardiovasc. Genet. 5: 42-50, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.111.960674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22062970">Pisciotta et al. (2012)</a> noted that the 4-bp deletion was previously found to be associated with low plasma TG levels in individuals from the large multiethnic population of the Dallas Heart Study by <a href="#13" class="mim-tip-reference" title="Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C. <strong>Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans.</strong> J. Clin. Invest. 119: 70-79, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075393[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/10.1172/JCI37118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19075393">Romeo et al. (2009)</a>, who designated it as being an in/del at chr1:62,836,264. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22062970+19075393" 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">rs398122987 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122987;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=rs398122987" 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=rs398122987" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the 4-bp deletion in the ANGPTL3 gene (c.439_442delAACT) that was found in compound heterozygous state in a patient with familial hypobetalipoproteinemia (FHBL2; <a href="/entry/605019">605019</a>) by <a href="#10" class="mim-tip-reference" title="Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S. <strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong> Circ. Cardiovasc. Genet. 5: 42-50, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.111.960674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22062970">Pisciotta et al. (2012)</a>, see <a href="#0004">604774.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22062970" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with FHBL2, <a href="#9" class="mim-tip-reference" title="Noto, D., Cefalu, A. B., Valenti, V., Fayer, F., Pinotti, E., Ditta, M., Spina, R., Vigna, G., Yue, P., Kathiresan, S., Tarugi, P., Averna, M. R. <strong>Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia.</strong> Arterioscler. Thromb. Vasc. Biol. 32: 805-809, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22247256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22247256</a>] [<a href="https://doi.org/10.1161/ATVBAHA.111.238766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22247256">Noto et al. (2012)</a> identified homozygosity for the c.439_442delAACT mutation in the ANGPTL3 gene, causing a frameshift predicted to result in premature termination (Asn147fsTer1). In another patient with a similar lipid profile, they detected compound heterozygosity for the 4-bp deletion and a c.883T-C transition in ANGPTL3, resulting in a phe295-to-leu (F295L; <a href="#0007">604774.0007</a>) substitution at a highly conserved residue. Neither mutation was found in 200 normolipemic controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22247256" 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">rs398122988 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122988;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=rs398122988" 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=rs398122988" 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=RCV000077769 OR RCV001854364 OR RCV003398666 OR RCV003458195" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077769, RCV001854364, RCV003398666, RCV003458195" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077769...</a>
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<p>In a Spanish brother and sister and an unrelated Spanish man with low total, HDL, and LDL cholesterol and triglyceride levels (FHBL2; <a href="/entry/605019">605019</a>), <a href="#6" class="mim-tip-reference" title="Martin-Campos, J. M., Roig, R., Mayoral, C., Martinez, S., Marti, G., Arroyo, J. A., Julve, J., Blanco-Vaca, F. <strong>Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation.</strong> Clin. Chim. Acta 413: 552-555, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22155345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22155345</a>] [<a href="https://doi.org/10.1016/j.cca.2011.11.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22155345">Martin-Campos et al. (2012)</a> identified homozygosity for a 5-bp deletion (delCTCAA) in exon 1 of the ANGPTL3 gene, causing a frameshift (Asn121LeuTer2) in the N-terminal coiled-coil domain predicted to result in a truncated protein of only 122 residues (26% of wildtype length). The 2 heterozygous sibs of the brother and sister presented different lipid profiles, with 1 showing a plasma triglyceride level in the first decile of the age- and sex-matched Spanish population, whereas the other had a plasma HDL cholesterol slightly above the 10th percentile. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22155345" 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> rs398122989 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122989;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/rs398122989?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=rs398122989" 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=rs398122989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the phe295-to-leu (F295L) mutation in the ANGPTL3 gene that was found in compound heterozygous state in a patient with familial hypobetalipoproteinemia (FHBL2; <a href="/entry/605019">605019</a>) by <a href="#9" class="mim-tip-reference" title="Noto, D., Cefalu, A. B., Valenti, V., Fayer, F., Pinotti, E., Ditta, M., Spina, R., Vigna, G., Yue, P., Kathiresan, S., Tarugi, P., Averna, M. R. <strong>Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia.</strong> Arterioscler. Thromb. Vasc. Biol. 32: 805-809, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22247256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22247256</a>] [<a href="https://doi.org/10.1161/ATVBAHA.111.238766" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22247256">Noto et al. (2012)</a>, see <a href="#0005">604774.0005</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22247256" 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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Curr. Opin. Lipidol. 24: 313-320, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23839332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23839332</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23839332" 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/10.1097/MOL.0b013e3283630cf0" target="_blank">Full Text</a>]
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<strong>ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha-v-beta-3 and induces blood vessel formation in vivo.</strong>
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J. Biol. Chem. 277: 17281-17290, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11877390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11877390</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11877390" 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.M109768200" target="_blank">Full Text</a>]
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Conklin, D., Gilbertson, D., Taft, D. W., Maurer, M. F., Whitmore, T. E., Smith, D. L., Walker, K. M., Chen, L. H., Wattler, S., Nehls, M., Lewis, K. B.
