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Entry
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- *600073 - LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2; LRP2
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- OMIM
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<p>
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<span class="h4">*600073</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600073">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>
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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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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000081479;t=ENST00000649046" 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=4036" 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=600073" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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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=ENSG00000081479;t=ENST00000649046" 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_004525,XM_011511183,XM_011511184,XM_047444340" 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_004525" 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=600073" 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=02509&isoform_id=02509_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/LRP2" 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/685061,1389559,1809240,7534312,32816595,32816597,62630220,62988879,119631685,126012573,160332309,194379030,194380930,444738401,767918153,767918155,2217327965,2462573238,2462573240,2462573242" 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/P98164" 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=4036" 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=ENSG00000081479;t=ENST00000649046" 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=LRP2" 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=LRP2" 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+4036" 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/LRP2" 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:4036" 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/4036" 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=chr2&hgg_gene=ENST00000649046.1&hgg_start=169127109&hgg_end=169362534&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6694" 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:6694" 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://medlineplus.gov/genetics/gene/lrp2" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=600073[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=600073[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/LRP2/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000081479" 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=LRP2" 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=LRP2" 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=LRP2" 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=LRP2&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/PA30452" 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:6694" 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/FBgn0261260.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:95794" 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/LRP2#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:95794" 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/4036/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=4036" 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=WBGene00003071;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-050119-2" 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:4036" 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=LRP2&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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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 702418009<br />
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">ICD+</a>
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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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600073
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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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LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2; LRP2
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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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GLYCOPROTEIN 330<br />
|
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MEGALIN
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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=LRP2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">LRP2</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/2/756?start=-3&limit=10&highlight=756">2q31.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:169127109-169362534&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'})">2:169,127,109-169,362,534</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>
|
|
<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">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/756?start=-3&limit=10&highlight=756">
|
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2q31.1
|
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</a>
|
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</span>
|
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</td>
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|
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<td>
|
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<span class="mim-font">
|
|
Donnai-Barrow syndrome
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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|
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<a href="/entry/222448"> 222448 </a>
|
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|
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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">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/600073" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600073" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</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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<p>Lipoprotein receptor-related protein-2 (LRP2), also called glycoprotein-330 or megalin (<a href="#10" class="mim-tip-reference" title="Farquhar, M. G. <strong>The unfolding story of megalin (gp330): now recognized as a drug receptor (Editorial)</strong> J. Clin. Invest. 96: 1184 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7657789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7657789</a>] [<a href="https://doi.org/10.1172/JCI118149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7657789">Farquhar, 1995</a>), is part of the Heymann nephritis antigenic complex with RAP (LRPAP1; <a href="/entry/104225">104225</a>) (<a href="#9" class="mim-tip-reference" title="Farquhar, M. G., Saito, A., Kerjaschki, D., Orlando, R. A. <strong>The Heymann nephritis antigenic complex: megalin (gp330) and RAP.</strong> J. Am. Soc. Nephrol. 6: 35-47, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7579068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7579068</a>] [<a href="https://doi.org/10.1681/ASN.V6135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7579068">Farquhar et al., 1995</a>) and is a member of a family of receptors with structural similarities to the low density lipoprotein receptor (LDLR; <a href="/entry/606945">606945</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7579068+7657789" 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>LRP2 was originally identified as the target antigen of Heymann nephritis, a rat model of membranous glomerulonephritis. Its location in clathrin-coated pits suggested that gp330 is an endocytic receptor. Gp330 is expressed in specialized epithelia, including those of the inner ear (<a href="#9" class="mim-tip-reference" title="Farquhar, M. G., Saito, A., Kerjaschki, D., Orlando, R. A. <strong>The Heymann nephritis antigenic complex: megalin (gp330) and RAP.</strong> J. Am. Soc. Nephrol. 6: 35-47, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7579068/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7579068</a>] [<a href="https://doi.org/10.1681/ASN.V6135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7579068">Farquhar et al., 1995</a>), neural tube, lung airway, epididymis, yolk sac, glomeruli, and proximal renal tubules (<a href="#14" class="mim-tip-reference" title="Kerjaschki, D., Farquhar, M. G. <strong>Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats.</strong> J. Exp. Med. 157: 667-686, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6337231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6337231</a>] [<a href="https://doi.org/10.1084/jem.157.2.667" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6337231">Kerjaschki and Farquhar, 1983</a>; <a href="#4" class="mim-tip-reference" title="Chatelet, F., Brianti, E., Ronco, P., Roland, J., Verroust, P. <strong>Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli: II. Extrarenal distribution.</strong> Am. J. Path. 122: 512-519, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3754090/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3754090</a>]" pmid="3754090">Chatelet et al., 1986</a>; <a href="#1" class="mim-tip-reference" title="Buc-Caron, M. H., Condamine, H., Kerjaschki, D. <strong>Rat Heymann nephritis antigen is closely related to brushin, a glycoprotein present in early mouse embryo epithelia.</strong> Ann. Inst. Pasteur Immun. 138: 707-722, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2449897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2449897</a>] [<a href="https://doi.org/10.1016/s0769-2625(87)80026-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2449897">Buc-Caron et al., 1987</a>). <a href="#24" class="mim-tip-reference" title="Raychowdhury, R., Niles, J. L., McCluskey, R. T., Smith, J. A. <strong>Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor.</strong> Science 244: 1163-1165, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2786251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2786251</a>] [<a href="https://doi.org/10.1126/science.2786251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2786251">Raychowdhury et al. (1989)</a> sequenced a partial cDNA clone which clearly established that gp330 is a member of the LDL receptor gene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3754090+7579068+2449897+6337231+2786251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Saito, A., Pietromonaco, S., Loo, A. K.-C., Farquhar, M. G. <strong>Complete cloning and sequencing of rat gp330/`megalin,' a distinctive member of the low density lipoprotein receptor gene family.</strong> Proc. Nat. Acad. Sci. 91: 9725-9729, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7937880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7937880</a>] [<a href="https://doi.org/10.1073/pnas.91.21.9725" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7937880">Saito et al. (1994)</a> reported the complete amino acid sequence of the 517,715-Da megalin protein. <a href="#12" class="mim-tip-reference" title="Hjalm, G., Murray, E., Crumley, G., Harazim, W., Lundgren, S., Onyango, I., Bo, E. K., Larsson, M., Juhlin, C., Hellman, P., Davis, H., Akerstrom, G., Rask, L., Morse, B. <strong>Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties.</strong> Europ. J. Biochem. 239: 132-137, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706697</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1996.0132u.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706697">Hjalm et al. (1996)</a> determined the nucleotide sequence of human gp330. They reported that the deduced 4,655-amino acid mature protein has a molecular mass of approximately 519,636 Da and consists of a probable 25-amino acid N-terminal signal peptide, an extracellular region of 4,398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acids. Three types of cysteine-rich repeats characteristic of the LDLR superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising 4 distinct domains, 16 growth factor repeats separated by 8 YWTD spacer regions, and 1 epidermal growth factor-like repeat. <a href="#12" class="mim-tip-reference" title="Hjalm, G., Murray, E., Crumley, G., Harazim, W., Lundgren, S., Onyango, I., Bo, E. K., Larsson, M., Juhlin, C., Hellman, P., Davis, H., Akerstrom, G., Rask, L., Morse, B. <strong>Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties.</strong> Europ. J. Biochem. 239: 132-137, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8706697/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8706697</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1996.0132u.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8706697">Hjalm et al. (1996)</a> detected no consensus cleavage sequence for the processing endoprotease furin. The intracellular tail contains 2 copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, as well as potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II, and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330, with minor differences between the extra- and intracellular regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8706697+7937880" 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 kidney tubule epithelial cells, gp330 has been shown to bind in vitro to lipoprotein lipase and apolipoprotein E-enriched beta-VLDL, suggesting a role for this receptor in lipoprotein metabolism. <a href="#16" class="mim-tip-reference" title="Kounnas, M. Z., Loukinova, E. B., Stefansson, S., Harmony, J. A. K., Brewer, B. H., Strickland, D. K., Argraves, W. S. <strong>Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin.</strong> J. Biol. Chem. 270: 13070-13075, 1995. Note: Erratum: J. Biol. Chem. 270: 23234 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7768901/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7768901</a>] [<a href="https://doi.org/10.1074/jbc.270.22.13070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7768901">Kounnas et al. (1995)</a> showed that gp330 can bind apolipoprotein J/clusterin (CLU; <a href="/entry/185430">185430</a>) with high affinity. Cells that express gp330 can mediate APOJ endocytosis, leading to its lysosomal degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7768901" 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="#19" class="mim-tip-reference" title="Moestrup, S. K., Cui, S., Vorum, H., Bregengard, C., Bjorn, S. E., Norris, K., Gliemann, J., Christensen, E. I. <strong>Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.</strong> J. Clin. Invest. 96: 1404-1413, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544804</a>] [<a href="https://doi.org/10.1172/JCI118176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7544804">Moestrup et al. (1995)</a> demonstrated that the antifibrinolytic polypeptide, aprotinin, and the nephro- and ototoxic antibiotics, aminoglycosides and polymyxin B, compete for binding of radioiodinated urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330. (Aprotinin, also known as bovine pancreatic trypsin inhibitor, is a 6-kD protein used clinically in acute pancreatitis and antifibrinolytic therapy. Intravenously administered aprotinin accumulates in the lysosomes of kidney proximal tubules and is only very slowly degraded.) Analyses of mutant aprotinins expressed in Saccharomyces cerevisiae demonstrated that basic residues are essential for the binding to gp330 and renal uptake. The polybasic drugs also antagonized ligand binding to the human alpha-2-macroglobulin receptor (<a href="/entry/107770">107770</a>). However, the rapid glomerular filtration of the drugs suggested kidney gp330 to be the quantitatively most important target. Thus, a novel role of gp330 as a drug receptor was demonstrated. <a href="#19" class="mim-tip-reference" title="Moestrup, S. K., Cui, S., Vorum, H., Bregengard, C., Bjorn, S. E., Norris, K., Gliemann, J., Christensen, E. I. <strong>Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.</strong> J. Clin. Invest. 96: 1404-1413, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7544804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7544804</a>] [<a href="https://doi.org/10.1172/JCI118176" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7544804">Moestrup et al. (1995)</a> stated that the insight into the mechanism of epithelial uptake of polybasic drugs might provide a basis for design of drugs with reduced toxicity. <a href="#10" class="mim-tip-reference" title="Farquhar, M. G. <strong>The unfolding story of megalin (gp330): now recognized as a drug receptor (Editorial)</strong> J. Clin. Invest. 96: 1184 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7657789/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7657789</a>] [<a href="https://doi.org/10.1172/JCI118149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7657789">Farquhar (1995)</a> reviewed briefly the literature on LRP2/gp330/megalin in light of these new findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7657789+7544804" 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>Megalin, a member of the low density lipoprotein receptor family abundant in kidney proximal tubules, mediates endocytic uptake of complexes between the steroid 25(OH) vitamin D3 and vitamin D-binding protein (DBP; <a href="/entry/139200">139200</a>) filtered in the glomeruli. The receptor-mediated uptake is required to prevent loss of 25(OH)D3 in the urine and to deliver the precursor for generation of 1,25(OH)2 vitamin D3, a potent regulator of calcium homeostasis and bone turnover. <a href="#22" class="mim-tip-reference" title="Nykjaer, A., Dragun, D., Walther, D., Vorum, H., Jacobsen, C., Herz, J. <strong>Melsen, F.; Christensen, E. I.; Willnow, T. E.: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.</strong> Cell 96: 507-515, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10052453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10052453</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80655-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10052453">Nykjaer et al. (1999)</a> showed that accordingly, megalin knockout mice lose DBP and 25(OH)D3 in the urine and develop severe vitamin D deficiency and bone disease. Megalin binds a large number of structurally unrelated ligands, and coreceptors may confer ligand specificity by sequestering and presenting their cargo to megalin. For example, the gastric intrinsic factor (IF; <a href="/entry/609342">609342</a>)-B12 complex is taken up in the intestine by a tandem receptor-mediated mechanism: the complex is first bound to a receptor, cubilin (<a href="/entry/602997">602997</a>), anchored to the outer leaflet of the plasma membrane possibly by an amphipathic helix, followed by endocytosis of cubilin and its cargo mediated by megalin (summary by <a href="#23" class="mim-tip-reference" title="Nykjaer, A., Fyfe, J. C., Kozyraki, R., Leheste, J.-R., Jacobsen, C., Nielsen, M. S., Verroust, P. J., Aminoff, M., de la Chapelle, A., Moestrup, S. K., Ray, R., Gliemann, J., Willnow, T. E., Christensen, E. I. <strong>Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3.</strong> Proc. Nat. Acad. Sci. 98: 13895-13900, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11717447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11717447</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11717447[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.241516998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11717447">Nykjaer et al., 2001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11717447+10052453" 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="#18" class="mim-tip-reference" title="Marino, M., Chiovato, L., Friedlander, J. A., Latrofa, F., Pinchera, A., McCluskey, R. T. <strong>Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis.</strong> J. Clin. Endocr. Metab. 84: 2468-2474, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10404822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10404822</a>] [<a href="https://doi.org/10.1210/jcem.84.7.5837" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10404822">Marino et al. (1999)</a> searched for antimegalin antibodies in 78 patients with autoimmune and nonautoimmune thyroid diseases. Significantly elevated values were found in 18 patients, including 13 of 26 (50%) patients with autoimmune thyroiditis and 2 of 19 (11%) patients with Graves disease (<a href="/entry/275000">275000</a>). Furthermore, 2 of 19 (11%) patients with nontoxic goiter and 1 of 14 (7%) patients with differentiated thyroid cancer had mean fluorescence intensity (MFI) values greater than 50.62, associated with the presence of circulating antithyroid autoantibodies. Binding of serum IgGs to L2 cells was significantly reduced by coincubation with purified megalin in 15 of 18 (83%) positive patients, and by a rabbit antimegalin antibody in 11 (61%) patients. Immunoprecipitation experiments provided further and more conclusive evidence that positive tests (MFI less than 50.62) for binding to L2 cells were attributable to serum antimegalin antibodies. The authors suggested that further studies are needed to determine whether antimegalin antibodies have pathogenic significance or diagnostic value in autoimmune thyroid diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10404822" 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 yeast 2-hybrid, pull-down, and coimmunoprecipitation assays, <a href="#21" class="mim-tip-reference" title="Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G. <strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong> Molec. Biol. Cell 14: 4984-4996, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[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/10.1091/mbc.e03-06-0385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14528014">Nagai et al. (2003)</a> found that rat Arh (LDLRAP1; <a href="/entry/605747">605747</a>) bound the first FxNPxY motif of megalin. Arh colocalized with megalin in clathrin-coated pits and in recycling endosomes in the Golgi region of rat L2 cells. Upon internalization of megalin, megalin and Arh colocalized in clathrin-coated pits, followed by their colocalization in early endosomes and tubular recycling endosomes in the pericentriolar region, and then by their reappearance at the cell surface. Expression of Arh in canine kidney cells expressing megalin minireceptors enhanced megalin-mediated uptake of lactoferrin (LTF; <a href="/entry/150210">150210</a>), a megalin ligand. <a href="#21" class="mim-tip-reference" title="Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G. <strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong> Molec. Biol. Cell 14: 4984-4996, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[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/10.1091/mbc.e03-06-0385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14528014">Nagai et al. (2003)</a> concluded that ARH facilitates endocytosis of megalin and escorts megalin along its endocytic route. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14528014" 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>Albumin (ALB; <a href="/entry/103600">103600</a>) does not readily cross the renal glomerular filter, and the fraction that does is reabsorbed by proximal tubule cells via clathrin- and receptor-mediated endocytosis. Overstressing this endocytic system with prolonged excess of albumin, which is often associated with kidney disease, is injurious to proximal tubule cells and leads to albumin-induced apoptosis. <a href="#2" class="mim-tip-reference" title="Caruso-Neves, C., Pinheiro, A. A. S., Cai, H., Souza-Menezes, J., Guggino, W. B. <strong>PKB and megalin determine the survival or death of renal proximal tubule cells.</strong> Proc. Nat. Acad. Sci. 103: 18810-18815, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17121993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17121993</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17121993[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.0605029103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17121993">Caruso-Neves et al. (2006)</a> identified megalin as the sensor that determines whether cells will be protected or injured by albumin. Using a porcine kidney cell line, they showed that megalin bound protein kinase B (PKB; see <a href="/entry/164730">164730</a>) in a phosphoinositide 3-kinase (see <a href="/entry/601232">601232</a>)-independent manner, anchoring PKB in the luminal plasma membrane. Low doses of albumin led to activation of PKB and phosphorylation of Bad (<a href="/entry/603167">603167</a>), an antiapoptotic protein. In contrast, pathophysiologic levels of albumin reduced the interaction between PKB and megalin, resulting in reduced Bad phosphorylation and albumin-induced apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17121993" 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="#11" class="mim-tip-reference" title="Hammes, A., Andreassen, T. K., Spoelgen, R., Raila, J., Hubner, N., Schulz, H., Metzger, J., Schweigert, F. J., Luppa, P. B., Nykjaer, A., Willnow, T. E. <strong>Role of endocytosis in cellular uptake of sex steroids.</strong> Cell 122: 751-762, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16143106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16143106</a>] [<a href="https://doi.org/10.1016/j.cell.2005.06.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16143106">Hammes et al. (2005)</a> found that megalin internalized complexes of sex steroids bound to sex hormone-binding globulin (SHBG; <a href="/entry/182205">182205</a>) in cultured rat carcinoma cells. Following internalization, the carrier was degraded in lysosomes while the steroids were released to induce steroid-responsive genes. Lack of megalin expression in knockout mice impaired descent of the testes and blocked vaginal opening, processes critically dependent on sex steroid signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16143106" 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="#15" class="mim-tip-reference" title="Korenberg, J. R., Argraves, K. M., Chen, X.-N., Tran, H., Strickland, D., Argraves, W. S. <strong>Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1).</strong> Genomics 22: 88-93, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959795</a>] [<a href="https://doi.org/10.1006/geno.1994.1348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959795">Korenberg et al. (1994)</a> designed degenerate oligonucleotide primers based on conserved regions of gp330, LDLR, and LRP1 (<a href="/entry/107770">107770</a>) and used homology-PCR cloning to isolate cDNAs encoding human gp330. They then used the human gp330 cDNA as a probe in fluorescence in situ hybridization to map the gene to the border of bands 2q24-q31 (<a href="#15" class="mim-tip-reference" title="Korenberg, J. R., Argraves, K. M., Chen, X.-N., Tran, H., Strickland, D., Argraves, W. S. <strong>Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1).</strong> Genomics 22: 88-93, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959795</a>] [<a href="https://doi.org/10.1006/geno.1994.1348" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959795">Korenberg et al., 1994</a>). By isotopic in situ hybridization, <a href="#5" class="mim-tip-reference" title="Chowdhary, B. P., Lundgren, S., Johansson, M., Hjalm, G., Akerstrom, G., Gustavsson, I., Rask, L. <strong>In situ hybridization mapping of a 500-kDa calcium-sensing protein gene (LRP2) to human chromosome region 2q31-q32.1 and porcine chromosome region 15q22-q24.</strong> Cytogenet. Cell Genet. 71: 120-123, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7656578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7656578</a>] [<a href="https://doi.org/10.1159/000134088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7656578">Chowdhary et al. (1995)</a> found that LRP2 maps to 2q31-q32.1 in human and to 15q22-q24 in pig. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7656578+7959795" 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 4 affected sibs with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) from the United Arab Emirates, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified a homozygous mutation in the LRP2 gene (<a href="#0001">600073.0001</a>). <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> also identified pathogenic mutations in the LRP2 gene in affected individuals reported by <a href="#8" class="mim-tip-reference" title="Donnai, D., Barrow, M. <strong>Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder?</strong> Am. J. Med. Genet. 47: 679-682, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8266995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8266995</a>] [<a href="https://doi.org/10.1002/ajmg.1320470518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8266995">Donnai and Barrow (1993)</a> (<a href="#0004">600073.0004</a>-<a href="#0006">600073.0006</a>) and <a href="#3" class="mim-tip-reference" title="Chassaing, N., Lacombe, D., Carles, D., Calvas, P., Saura, R., Bieth, E. <strong>Donnai-Barrow syndrome: four additional patients.</strong> Am. J. Med. Genet. 121A: 258-262, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923867</a>] [<a href="https://doi.org/10.1002/ajmg.a.20266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12923867">Chassaing et al. (2003)</a> (see, e.g., <a href="#0002">600073.0002</a>-<a href="#0003">600073.0003</a>). In addition, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified mutations in the LRP2 gene (<a href="#0007">600073.0007</a>; <a href="#0008">600073.0008</a>) in a Belgian child reported by <a href="#7" class="mim-tip-reference" title="Devriendt, K., Standaert, L., Van Hole, C., Devlieger, H., Fryns, J.-P. <strong>Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity.</strong> J. Med. Genet. 35: 70-71, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475100</a>] [<a href="https://doi.org/10.1136/jmg.35.1.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9475100">Devriendt et al. (1998)</a> as having faciooculoacousticorenal syndrome (FOAR). Urine samples from affected individuals showed proteinuria with spillage of retinol-binding proteins (see RBP1, <a href="/entry/180260">180260</a>) and vitamin D-binding proteins (see DBP, <a href="/entry/139200">139200</a>). The findings confirmed that FOAR and Donnai-Barrow syndrome are the same entity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12923867+8266995+9475100+17632512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For discussion of a possible association between variation in the LRP2 gene and susceptibility to autism, see <a href="/entry/209850">209850</a>.</p>
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<p><a href="#28" class="mim-tip-reference" title="Willnow, T. E., Hilpert, J., Armstrong, S. A., Rohlmann, A., Hammer, R. E., Burns, D. K., Herz, J. <strong>Defective forebrain development in mice lacking gp330/megalin.</strong> Proc. Nat. Acad. Sci. 93: 8460-8464, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8710893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8710893</a>] [<a href="https://doi.org/10.1073/pnas.93.16.8460" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8710893">Willnow et al. (1996)</a> constructed gp330/megalin knockout mice by targeted disruption of the murine gene. Homozygous knockout mice manifested abnormalities in epithelial tissues including lung and kidney that normally express the protein. The mice died perinatally from respiratory insufficiency. In brain, impaired proliferation of neuroepithelium produced a holoprosencephalic syndrome, characterized by lack of olfactory bulbs, forebrain fusion, and a common ventricular system. Because megalin can bind lipoproteins, these investigators proposed that the receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8710893" 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>Although most megalin-deficient mice die perinatally from holoprosencephaly, approximately 1 in 50 of these mice survive to adulthood. <a href="#22" class="mim-tip-reference" title="Nykjaer, A., Dragun, D., Walther, D., Vorum, H., Jacobsen, C., Herz, J. <strong>Melsen, F.; Christensen, E. I.; Willnow, T. E.: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.</strong> Cell 96: 507-515, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10052453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10052453</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80655-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10052453">Nykjaer et al. (1999)</a> used surviving knockout animals to study the role of megalin in the renal proximal tubules. They found that complexes of 25-(OH) vitamin D3 and the 58-kD vitamin D-binding protein (DBP) are filtered through the glomerulus and reabsorbed by megalin into the proximal tubular cells. Abnormal urinary excretion of 25-(OH) vitamin D3 and DBP in megalin knockout mice resulted in severe vitamin D deficiency and bone disease. Thus, <a href="#22" class="mim-tip-reference" title="Nykjaer, A., Dragun, D., Walther, D., Vorum, H., Jacobsen, C., Herz, J. <strong>Melsen, F.; Christensen, E. I.; Willnow, T. E.: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.</strong> Cell 96: 507-515, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10052453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10052453</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80655-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10052453">Nykjaer et al. (1999)</a> identified a renal uptake pathway that is essential to preserve vitamin D metabolites and to deliver the precursor for generation of 1,25-(OH)2 vitamin D3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10052453" 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 the megalin-deficient mouse model, <a href="#26" class="mim-tip-reference" title="Schmitz, C., Hilpert, J., Jacobsen, C., Boensch, C., Christensen, E. I., Luft, F. C., Willnow, T. E. <strong>Megalin deficiency offers protection from renal aminoglycoside accumulation.