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<strong>Identification of a mammalian angiopoietin-related protein expressed specifically in liver.</strong>
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Genomics 62: 477-482, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10644446/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10644446</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10644446" 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.1999.6041" target="_blank">Full Text</a>]
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<a id="Dewey2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Dewey, F. E., Gusarova, V., Dunbar, R. L., O'Dushlaine, C., Schurmann, C., Gottesman, O., McCarthy, S., Van Hout, C. V., Bruse, S., Dansky, H. M., Leader, J. B., Murray, M. F., and 45 others.
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<strong>Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28538136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28538136</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28538136[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=28538136" 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/NEJMoa1612790" target="_blank">Full Text</a>]
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<a id="Koishi2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Koishi, R., Ando, Y., Ono, M., Shimamura, M., Yasumo, H., Fujiwara, T., Horikoshi, H., Furukawa, H.
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<strong>Angptl3 regulates lipid metabolism in mice.</strong>
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[<a href="https://doi.org/10.1038/ng814" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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<strong>Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation.</strong>
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Clin. Chim. Acta 413: 552-555, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22155345/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22155345</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22155345" 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.cca.2011.11.020" target="_blank">Full Text</a>]
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<a id="Minicocci2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Minicocci, I., Montali, A., Robciuc, M. R., Quagliarini, F., Censi, V., Labbadia, G., Gabiati, C., Pigna, G., Sepe, M. L., Pannozzo, F., Lutjohann, D., Fazio, S., Jauhiainen, M., Ehnholm, C., Arca, M.
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<strong>Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.</strong>
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J. Clin. Endocr. Metab. 97: E1266-E1275, 2012. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22659251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22659251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22659251[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=22659251" 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/10.1210/jc.2012-1298" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Musunuru2010" class="mim-anchor"></a>
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<div class="">
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Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., Fennell, T., Banks, E., and 15 others.
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<strong>Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.</strong>
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New Eng. J. Med. 363: 2220-2227, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20942659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20942659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20942659[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=20942659" 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/NEJMoa1002926" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Noto2012" class="mim-anchor"></a>
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<div class="">
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Noto, D., Cefalu, A. B., Valenti, V., Fayer, F., Pinotti, E., Ditta, M., Spina, R., Vigna, G., Yue, P., Kathiresan, S., Tarugi, P., Averna, M. R.
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<strong>Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia.</strong>
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Arterioscler. Thromb. Vasc. Biol. 32: 805-809, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22247256/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22247256</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22247256" 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/10.1161/ATVBAHA.111.238766" target="_blank">Full Text</a>]
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</p>
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<a id="10" class="mim-anchor"></a>
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<a id="Pisciotta2012" class="mim-anchor"></a>
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<div class="">
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Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S.
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<strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22062970/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22062970</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22062970" 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/10.1161/CIRCGENETICS.111.960674" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Pulai1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pulai, J. I., Neuman, R. J., Groenewegen, A. W., Wu, J., Schonfeld, G.
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<strong>Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the ApoB gene in Caucasian families.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9508071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9508071</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9508071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<a id="12" class="mim-anchor"></a>
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<a id="Quagliarini2012" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., Hobbs, H. H.
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<strong>Atypical angiopoietin-like protein that regulates ANGPTL3.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23150577/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23150577</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23150577[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=23150577" 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/10.1073/pnas.1217552109" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
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<a id="Romeo2009" class="mim-anchor"></a>
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<div class="">
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Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C.
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J. Clin. Invest. 119: 70-79, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19075393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19075393</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19075393[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=19075393" 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/10.1172/JCI37118" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Shimizugawa2002" class="mim-anchor"></a>
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<div class="">
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Shimizugawa, T., Ono, M, Shimamura, M, Yoshida, K., Ando, Y., Koishi, R., Ueda, K., Inaba, T, Minekura, H, Kohama, T., Furukawa, H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12097324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12097324</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12097324" 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.M203215200" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Zhang2006" class="mim-anchor"></a>
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<div class="">
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Zhang, C. C., Kaba, M., Ge, G., Xie, K., Tong, W., Hug, C., Lodish, H. F.
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<strong>Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16429146/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16429146</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16429146[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=16429146" 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/nm1342" target="_blank">Full Text</a>]
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<a id="Zheng2012" class="mim-anchor"></a>
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<div class="">
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Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Canto, A. P., Chen, S.-H., Wang, H.-Y., Ward, E. S., Zhang, C. C.