</strong> J. Biol. Chem. 277: 618-622, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11700326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11700326</a>] [<a href="https://doi.org/10.1074/jbc.M109959200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11700326">Schmitz et al. (2002)</a> found that megalin is a major contributor to renal aminoglycoside accumulation and nephrotoxicity. In normal mice, they found that the aminoglycoside gentamicin accumulated only in the kidney and in urine; within the kidney, it accumulated exclusively within proximal tubular cells. Megalin-deficient mice excreted similar amounts of labeled gentamicin but exhibited no renal accumulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11700326" 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>Similarly, <a href="#17" class="mim-tip-reference" title="Leheste, J.-R., Rolinski, B., Vorum, H., Hilpert, J., Nykjaer, A., Jacobsen, C., Aucouturier, P., Moskaug, J. O., Otto, A., Christensen, E. I., Willnow, T. E. <strong>Megalin knockout mice as an animal model of low molecular weight proteinuria.</strong> Am. J. Path. 155: 1361-1370, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10514418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10514418</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10514418[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/10.1016/S0002-9440(10)65238-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10514418">Leheste et al. (1999)</a> demonstrated that megalin-deficient mice exhibit tubular resorption deficiency and excrete low molecular mass plasma proteins in the urine. Proteins excreted included small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, alpha-1-microglobulin, and odorant-binding protein. Megalin normally binds these proteins and mediates their cellular uptake. Urinary loss of carrier proteins resulted in concomitant loss of lipophilic vitamins bound to the carriers. <a href="#17" class="mim-tip-reference" title="Leheste, J.-R., Rolinski, B., Vorum, H., Hilpert, J., Nykjaer, A., Jacobsen, C., Aucouturier, P., Moskaug, J. O., Otto, A., Christensen, E. I., Willnow, T. E. <strong>Megalin knockout mice as an animal model of low molecular weight proteinuria.</strong> Am. J. Path. 155: 1361-1370, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10514418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10514418</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10514418[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/10.1016/S0002-9440(10)65238-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10514418">Leheste et al. (1999)</a> showed that patients with Fanconi syndrome, who have low molecular mass proteinuria, also excrete vitamin/carrier complexes. Thus, these results identified a crucial role of the proximal tubule in retrieval of filtered vitamin/carrier complexes and the central role played by megalin in this process. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10514418" 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="#27" class="mim-tip-reference" title="Tramontano, A., Makker, S. P. <strong>Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis.</strong> J. Immun. 172: 2367-2373, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764706</a>] [<a href="https://doi.org/10.4049/jimmunol.172.4.2367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764706">Tramontano and Makker (2004)</a> showed that rats immunized with a soluble, secreted 563-amino acid N-terminal sequence of megalin encoded by a baculovirus construct elicited a response consistent with active Heymann nephritis (AHN). In contrast, bacterial or nonsecreted insect cell proteins induced a milder antimegalin response and no disease. All 3 recombinant proteins were detectable in Western blot analysis using rabbit antimegalin antiserum, although the insect proteins reacted preferentially with autoantibodies from rats with AHN induced by native megalin. Lectin blot analysis detected only the secreted protein, suggesting that it is glycosylated. <a href="#27" class="mim-tip-reference" title="Tramontano, A., Makker, S. P. <strong>Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis.</strong> J. Immun. 172: 2367-2373, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764706</a>] [<a href="https://doi.org/10.4049/jimmunol.172.4.2367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14764706">Tramontano and Makker (2004)</a> proposed that the megalin N-terminal domain contains epitopes sufficient for a pathogenic autoimmune response and that conformational B-cell epitopes, as well as glycosidic posttranslational modifications, are involved in nephritogenicity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764706" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Naccache, S. N., Hasson, T., Horowitz, A. <strong>Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles.</strong> Proc. Nat. Acad. Sci. 103: 12735-12740, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 15272 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16908842[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.0605317103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908842">Naccache et al. (2006)</a> found that synectin (GIPC1; <a href="/entry/605072">605072</a>)-null mice, like megalin-null mice, showed proteinuria. Urine from synectin-null mice contained retinol-binding protein (see RBP1; <a href="/entry/180260">180260</a>), a known megalin ligand. Megalin expression in proximal tubules of synectin-null mouse kidneys was normal compared to wildtype, suggesting that megalin recycling is defective in synectin-null mice. <a href="#20" class="mim-tip-reference" title="Naccache, S. N., Hasson, T., Horowitz, A. <strong>Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles.</strong> Proc. Nat. Acad. Sci. 103: 12735-12740, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 15272 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16908842[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.0605317103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16908842">Naccache et al. (2006)</a> concluded that synectin is required for proper megalin trafficking in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16908842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600073[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338747 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338747;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=rs80338747" 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=rs80338747" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 affected sibs with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>), <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified a homozygous 7564T-C transition in exon 41 of the LRP2 gene, resulting in a tyr2522-to-his (Y2522H) substitution in a highly conserved residue within the LDL-receptor class B domain. The sibs were born of consanguineous parents from the United Arab Emirates and showed characteristic clinical features, including large anterior fontanel, sensorineural deafness, diaphragmatic eventration, absence of the corpus callosum, and proteinuria. The mutation was not identified in 96 ethnically matched controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17632512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 affected sibs of a French family with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally described by <a href="#3" class="mim-tip-reference" title="Chassaing, N., Lacombe, D., Carles, D., Calvas, P., Saura, R., Bieth, E. <strong>Donnai-Barrow syndrome: four additional patients.</strong> Am. J. Med. Genet. 121A: 258-262, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923867</a>] [<a href="https://doi.org/10.1002/ajmg.a.20266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12923867">Chassaing et al. (2003)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified compound heterozygosity for 2 mutations in the LRP2 gene: a 2-bp deletion (9484delGT) in exon 50, resulting in a frameshift and premature termination, and a transition in intron 18 (<a href="#0003">600073.0003</a>). Both patients had brain malformations and 1 had congenital diaphragmatic hernia. Neither mutation was identified in 96 ethnically matched controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12923867+17632512" 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">rs587776717 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776717;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=rs587776717" 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=rs587776717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338746 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338746;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=rs80338746" 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=rs80338746" 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 of a French family with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally described by <a href="#3" class="mim-tip-reference" title="Chassaing, N., Lacombe, D., Carles, D., Calvas, P., Saura, R., Bieth, E. <strong>Donnai-Barrow syndrome: four additional patients.</strong> Am. J. Med. Genet. 121A: 258-262, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923867</a>] [<a href="https://doi.org/10.1002/ajmg.a.20266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12923867">Chassaing et al. (2003)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified compound heterozygosity for 2 mutations in the LRP2 gene: a G-to-A transition in intron 18 (IVS18-1G-A) and a 2-bp deletion (<a href="#0002">600073.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12923867+17632512" 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">rs80338749 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338749;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=rs80338749" 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=rs80338749" 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=RCV000010061" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010061" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010061</a>
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<p>In a girl with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally reported by <a href="#8" class="mim-tip-reference" title="Donnai, D., Barrow, M. <strong>Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder?</strong> Am. J. Med. Genet. 47: 679-682, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8266995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8266995</a>] [<a href="https://doi.org/10.1002/ajmg.1320470518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8266995">Donnai and Barrow (1993)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified a homozygous 4-bp deletion (8516delTTTA) in exon 45 of the LRP2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8266995+17632512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 DONNAI-BARROW SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80338748 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338748;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=rs80338748" 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=rs80338748" 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=RCV000010062 OR RCV003555994" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010062, RCV003555994" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010062...</a>