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<strong>Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.</strong>
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Nature 485: 656-660, 2012. Note: Erratum: Nature 488: 684 only, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22660330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22660330</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22660330[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=22660330" 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/nature11095" 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 : 07/02/2018
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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 : 2/19/2015<br>Marla J. F. O'Neill - updated : 12/23/2013<br>Ada Hamosh - updated : 7/23/2012<br>Marla J. F. O'Neill - updated : 12/21/2010<br>Paul J. Converse - updated : 7/14/2006<br>Patricia A. Hartz - updated : 11/12/2002<br>Victor A. McKusick - updated : 1/18/2002
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Creation Date:
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Patti M. Sherman : 3/31/2000
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carol : 09/17/2024
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carol : 09/17/2024<br>alopez : 11/13/2023<br>alopez : 07/02/2018<br>carol : 07/15/2015<br>mcolton : 7/2/2015<br>mgross : 2/19/2015<br>alopez : 1/30/2015<br>carol : 7/10/2014<br>joanna : 12/26/2013<br>carol : 12/23/2013<br>carol : 9/5/2012<br>alopez : 7/23/2012<br>wwang : 12/28/2010<br>terry : 12/21/2010<br>mgross : 7/14/2006<br>cwells : 11/12/2002<br>alopez : 2/5/2002<br>alopez : 1/23/2002<br>terry : 1/18/2002<br>mcapotos : 4/13/2000<br>psherman : 3/31/2000
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<strong>*</strong> 604774
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ANGIOPOIETIN-LIKE 3; ANGPTL3
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<em>Alternative titles; symbols</em>
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ANGIOPOIETIN 5; ANGPT5
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ANGPTL3</em></strong>
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Cytogenetic location: 1p31.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:62,597,520-62,606,313 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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1p31.3
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Hypobetalipoproteinemia, familial, 2
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<span class="mim-font">
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605019
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<span class="mim-font">
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Autosomal recessive
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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>Cloning and Expression</strong>
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<p>The angiopoietins are a family of growth factors that are specific for vascular endothelium. By searching an EST database for signal sequences and amphipathic helices, Conklin et al. (1999) identified the ANGPTL3 gene. They isolated a full-length ANGPTL3 cDNA from a human fetal liver/spleen cDNA library. The deduced 460-amino acid ANGPTL3 protein has the characteristic structure of angiopoietins: a signal peptide, an extended helical domain predicted to form dimeric or trimeric coiled-coils, a short linker peptide, and a globular fibrinogen homology domain (FHD). ANGPTL3 contains the 4 conserved cysteine residues implicated in the intramolecular disulfide bonds within the FHD, but it does not contain 2 other cysteines that are found within the FHDs of ANGPT1 (601667), ANGPT2 (601922), and ANGPT4 (603705). ANGPTL3 also does not contain the characteristic calcium-binding motif found in other angiopoietins. The authors found that ANGPTL3 is glycosylated at 1 of 2 potential N-glycosylation sites. Human ANGPTL3 shares 76% amino acid sequence identity with mouse Angptl3, which Conklin et al. (1999) also cloned. Northern blot analysis of human tissues showed 4 ANGPTL3 transcripts of approximately 4.5, 3.0, 2.8, and 1.7 kb in liver; the 1.7-kb transcript was also weakly expressed in kidney. No ANGPTL3 expression was detected in the other tissues examined, namely heart, brain, placenta, lung, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon, peripheral blood leukocytes, stomach, thyroid, spinal cord, lymph node, trachea, adrenal gland, and bone marrow. Mouse Angptl3 expression was observed in 15- and 17-day embryos, but not in 7- or 11-day embryos. </p><p>Romeo et al. (2009) examined levels of ANGPTL3 mRNA in 48 human tissues and found that expression was largely restricted to the liver. </p>
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<strong>Gene Structure</strong>
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<p>Quagliarini et al. (2012) reported that the ANGPTL3 gene contains 7 exons. </p>
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<strong>Mapping</strong>
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<p>By radiation hybrid mapping and the use of surrounding genes, Conklin et al. (1999) mapped the ANGPTL3 gene to chromosome 1p31. They mapped the mouse Angptl3 gene to a region in chromosome 4 that shows homology of synteny with human 1p31. </p><p>Quagliarini et al. (2012) noted that the ANGPTL3 gene resides within an intron of the DOCK7 gene (615730) on the opposite strand of chromosome 1. </p>
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<strong>Gene Function</strong>