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<p>In 3 affected sibs from a family with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally reported by <a href="#8" class="mim-tip-reference" title="Donnai, D., Barrow, M. <strong>Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder?</strong> Am. J. Med. Genet. 47: 679-682, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8266995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8266995</a>] [<a href="https://doi.org/10.1002/ajmg.1320470518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8266995">Donnai and Barrow (1993)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified compound heterozygosity for 2 mutations in the LRP2 gene: a G-to-A transition in intron 44 and R3399X (<a href="#0006">600073.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8266995+17632512" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 DONNAI-BARROW SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs80338752 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338752;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/rs80338752?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=rs80338752" 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=rs80338752" 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=RCV000010063 OR RCV003555995" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010063, RCV003555995" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010063...</a>
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<p>In 3 affected sibs from a family with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally reported by <a href="#8" class="mim-tip-reference" title="Donnai, D., Barrow, M. <strong>Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder?</strong> Am. J. Med. Genet. 47: 679-682, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8266995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8266995</a>] [<a href="https://doi.org/10.1002/ajmg.1320470518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8266995">Donnai and Barrow (1993)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified compound heterozygosity for 2 mutations in the LRP2 gene: a 10195C-T transition in exon 53, resulting in an arg3399-to-ter (R3399X) substitution, and a splice site mutation in intron 44 (<a href="#0005">600073.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8266995+17632512" 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">rs80338745 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338745;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=rs80338745" 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=rs80338745" 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=RCV000010064" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000010064" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000010064</a>
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<p>In a child with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally reported by <a href="#7" class="mim-tip-reference" title="Devriendt, K., Standaert, L., Van Hole, C., Devlieger, H., Fryns, J.-P. <strong>Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity.</strong> J. Med. Genet. 35: 70-71, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475100</a>] [<a href="https://doi.org/10.1136/jmg.35.1.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9475100">Devriendt et al. (1998)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified compound heterozygosity for 2 mutations in the LRP2 gene: a T-to-G transversion in exon 11 and R365X (<a href="#0008">600073.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9475100+17632512" 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">rs80338744 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338744;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=rs80338744" 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=rs80338744" 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 child with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) originally reported by <a href="#7" class="mim-tip-reference" title="Devriendt, K., Standaert, L., Van Hole, C., Devlieger, H., Fryns, J.-P. <strong>Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity.</strong> J. Med. Genet. 35: 70-71, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9475100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9475100</a>] [<a href="https://doi.org/10.1136/jmg.35.1.70" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9475100">Devriendt et al. (1998)</a>, <a href="#13" class="mim-tip-reference" title="Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R. <strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong> Nature Genet. 39: 957-959, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17632512/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17632512</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17632512[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/ng2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17632512">Kantarci et al. (2007)</a> identified compound heterozygosity for 2 mutations in the LRP2 gene: a 1093C-T transition in exon 10 resulting in an arg365-to-ter (R365X) substitution, and a splice site mutation in intron 11 (<a href="#0007">600073.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9475100+17632512" 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">rs786205122 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786205122;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=rs786205122" 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=rs786205122" 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 36-year-old man studied as part of a cohort of individuals with intellectual disability, <a href="#6" class="mim-tip-reference" title="de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. <strong>Diagnostic exome sequencing in persons with severe intellectual disability.</strong> New Eng. J. Med. 367: 1921-1929, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23033978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23033978</a>] [<a href="https://doi.org/10.1056/NEJMoa1206524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23033978">de Ligt et al. (2012)</a> identified a heterozygous de novo mutation in the LRP2 gene, a 1-bp deletion at position 12437, resulting in a frameshift (Gly4146GlufsTer2). The patient had had seizures from the first day of life and showed developmental delay. As an adult, he was slender but of normal stature and head circumference. Facial dysmorphism included hypertelorism, mild scaphocephaly, deeply set eyes, prominent cheek bones, over-folded helices with bilateral ear tags, broad nasal bridge, and large mouth with downturned corners and a full lower lip; he also had poor vision. The man was diagnosed with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) after an additional mutation was detected in the LRP2 gene: a rare, paternally inherited 6160G-A transition, resulting in an asp2054-to-asn (D2054N) substitution (<a href="#0010">600073.0010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23033978" 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> rs138269726 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs138269726;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/rs138269726?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=rs138269726" 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=rs138269726" 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=RCV000033108 OR RCV001362989" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000033108, RCV001362989" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000033108...</a>
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<p>For discussion of the asp205-to-asn (D205N) mutation in the LRP2 gene that was found in compound heterozygous state in a patient with Donnai-Barrow syndrome (DBS; <a href="/entry/222448">222448</a>) by <a href="#6" class="mim-tip-reference" title="de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. <strong>Diagnostic exome sequencing in persons with severe intellectual disability.</strong> New Eng. J. Med. 367: 1921-1929, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23033978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23033978</a>] [<a href="https://doi.org/10.1056/NEJMoa1206524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23033978">de Ligt et al. (2012)</a>, see <a href="#0009">600073.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23033978" 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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Buc-Caron, M. H., Condamine, H., Kerjaschki, D.
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<strong>Rat Heymann nephritis antigen is closely related to brushin, a glycoprotein present in early mouse embryo epithelia.</strong>
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Ann. Inst. Pasteur Immun. 138: 707-722, 1987.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2449897/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2449897</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2449897" 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/s0769-2625(87)80026-0" target="_blank">Full Text</a>]
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Caruso-Neves, C., Pinheiro, A. A. S., Cai, H., Souza-Menezes, J., Guggino, W. B.
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<strong>PKB and megalin determine the survival or death of renal proximal tubule cells.</strong>
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Proc. Nat. Acad. Sci. 103: 18810-18815, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17121993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17121993</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17121993[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=17121993" 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.0605029103" target="_blank">Full Text</a>]
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Chassaing, N., Lacombe, D., Carles, D., Calvas, P., Saura, R., Bieth, E.
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<strong>Donnai-Barrow syndrome: four additional patients.</strong>
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Am. J. Med. Genet. 121A: 258-262, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12923867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12923867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12923867" 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/10.1002/ajmg.a.20266" target="_blank">Full Text</a>]
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Chatelet, F., Brianti, E., Ronco, P., Roland, J., Verroust, P.
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<strong>Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli: II. Extrarenal distribution.</strong>
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[<a href="https://doi.org/10.1681/ASN.V6135" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16908842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16908842</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16908842[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=16908842" 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.0605317103" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Nagai2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Nagai, M., Meerloo, T., Takeda, T., Farquhar, M. G.
|
|
<strong>The adaptor protein ARH escorts megalin to and through endosomes.</strong>
|
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Molec. Biol. Cell 14: 4984-4996, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14528014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14528014</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14528014[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=14528014" 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/10.1091/mbc.e03-06-0385" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Nykjaer1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Nykjaer, A., Dragun, D., Walther, D., Vorum, H., Jacobsen, C., Herz, J.
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|
<strong>Melsen, F.; Christensen, E. I.; Willnow, T. E.: An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.</strong>
|
|
Cell 96: 507-515, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10052453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10052453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10052453" 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/s0092-8674(00)80655-8" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Nykjaer2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nykjaer, A., Fyfe, J. C., Kozyraki, R., Leheste, J.-R., Jacobsen, C., Nielsen, M. S., Verroust, P. J., Aminoff, M., de la Chapelle, A., Moestrup, S. K., Ray, R., Gliemann, J., Willnow, T. E., Christensen, E. I.
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<strong>Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D3.</strong>
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Proc. Nat. Acad. Sci. 98: 13895-13900, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11717447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11717447</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11717447[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=11717447" 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.241516998" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Raychowdhury1989" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Raychowdhury, R., Niles, J. L., McCluskey, R. T., Smith, J. A.
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<strong>Autoimmune target in Heymann nephritis is a glycoprotein with homology to the LDL receptor.</strong>
|
|
Science 244: 1163-1165, 1989.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2786251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2786251</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2786251" 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/10.1126/science.2786251" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Saito1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saito, A., Pietromonaco, S., Loo, A. K.-C., Farquhar, M. G.
|
|
<strong>Complete cloning and sequencing of rat gp330/`megalin,' a distinctive member of the low density lipoprotein receptor gene family.</strong>
|
|
Proc. Nat. Acad. Sci. 91: 9725-9729, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7937880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7937880</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7937880" 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.91.21.9725" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Schmitz2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schmitz, C., Hilpert, J., Jacobsen, C., Boensch, C., Christensen, E. I., Luft, F. C., Willnow, T. E.
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<strong>Megalin deficiency offers protection from renal aminoglycoside accumulation.</strong>
|
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J. Biol. Chem. 277: 618-622, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11700326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11700326</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11700326" 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.M109959200" target="_blank">Full Text</a>]
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Tramontano2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tramontano, A., Makker, S. P.
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<strong>Conformation and glycosylation of a megalin fragment correlate with nephritogenicity in Heymann nephritis.</strong>
|
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J. Immun. 172: 2367-2373, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14764706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14764706</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14764706" 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/10.4049/jimmunol.172.4.2367" target="_blank">Full Text</a>]
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<li>
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<a id="28" class="mim-anchor"></a>
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<a id="Willnow1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Willnow, T. E., Hilpert, J., Armstrong, S. A., Rohlmann, A., Hammer, R. E., Burns, D. K., Herz, J.
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<strong>Defective forebrain development in mice lacking gp330/megalin.</strong>
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Proc. Nat. Acad. Sci. 93: 8460-8464, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8710893/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8710893</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8710893" 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.93.16.8460" target="_blank">Full Text</a>]
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</p>
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</ol>
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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="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
|
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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 : 2/13/2013
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 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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Patricia A. Hartz - updated : 1/14/2008<br>Cassandra L. Kniffin - updated : 8/20/2007<br>Patricia A. Hartz - updated : 5/3/2007<br>Patricia A. Hartz - updated : 12/5/2006<br>Patricia A. Hartz - updated : 10/10/2006<br>Paul J. Converse - updated : 8/17/2004<br>Patricia A. Hartz - updated : 5/28/2002<br>John A. Phillips, III - updated : 3/3/2000<br>Victor A. McKusick - updated : 1/19/2000<br>Stylianos E. Antonarakis - updated : 3/8/1999<br>Stylianos E. Antonarakis - updated : 5/2/1998<br>Alan F. Scott - updated : 9/17/1995
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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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Victor A. McKusick : 8/4/1994
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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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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alopez : 11/15/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 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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carol : 11/14/2023<br>carol : 07/08/2019<br>alopez : 07/01/2019<br>alopez : 12/19/2018<br>ckniffin : 12/07/2018<br>alopez : 09/23/2016<br>alopez : 04/27/2015<br>mcolton : 4/21/2015<br>carol : 9/10/2013<br>carol : 2/13/2013<br>alopez : 8/29/2012<br>terry : 8/28/2012<br>terry : 8/9/2012<br>alopez : 3/8/2012<br>alopez : 4/22/2010<br>wwang : 5/7/2009<br>mgross : 1/15/2008<br>mgross : 1/15/2008<br>terry : 1/14/2008<br>carol : 8/21/2007<br>ckniffin : 8/21/2007<br>ckniffin : 8/20/2007<br>mgross : 5/3/2007<br>mgross : 5/3/2007<br>mgross : 12/5/2006<br>wwang : 12/1/2006<br>wwang : 10/11/2006<br>terry : 10/10/2006<br>mgross : 8/18/2004<br>mgross : 8/18/2004<br>terry : 8/17/2004<br>ckniffin : 6/5/2002<br>carol : 5/30/2002<br>carol : 5/30/2002<br>terry : 5/28/2002<br>mgross : 3/3/2000<br>mcapotos : 1/27/2000<br>mcapotos : 1/19/2000<br>mcapotos : 1/19/2000<br>terry : 1/19/2000<br>carol : 3/8/1999<br>carol : 3/8/1999<br>psherman : 10/14/1998<br>dholmes : 5/12/1998<br>joanna : 5/8/1998<br>carol : 5/2/1998<br>mark : 12/6/1995<br>mark : 11/13/1995<br>mark : 9/17/1995<br>terry : 8/23/1994<br>terry : 8/22/1994<br>terry : 8/4/1994
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</span>
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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 class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600073
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 2; LRP2
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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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<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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
GLYCOPROTEIN 330<br />
|
|
MEGALIN
|
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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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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: LRP2</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 702418009;
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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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<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: 2q31.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:169,127,109-169,362,534 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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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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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
2q31.1
|
|
</span>
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</td>
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<td>
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<span class="mim-font">
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Donnai-Barrow syndrome
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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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222448
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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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Autosomal recessive
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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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3
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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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<br />
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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>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Lipoprotein receptor-related protein-2 (LRP2), also called glycoprotein-330 or megalin (Farquhar, 1995), is part of the Heymann nephritis antigenic complex with RAP (LRPAP1; 104225) (Farquhar et al., 1995) and is a member of a family of receptors with structural similarities to the low density lipoprotein receptor (LDLR; 606945). </p>
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</span>
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<div>
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<br />