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<p>Camenisch et al. (2002) determined that ANGPTL3 binds to human vascular endothelial cells; however, it does not bind to the Tie2 receptor (TEK; 600221), which is utilized by other members of the angiopoietin family to regulate blood vessel formation. Crystallographic studies and sequence analysis revealed that the fibrinogen-like domain of ANGPTL3 shares significant similarity with the C terminus of the gamma chain of human fibrinogen (134850), suggesting that ANGPTL3 may bind integrins. Using a panel of integrin subunits expressed in 293 cells, they determined that cells expressing alpha-5/beta-3 integrins (135620, 173470) adhered to ANGPTL3-coated dishes. Binding induced integrin alpha-5/beta-3-dependent haptotactic endothelial cell adhesion and migration, and stimulated signal transduction pathways characteristic for integrin activation. ANGPTL3 also induced angiogenesis in the rat corneal assay. The C-terminal fibrinogen-like domain alone was sufficient to induce endothelial cell adhesion and in vivo angiogenesis. </p><p>By microarray analysis, Zhang et al. (2006) showed that mouse hematopoietic stem cell (HSC)-supportive fetal liver Cd3 (see 186830)-positive cells expressed Angptl2 (605001) and Angptl3. Long-term HSC expansion occurred when HSCs were cultured in the presence of Angptl2 and Angptl3 together with saturating levels of other growth factors. Several other angiopoietin-like proteins, though not all, also supported HSC growth. Zhang et al. (2006) concluded that angiopoietin-like proteins can be potent stimulators of ex vivo expansion of HSCs. </p><p>Zheng et al. (2012) showed that the human immune inhibitory receptor leukocyte immunoglobulin-like receptor B2 (LILRB2; 604815) and its mouse ortholog paired immunoglobulin-like receptor (PIRB) are receptors for several angiopoietin-like proteins, including ANGPTL3. LILRB2 and PIRB are expressed on human and mouse hematopoietic stem cells, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of hematopoietic stem cells. In mouse transplantation acute myeloid leukemia models, a deficiency in intracellular signaling of PIRB resulted in increased differentiation of leukemia cells, revealing that PIRB supports leukemia development. Zheng et al. (2012) concluded that their study indicated an unexpected functional significance of classical immune inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development. </p><p>Using immunoprecipitation analysis, Quagliarini et al. (2012) found that human ANGPTL8 (C19ORF80; 616223) interacted with full-length ANGPTL3 and the isolated N-terminal fragment of ANGPTL3. Expression of ANGPTL8 increased plasma levels of triglycerides and nonesterified fatty acids in wildtype mice, but not in Angptl3 -/- mice. Infection of mice with both ANGPTL8 and ANGPTL3 dramatically increased plasma triglyceride and fatty acid levels. In cultured HepG2 hepatocytes, ANGPTL8 promoted cleavage and secretion of the functional ANGPTL3 N-terminal fragment. Serum ALGPTL8 levels were low after a 12-hour fast in humans and increased significantly within 3 hours of feeding. Quagliarini et al. (2012) concluded that ANGPTL8 regulates postprandial triacylglycerol and fatty acid metabolism by activating ANGPTL3. </p><p>Arca et al. (2013) reviewed the role of liver-derived ANGPTL3 in metabolic processes and concluded that ANGPTL3 modulates the metabolism of triglyceride-rich lipoproteins mainly by inhibiting the activity of lipoprotein lipase (LPL; 609708). </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Musunuru et al. (2010) performed whole-genome exome sequencing in 2 affected sibs from a 4-generation family with hypobetalipoproteinemia (FHLB2; 605019), previously reported by Pulai et al. (1998) as family 'F' in which linkage to the APOB gene (107730) was excluded. Only the ANGPTL3 gene harbored novel variants in both alleles in both sibs, who were compound heterozygous for 2 nonsense mutations (604774.0001)-(604774.0002). Genomewide linkage analysis ruled out significant linkage elsewhere in the genome. </p><p>Romeo et al. (2009) sequenced the ANGPTL3, ANGPTL5 (607666), and ANGPTL6 (609336) genes in a large multiethnic population and identified multiple rare nonsynonymous sequence variations (see, e.g., 604774.0003 and 604774.0005) that were associated with low plasma triglyceride (TG) levels but not other metabolic phenotypes. Functional studies showed that all mutant alleles of ANGPTL3 that were associated with low plasma TG levels interfered either with the synthesis or secretion of the protein, or with the ability of the ANGPTL protein to inhibit LPL. </p><p>In 4 affected members of 3 kindreds with hypobetalipoproteinemia, who were negative for mutation in 6 genes known to be associated with lipid disorders, Pisciotta et al. (2012) identified homozygosity for a splice site mutation (604774.0003) in 1 family and compound heterozygosity for a 1-bp and a 4-bp deletion in the other 2 families (604774.0004 and 604774.0005). </p><p>In 4 unrelated Spanish patients with severe hypolipidemia who were negative for mutation in the APOB gene, Martin-Campos et al. (2012) analyzed ANGPTL3 and identified homozygosity for a 5-bp deletion in 2 of the patients (604774.0006). </p><p>In a cohort of 78 patients with low total, LDL, and HDL cholesterol and TG levels, who were negative for mutation in the APOB, PCSK9 (607786), and MTP (157147) genes, Noto et al. (2012) sequenced the ANGPTL3 gene and identified homozygous or compound heterozygous mutations in 4 patients (see, e.g., 604774.0005 and 604774.0007) as well as heterozygous mutations in 4 patients. Compared to ANGPTL3 mutation-negative individuals from the cohort, ANGPTL3 heterozygotes had lower TG levels but similar levels of total, LDL, and HDL cholesterol, suggesting that gene dosage affects only the TG plasma levels. </p><p>In a small town in Italy, Minicocci et al. (2012) identified homozygosity or heterozygosity for the ANGPTL3 S17X mutation (604774.0001) in the probands of 9 hypocholesterolemic families and 20 affected family members, as well as 32 individuals from the community; in addition, heterozygosity for a 2-bp deletion and a 3-bp deletion in ANGPTL3 were identified in 2 hypocholesterolemic individuals, respectively. The prevalence of ANGPTL3 variants in the whole population sample was 9.4%; in hypocholesterolemic individuals, prevalence was 15.2%. Homozygotes for S17X had no circulating ANGPTL3 and a marked reduction of all plasma lipids, whereas heterozygotes had 42% reduction in ANGPTL3 compared with noncarriers, but a significant reduction of only total cholesterol and HDL cholesterol. No differences were observed in plasma noncholesterol sterols between carriers and noncarriers, and there was no association detected between familial combined hypolipidemia and the risk of hepatic or cardiovascular disease. Minicocci et al. (2012) concluded that hypobetalipoproteinemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae. </p><p>Dewey et al. (2017) sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study. They identified 13 different loss-of-function variants in 43 (0.33%) patients with coronary artery disease and in 183 (0.45%) controls (adjusted OR, 0.59; 95% CI, 0.41 to 0.85; p = 0.004). They then performed tests of association for loss-of-function variants in ANGPTL3 with lipid levels and with coronary artery disease in 13,102 case patients and 40,430 controls from the DiscovEHR study, with follow-up studies involving 23,317 case patients and 107,166 controls from 4 population studies. In the DiscovEHR study, participants with heterozygous loss-of-function variants in ANGPTL3 had significantly lower serum levels of triglycerides, HDL cholesterol, and LDL cholesterol than participants without these variants. The results were confirmed in the follow-up studies. </p>
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<strong>Animal Model</strong>
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<p>The KK mouse is moderately obese and has abnormally high levels of plasma insulin, glucose, and lipids. This is a multigenic syndrome that resembles type 2 diabetes in humans. Koishi et al. (2002) observed 1 strain, KK/San, that showed abnormally low plasma lipid levels (hypolipidemia) inherited as a mendelian recessive. They mapped the hypolipidemia locus (hypl) to the middle of mouse chromosome 4 and by positional cloning identified the gene carrying the mutation responsible for the hypolipidemia. They found that the hypl locus encodes a unique angiopoietin-like lipoprotein modulator, which they named Allm1. It was found to be identical to angiopoietin-like protein-3, encoded by Angptl3, and had a highly conserved counterpart in humans. Overexpression of Angptl3 or intravenous injection of the purified protein in KK/San mice elicited an increase in circulating plasma lipid levels. This increase was also observed in normal C57BL/6J mice. Taken together, these data suggested that Angptl3 regulates lipid metabolism in animals. The authors suggested the possibility that genetic variation in ANGPTL3 contributes to atherosclerosis, coronary artery disease, and diabetes mellitus and stated that animal studies demonstrated that an Angptl3 mutation reduces atherosclerosis in mice. </p><p>In characterizing the KK/San mouse model, Shimizugawa et al. (2002) determined that overexpression of Angptl3 in KK/San mice results in a marked increase of triglyceride-enriched very low density lipoprotein (VLDL). In vivo studies revealed that there is no significant difference between mutant and wildtype KK mice in the hepatic VLDL triglyceride secretion rate. However, turnover studies using radiolabeled VLDL revealed that the clearance of 3H-triglyceride-labeled VLDL was significantly enhanced in KK/San mice, whereas the clearance of 125I-labeled protein from VLDL was only slightly enhanced. In vitro analysis of recombinant protein revealed that Angptl3 directly inhibits lipoprotein lipase (LPL) activity. From these data, Shimizugawa et al. (2002) concluded that Angptl3 regulates VLDL triglyceride levels through the inhibition of LPL activity. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>7 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
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ANGPTL3, SER17TER
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<br />
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SNP: rs267606655,
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ClinVar: RCV000005684
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<p>In 2 affected sibs from a 4-generation family with hypobetalipoproteinemia (FHLB2; 605019), originally studied by Pulai et al. (1998) (family 'F'), Musunuru et al. (2010) performed whole-genome exome sequencing and identified compound heterozygosity for a CC-to-GA double transversion at nucleotide 62,835,875 to 62,835,876 in exon 1 of the ANGPTL3 gene, resulting in a ser17-to-ter (S17X) substitution, and a G-T transversion at nucleotide 62,836,210 in exon 1 of the ANGPTL3 gene, resulting in a glu129-to-ter (E129X) substitution (604774.0002). The 2 sibs had a clinical syndrome of combined hypolipidemia, consisting of extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Family members who were heterozygous for either mutation had plasma levels of LDL cholesterol and triglycerides that were intermediate between the levels in persons with neither mutation and those with both mutations, findings consistent with a codominant mode of inheritance for the LDL cholesterol and