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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>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>LRP2 was originally identified as the target antigen of Heymann nephritis, a rat model of membranous glomerulonephritis. Its location in clathrin-coated pits suggested that gp330 is an endocytic receptor. Gp330 is expressed in specialized epithelia, including those of the inner ear (Farquhar et al., 1995), neural tube, lung airway, epididymis, yolk sac, glomeruli, and proximal renal tubules (Kerjaschki and Farquhar, 1983; Chatelet et al., 1986; Buc-Caron et al., 1987). Raychowdhury et al. (1989) sequenced a partial cDNA clone which clearly established that gp330 is a member of the LDL receptor gene family. </p><p>Saito et al. (1994) reported the complete amino acid sequence of the 517,715-Da megalin protein. Hjalm et al. (1996) determined the nucleotide sequence of human gp330. They reported that the deduced 4,655-amino acid mature protein has a molecular mass of approximately 519,636 Da and consists of a probable 25-amino acid N-terminal signal peptide, an extracellular region of 4,398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acids. Three types of cysteine-rich repeats characteristic of the LDLR superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising 4 distinct domains, 16 growth factor repeats separated by 8 YWTD spacer regions, and 1 epidermal growth factor-like repeat. Hjalm et al. (1996) detected no consensus cleavage sequence for the processing endoprotease furin. The intracellular tail contains 2 copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, as well as potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II, and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330, with minor differences between the extra- and intracellular regions. </p>
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</span>
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<div>
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<br />
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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>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In kidney tubule epithelial cells, gp330 has been shown to bind in vitro to lipoprotein lipase and apolipoprotein E-enriched beta-VLDL, suggesting a role for this receptor in lipoprotein metabolism. Kounnas et al. (1995) showed that gp330 can bind apolipoprotein J/clusterin (CLU; 185430) with high affinity. Cells that express gp330 can mediate APOJ endocytosis, leading to its lysosomal degradation. </p><p>Moestrup et al. (1995) demonstrated that the antifibrinolytic polypeptide, aprotinin, and the nephro- and ototoxic antibiotics, aminoglycosides and polymyxin B, compete for binding of radioiodinated urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330. (Aprotinin, also known as bovine pancreatic trypsin inhibitor, is a 6-kD protein used clinically in acute pancreatitis and antifibrinolytic therapy. Intravenously administered aprotinin accumulates in the lysosomes of kidney proximal tubules and is only very slowly degraded.) Analyses of mutant aprotinins expressed in Saccharomyces cerevisiae demonstrated that basic residues are essential for the binding to gp330 and renal uptake. The polybasic drugs also antagonized ligand binding to the human alpha-2-macroglobulin receptor (107770). However, the rapid glomerular filtration of the drugs suggested kidney gp330 to be the quantitatively most important target. Thus, a novel role of gp330 as a drug receptor was demonstrated. Moestrup et al. (1995) stated that the insight into the mechanism of epithelial uptake of polybasic drugs might provide a basis for design of drugs with reduced toxicity. Farquhar (1995) reviewed briefly the literature on LRP2/gp330/megalin in light of these new findings. </p><p>Megalin, a member of the low density lipoprotein receptor family abundant in kidney proximal tubules, mediates endocytic uptake of complexes between the steroid 25(OH) vitamin D3 and vitamin D-binding protein (DBP; 139200) filtered in the glomeruli. The receptor-mediated uptake is required to prevent loss of 25(OH)D3 in the urine and to deliver the precursor for generation of 1,25(OH)2 vitamin D3, a potent regulator of calcium homeostasis and bone turnover. Nykjaer et al. (1999) showed that accordingly, megalin knockout mice lose DBP and 25(OH)D3 in the urine and develop severe vitamin D deficiency and bone disease. Megalin binds a large number of structurally unrelated ligands, and coreceptors may confer ligand specificity by sequestering and presenting their cargo to megalin. For example, the gastric intrinsic factor (IF; 609342)-B12 complex is taken up in the intestine by a tandem receptor-mediated mechanism: the complex is first bound to a receptor, cubilin (602997), anchored to the outer leaflet of the plasma membrane possibly by an amphipathic helix, followed by endocytosis of cubilin and its cargo mediated by megalin (summary by Nykjaer et al., 2001). </p><p>Marino et al. (1999) searched for antimegalin antibodies in 78 patients with autoimmune and nonautoimmune thyroid diseases. Significantly elevated values were found in 18 patients, including 13 of 26 (50%) patients with autoimmune thyroiditis and 2 of 19 (11%) patients with Graves disease (275000). Furthermore, 2 of 19 (11%) patients with nontoxic goiter and 1 of 14 (7%) patients with differentiated thyroid cancer had mean fluorescence intensity (MFI) values greater than 50.62, associated with the presence of circulating antithyroid autoantibodies. Binding of serum IgGs to L2 cells was significantly reduced by coincubation with purified megalin in 15 of 18 (83%) positive patients, and by a rabbit antimegalin antibody in 11 (61%) patients. Immunoprecipitation experiments provided further and more conclusive evidence that positive tests (MFI less than 50.62) for binding to L2 cells were attributable to serum antimegalin antibodies. The authors suggested that further studies are needed to determine whether antimegalin antibodies have pathogenic significance or diagnostic value in autoimmune thyroid diseases. </p><p>Using yeast 2-hybrid, pull-down, and coimmunoprecipitation assays, Nagai et al. (2003) found that rat Arh (LDLRAP1; 605747) bound the first FxNPxY motif of megalin. Arh colocalized with megalin in clathrin-coated pits and in recycling endosomes in the Golgi region of rat L2 cells. Upon internalization of megalin, megalin and Arh colocalized in clathrin-coated pits, followed by their colocalization in early endosomes and tubular recycling endosomes in the pericentriolar region, and then by their reappearance at the cell surface. Expression of Arh in canine kidney cells expressing megalin minireceptors enhanced megalin-mediated uptake of lactoferrin (LTF; 150210), a megalin ligand. Nagai et al. (2003) concluded that ARH facilitates endocytosis of megalin and escorts megalin along its endocytic route. </p><p>Albumin (ALB; 103600) does not readily cross the renal glomerular filter, and the fraction that does is reabsorbed by proximal tubule cells via clathrin- and receptor-mediated endocytosis. Overstressing this endocytic system with prolonged excess of albumin, which is often associated with kidney disease, is injurious to proximal tubule cells and leads to albumin-induced apoptosis. Caruso-Neves et al. (2006) identified megalin as the sensor that determines whether cells will be protected or injured by albumin. Using a porcine kidney cell line, they showed that megalin bound protein kinase B (PKB; see 164730) in a phosphoinositide 3-kinase (see 601232)-independent manner, anchoring PKB in the luminal plasma membrane. Low doses of albumin led to activation of PKB and phosphorylation of Bad (603167), an antiapoptotic protein. In contrast, pathophysiologic levels of albumin reduced the interaction between PKB and megalin, resulting in reduced Bad phosphorylation and albumin-induced apoptosis. </p><p>Hammes et al. (2005) found that megalin internalized complexes of sex steroids bound to sex hormone-binding globulin (SHBG; 182205) in cultured rat carcinoma cells. Following internalization, the carrier was degraded in lysosomes while the steroids were released to induce steroid-responsive genes. Lack of megalin expression in knockout mice impaired descent of the testes and blocked vaginal opening, processes critically dependent on sex steroid signaling. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Korenberg et al. (1994) designed degenerate oligonucleotide primers based on conserved regions of gp330, LDLR, and LRP1 (107770) and used homology-PCR cloning to isolate cDNAs encoding human gp330. They then used the human gp330 cDNA as a probe in fluorescence in situ hybridization to map the gene to the border of bands 2q24-q31 (Korenberg et al., 1994). By isotopic in situ hybridization, Chowdhary et al. (1995) found that LRP2 maps to 2q31-q32.1 in human and to 15q22-q24 in pig. </p>
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</span>
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<div>
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<br />
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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>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 4 affected sibs with Donnai-Barrow syndrome (DBS; 222448) from the United Arab Emirates, Kantarci et al. (2007) identified a homozygous mutation in the LRP2 gene (600073.0001). Kantarci et al. (2007) also identified pathogenic mutations in the LRP2 gene in affected individuals reported by Donnai and Barrow (1993) (600073.0004-600073.0006) and Chassaing et al. (2003) (see, e.g., 600073.0002-600073.0003). In addition, Kantarci et al. (2007) identified mutations in the LRP2 gene (600073.0007; 600073.0008) in a Belgian child reported by Devriendt et al. (1998) as having faciooculoacousticorenal syndrome (FOAR). Urine samples from affected individuals showed proteinuria with spillage of retinol-binding proteins (see RBP1, 180260) and vitamin D-binding proteins (see DBP, 139200). The findings confirmed that FOAR and Donnai-Barrow syndrome are the same entity. </p><p>For discussion of a possible association between variation in the LRP2 gene and susceptibility to autism, see 209850.