triglyceride phenotypes. In contrast, the level of HDL cholesterol appeared to segregate as a recessive trait: family members who carried both nonsense alleles had significantly lower plasma HDL cholesterol levels than members with 1 or no mutations. </p><p>In the probands of 9 hypocholesterolemic families from a small town in Italy, Minicocci et al. (2012) identified the S17X mutation in the ANGPTL3 gene, present in heterozygosity in 7 probands and in homozygosity in 2. Screening of family members revealed 20 additional individuals carrying the S17X mutation, 4 homozygotes and 16 heterozygotes; all but 3 heterozygous carriers showed a hypocholesterolemic phenotype. Only homozygous carriers showed comprehensive reduction of plasma lipoproteins; in heterozygous carriers, significant reduction was limited to total and HDL cholesterol levels. All of the S17X alleles shared the same haplotype, suggesting that the S17X mutation arose from a common ancestor. </p>
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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 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ANGPTL3, GLU129TER
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<br />
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SNP: rs200785483,
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gnomAD: rs200785483,
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ClinVar: RCV000005685
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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>For discussion of the glu129-to-ter (E129X) mutation that was found in the ANGPTL3 gene in compound heterozygous state in 2 sibs with hypobetalipoproteinemia (FHLB2; 605019) by Musunuru et al. (2010), see 604774.0001. </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 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ANGPTL3, IVS6DS, G-T, +1
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<br />
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SNP: rs398122985,
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ClinVar: RCV000077766
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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 65-year-old Italian woman with very low plasma lipid levels (FHBL2; 605019), Pisciotta et al. (2012) identified homozygosity for a G-T transversion in intron 6 (c.1198+1G-T) of the ANGPTL3 gene, causing partial retention of intron 6 in mature mRNA and resulting in a frameshift and formation of a premature termination codon (Gly400ValfsTer5). The proband's clinically unaffected children were heterozygous carriers of the mutation; screening of 200 controls from the general Italian population identified 1 heterozygous carrier of the c.1198+1G-T mutation, a 36-year-old woman with low plasma ANGPTL3, moderately reduced LDL cholesterol, and normal HDL cholesterol. Pisciotta et al. (2012) noted that this splice site mutation was previously found to be associated with low plasma TG levels in individuals from the large multiethnic population of the Dallas Heart Study by Romeo et al. (2009), who reported its occurrence at chr1:62,842,495. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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|
<span class="mim-font">
|
|
<strong>.0004 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ANGPTL3, 1-BP DEL, 55A
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<br />
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SNP: rs398122986,
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ClinVar: RCV000077767
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 59-year-old Italian man with low total, HDL, and LDL cholesterol and triglyceride levels (FHBL2; 605019), Pisciotta et al. (2012) identified compound heterozygosity for 2 mutations in the ANGPTL3 gene: a 1-bp deletion (c.55delA) in exon 1, resulting in a frameshift and a premature termination codon (Ile19LeufsTer22), and a 4-bp deletion in exon 1 (c.439_442delAACT; 604774.0005), also resulting in a frameshift and a premature termination codon (N147X). The proband's healthy brother, who had an identical lipid profile, was also compound heterozygous for the deletions; their mother and the brother's daughter were both heterozygous for the 1-bp deletion. A woman from an unrelated Italian kindred, who presented at 85 years of age with an acute respiratory tract infection and was found to have marked hypolipidemia, was also compound heterozygous for the 1-bp and 4-bp deletions; she died suddenly at 91 years of age. Pisciotta et al. (2012) noted that the 4-bp deletion was previously found to be associated with low plasma TG levels in individuals from the large multiethnic population of the Dallas Heart Study by Romeo et al. (2009), who designated it as being an in/del at chr1:62,836,264. </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>
|
|
<span class="mim-font">
|
|
<strong>.0005 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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ANGPTL3, 4-BP DEL, 439AACT
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<br />
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SNP: rs398122987,
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ClinVar: RCV000077768, RCV005089534
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the 4-bp deletion in the ANGPTL3 gene (c.439_442delAACT) that was found in compound heterozygous state in a patient with familial hypobetalipoproteinemia (FHBL2; 605019) by Pisciotta et al. (2012), see 604774.0004. </p><p>In a patient with FHBL2, Noto et al. (2012) identified homozygosity for the c.439_442delAACT mutation in the ANGPTL3 gene, causing a frameshift predicted to result in premature termination (Asn147fsTer1). In another patient with a similar lipid profile, they detected compound heterozygosity for the 4-bp deletion and a c.883T-C transition in ANGPTL3, resulting in a phe295-to-leu (F295L; 604774.0007) substitution at a highly conserved residue. Neither mutation was found in 200 normolipemic controls. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
ANGPTL3, 5-BP DEL, EXON 1, CTCAA
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<br />
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|
|
SNP: rs398122988,
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|
|
ClinVar: RCV000077769, RCV001854364, RCV003398666, RCV003458195
|
|
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|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Spanish brother and sister and an unrelated Spanish man with low total, HDL, and LDL cholesterol and triglyceride levels (FHBL2; 605019), Martin-Campos et al. (2012) identified homozygosity for a 5-bp deletion (delCTCAA) in exon 1 of the ANGPTL3 gene, causing a frameshift (Asn121LeuTer2) in the N-terminal coiled-coil domain predicted to result in a truncated protein of only 122 residues (26% of wildtype length). The 2 heterozygous sibs of the brother and sister presented different lipid profiles, with 1 showing a plasma triglyceride level in the first decile of the age- and sex-matched Spanish population, whereas the other had a plasma HDL cholesterol slightly above the 10th percentile. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 HYPOBETALIPOPROTEINEMIA, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
|
ANGPTL3, PHE295LEU
|
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|
<br />
|
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|
|
SNP: rs398122989,
|
|
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|
|
|
gnomAD: rs398122989,
|
|
|
|
|
|
ClinVar: RCV000077770
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the phe295-to-leu (F295L) mutation in the ANGPTL3 gene that was found in compound heterozygous state in a patient with familial hypobetalipoproteinemia (FHBL2; 605019) by Noto et al. (2012), see 604774.0005. </p>
|
|
</span>
|
|
</div>
|
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|
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|
<div>
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|
<br />
|
|
</div>
|
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|
|
</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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<ol>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Arca, M., Minicocci, I., Maranghi, M.
|
|
<strong>The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism.</strong>
|
|
Curr. Opin. Lipidol. 24: 313-320, 2013.
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[PubMed: 23839332]
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[Full Text: https://doi.org/10.1097/MOL.0b013e3283630cf0]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Camenisch, G, Pisabarro, M. T., Sherman, D., Kowalski, J., Nagel, M., Hass, P, Xie, M.-H., Gurney, A., Bodary, S., Liang, X. H., Clark, K., Beresini, M, Ferrara, N., Gerber, H.-P.
|
|
<strong>ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha-v-beta-3 and induces blood vessel formation in vivo.</strong>
|
|
J. Biol. Chem. 277: 17281-17290, 2002.
|
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[PubMed: 11877390]
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[Full Text: https://doi.org/10.1074/jbc.M109768200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Conklin, D., Gilbertson, D., Taft, D. W., Maurer, M. F., Whitmore, T. E., Smith, D. L., Walker, K. M., Chen, L. H., Wattler, S., Nehls, M., Lewis, K. B.
|
|
<strong>Identification of a mammalian angiopoietin-related protein expressed specifically in liver.</strong>
|
|
Genomics 62: 477-482, 1999.
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[PubMed: 10644446]
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[Full Text: https://doi.org/10.1006/geno.1999.6041]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dewey, F. E., Gusarova, V., Dunbar, R. L., O'Dushlaine, C., Schurmann, C., Gottesman, O., McCarthy, S., Van Hout, C. V., Bruse, S., Dansky, H. M., Leader, J. B., Murray, M. F., and 45 others.
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|
<strong>Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.</strong>
|
|
New Eng. J. Med. 377: 211-221, 2017.
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[PubMed: 28538136]
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[Full Text: https://doi.org/10.1056/NEJMoa1612790]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Koishi, R., Ando, Y., Ono, M., Shimamura, M., Yasumo, H., Fujiwara, T., Horikoshi, H., Furukawa, H.
|
|
<strong>Angptl3 regulates lipid metabolism in mice.</strong>
|
|
Nature Genet. 30: 151-157, 2002.
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[PubMed: 11788823]
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[Full Text: https://doi.org/10.1038/ng814]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Martin-Campos, J. M., Roig, R., Mayoral, C., Martinez, S., Marti, G., Arroyo, J. A., Julve, J., Blanco-Vaca, F.
|
|
<strong>Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation.</strong>
|
|
Clin. Chim. Acta 413: 552-555, 2012.
|
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|
|
[PubMed: 22155345]
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[Full Text: https://doi.org/10.1016/j.cca.2011.11.020]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Minicocci, I., Montali, A., Robciuc, M. R., Quagliarini, F., Censi, V., Labbadia, G., Gabiati, C., Pigna, G., Sepe, M. L., Pannozzo, F., Lutjohann, D., Fazio, S., Jauhiainen, M., Ehnholm, C., Arca, M.
|
|
<strong>Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.</strong>
|
|
J. Clin. Endocr. Metab. 97: E1266-E1275, 2012. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 22659251]
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|
|
[Full Text: https://doi.org/10.1210/jc.2012-1298]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Musunuru, K., Pirruccello, J. P., Do, R., Peloso, G. M., Guiducci, C., Sougnez, C., Garimella, K. V., Fisher, S., Abreu, J., Barry, A. J., Fennell, T., Banks, E., and 15 others.
|
|
<strong>Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.</strong>
|
|
New Eng. J. Med. 363: 2220-2227, 2010.
|
|
|
|
|
|
[PubMed: 20942659]
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|
|
[Full Text: https://doi.org/10.1056/NEJMoa1002926]
|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Noto, D., Cefalu, A. B., Valenti, V., Fayer, F., Pinotti, E., Ditta, M., Spina, R., Vigna, G., Yue, P., Kathiresan, S., Tarugi, P., Averna, M. R.
|
|
<strong>Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia.</strong>
|
|
Arterioscler. Thromb. Vasc. Biol. 32: 805-809, 2012.
|
|
|
|
|
|
[PubMed: 22247256]
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|
|
|
[Full Text: https://doi.org/10.1161/ATVBAHA.111.238766]
|
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</p>
|
|
</li>
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Pisciotta, L., Favari, E., Magnolo, L., Simonelli, S., Adorni, M. P., Sallo, R., Fancello, T., Zavaroni, I., Ardigo, D., Bernini, F., Calabresi, L., Franceschini, G., Tarugi, P., Calandra, S., Bertolini, S.
|
|
<strong>Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.</strong>
|
|
Circ. Cardiovasc. Genet. 5: 42-50, 2012.
|
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|
|
|
|
[PubMed: 22062970]
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|
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|
|
[Full Text: https://doi.org/10.1161/CIRCGENETICS.111.960674]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Pulai, J. I., Neuman, R. J., Groenewegen, A. W., Wu, J., Schonfeld, G.
|
|
<strong>Genetic heterogeneity in familial hypobetalipoproteinemia: linkage and non-linkage to the ApoB gene in Caucasian families.</strong>
|
|
Am. J. Med. Genet. 76: 79-86, 1998.
|
|
|
|
|
|
[PubMed: 9508071]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Quagliarini, F., Wang, Y., Kozlitina, J., Grishin, N. V., Hyde, R., Boerwinkle, E., Valenzuela, D. M., Murphy, A. J., Cohen, J. C., Hobbs, H. H.
|
|
<strong>Atypical angiopoietin-like protein that regulates ANGPTL3.</strong>
|
|
Proc. Nat. Acad. Sci. 109: 19751-19756, 2012.
|
|
|
|
|
|
[PubMed: 23150577]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.1217552109]
|
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|
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</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Romeo, S., Yin, W., Kozlitina, J., Pennacchio, L. A., Boerwinkle, E., Hobbs, H. H., Cohen, J. C.
|
|
<strong>Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans.</strong>
|
|
J. Clin. Invest. 119: 70-79, 2009.
|
|
|
|
|
|
[PubMed: 19075393]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1172/JCI37118]
|
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|
</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Shimizugawa, T., Ono, M, Shimamura, M, Yoshida, K., Ando, Y., Koishi, R., Ueda, K., Inaba, T, Minekura, H, Kohama, T., Furukawa, H.
|
|
<strong>ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase.</strong>
|
|
J. Biol. Chem. 277: 33742-33748, 2002.
|
|
|
|
|
|
[PubMed: 12097324]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M203215200]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Zhang, C. C., Kaba, M., Ge, G., Xie, K., Tong, W., Hug, C., Lodish, H. F.
|
|
<strong>Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells.</strong>
|
|
Nature Med. 12: 240-245, 2006.
|
|
|
|
|
|
[PubMed: 16429146]
|
|
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|
|
[Full Text: https://doi.org/10.1038/nm1342]
|
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|
</p>
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Zheng, J., Umikawa, M., Cui, C., Li, J., Chen, X., Zhang, C., Huynh, H., Kang, X., Silvany, R., Wan, X., Ye, J., Canto, A. P., Chen, S.-H., Wang, H.-Y., Ward, E. S., Zhang, C. C.
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<strong>Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.</strong>
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Nature 485: 656-660, 2012. Note: Erratum: Nature 488: 684 only, 2012.
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[PubMed: 22660330]
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[Full Text: https://doi.org/10.1038/nature11095]
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Ada Hamosh - updated : 07/02/2018<br>Patricia A. Hartz - updated : 2/19/2015<br>Marla J. F. O'Neill - updated : 12/23/2013<br>Ada Hamosh - updated : 7/23/2012<br>Marla J. F. O'Neill - updated : 12/21/2010<br>Paul J. Converse - updated : 7/14/2006<br>Patricia A. Hartz - updated : 11/12/2002<br>Victor A. McKusick - updated : 1/18/2002
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Patti M. Sherman : 3/31/2000
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