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Willnow et al. (1996) constructed gp330/megalin knockout mice by targeted disruption of the murine gene. Homozygous knockout mice manifested abnormalities in epithelial tissues including lung and kidney that normally express the protein. The mice died perinatally from respiratory insufficiency. In brain, impaired proliferation of neuroepithelium produced a holoprosencephalic syndrome, characterized by lack of olfactory bulbs, forebrain fusion, and a common ventricular system. Because megalin can bind lipoproteins, these investigators proposed that the receptor is part of the maternal-fetal lipoprotein transport system and mediates the endocytic uptake of essential nutrients in the postgastrulation stage. </p><p>Although most megalin-deficient mice die perinatally from holoprosencephaly, approximately 1 in 50 of these mice survive to adulthood. Nykjaer et al. (1999) used surviving knockout animals to study the role of megalin in the renal proximal tubules. They found that complexes of 25-(OH) vitamin D3 and the 58-kD vitamin D-binding protein (DBP) are filtered through the glomerulus and reabsorbed by megalin into the proximal tubular cells. Abnormal urinary excretion of 25-(OH) vitamin D3 and DBP in megalin knockout mice resulted in severe vitamin D deficiency and bone disease. Thus, Nykjaer et al. (1999) identified a renal uptake pathway that is essential to preserve vitamin D metabolites and to deliver the precursor for generation of 1,25-(OH)2 vitamin D3. </p><p>Using the megalin-deficient mouse model, Schmitz et al. (2002) found that megalin is a major contributor to renal aminoglycoside accumulation and nephrotoxicity. In normal mice, they found that the aminoglycoside gentamicin accumulated only in the kidney and in urine; within the kidney, it accumulated exclusively within proximal tubular cells. Megalin-deficient mice excreted similar amounts of labeled gentamicin but exhibited no renal accumulation. </p><p>Similarly, Leheste et al. (1999) demonstrated that megalin-deficient mice exhibit tubular resorption deficiency and excrete low molecular mass plasma proteins in the urine. Proteins excreted included small plasma proteins that carry lipophilic compounds including vitamin D-binding protein, retinol-binding protein, alpha-1-microglobulin, and odorant-binding protein. Megalin normally binds these proteins and mediates their cellular uptake. Urinary loss of carrier proteins resulted in concomitant loss of lipophilic vitamins bound to the carriers. Leheste et al. (1999) showed that patients with Fanconi syndrome, who have low molecular mass proteinuria, also excrete vitamin/carrier complexes. Thus, these results identified a crucial role of the proximal tubule in retrieval of filtered vitamin/carrier complexes and the central role played by megalin in this process. </p><p>Tramontano and Makker (2004) showed that rats immunized with a soluble, secreted 563-amino acid N-terminal sequence of megalin encoded by a baculovirus construct elicited a response consistent with active Heymann nephritis (AHN). In contrast, bacterial or nonsecreted insect cell proteins induced a milder antimegalin response and no disease. All 3 recombinant proteins were detectable in Western blot analysis using rabbit antimegalin antiserum, although the insect proteins reacted preferentially with autoantibodies from rats with AHN induced by native megalin. Lectin blot analysis detected only the secreted protein, suggesting that it is glycosylated. Tramontano and Makker (2004) proposed that the megalin N-terminal domain contains epitopes sufficient for a pathogenic autoimmune response and that conformational B-cell epitopes, as well as glycosidic posttranslational modifications, are involved in nephritogenicity. </p><p>Naccache et al. (2006) found that synectin (GIPC1; 605072)-null mice, like megalin-null mice, showed proteinuria. Urine from synectin-null mice contained retinol-binding protein (see RBP1; 180260), a known megalin ligand. Megalin expression in proximal tubules of synectin-null mouse kidneys was normal compared to wildtype, suggesting that megalin recycling is defective in synectin-null mice. Naccache et al. (2006) concluded that synectin is required for proper megalin trafficking in vivo. </p>
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</span>
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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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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0001 DONNAI-BARROW SYNDROME</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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LRP2, TYR2522HIS
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<br />
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SNP: rs80338747,
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ClinVar: RCV000010058, RCV000412752
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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 4 affected sibs with Donnai-Barrow syndrome (DBS; 222448), Kantarci et al. (2007) identified a homozygous 7564T-C transition in exon 41 of the LRP2 gene, resulting in a tyr2522-to-his (Y2522H) substitution in a highly conserved residue within the LDL-receptor class B domain. The sibs were born of consanguineous parents from the United Arab Emirates and showed characteristic clinical features, including large anterior fontanel, sensorineural deafness, diaphragmatic eventration, absence of the corpus callosum, and proteinuria. The mutation was not identified in 96 ethnically matched 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>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 DONNAI-BARROW SYNDROME</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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LRP2, 2-BP DEL, 9484GT
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<br />
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SNP: rs80338751,
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ClinVar: RCV000010059
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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 2 affected sibs of a French family with Donnai-Barrow syndrome (DBS; 222448) originally described by Chassaing et al. (2003), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a 2-bp deletion (9484delGT) in exon 50, resulting in a frameshift and premature termination, and a transition in intron 18 (600073.0003). Both patients had brain malformations and 1 had congenital diaphragmatic hernia. Neither mutation was identified in 96 ethnically matched 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>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0003 DONNAI-BARROW SYNDROME</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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LRP2, IVS18AS, G-A, -1
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<br />
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SNP: rs587776717, rs80338746,
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ClinVar: RCV000010060
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 affected sibs of a French family with Donnai-Barrow syndrome (DBS; 222448) originally described by Chassaing et al. (2003), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a G-to-A transition in intron 18 (IVS18-1G-A) and a 2-bp deletion (600073.0002). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0004 DONNAI-BARROW SYNDROME</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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LRP2, 4-BP DEL, 8516TTTA
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<br />
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SNP: rs80338749,
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ClinVar: RCV000010061
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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 girl with Donnai-Barrow syndrome (DBS; 222448) originally reported by Donnai and Barrow (1993), Kantarci et al. (2007) identified a homozygous 4-bp deletion (8516delTTTA) in exon 45 of the LRP2 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0005 DONNAI-BARROW SYNDROME</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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LRP2, IVS44DS, G-A, +1
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<br />
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SNP: rs80338748,
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ClinVar: RCV000010062, RCV003555994
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected sibs from a family with Donnai-Barrow syndrome (DBS; 222448) originally reported by Donnai and Barrow (1993), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a G-to-A transition in intron 44 and R3399X (600073.0006). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 DONNAI-BARROW SYNDROME</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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LRP2, ARG3399TER
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<br />
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SNP: rs80338752,
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gnomAD: rs80338752,
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ClinVar: RCV000010063, RCV003555995
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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 3 affected sibs from a family with Donnai-Barrow syndrome (DBS; 222448) originally reported by Donnai and Barrow (1993), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a 10195C-T transition in exon 53, resulting in an arg3399-to-ter (R3399X) substitution, and a splice site mutation in intron 44 (600073.0005). </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>.0007 DONNAI-BARROW SYNDROME</strong>
|
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</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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LRP2, IVS11DS, T-G, +2
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<br />
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SNP: rs80338745,
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ClinVar: RCV000010064
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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 child with Donnai-Barrow syndrome (DBS; 222448) originally reported by Devriendt et al. (1998), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a T-to-G transversion in exon 11 and R365X (600073.0008). </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>.0008 DONNAI-BARROW SYNDROME</strong>
|
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</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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LRP2, ARG365TER
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<br />
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SNP: rs80338744,
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ClinVar: RCV000010065, RCV002298439
|
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|
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|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a child with Donnai-Barrow syndrome (DBS; 222448) originally reported by Devriendt et al. (1998), Kantarci et al. (2007) identified compound heterozygosity for 2 mutations in the LRP2 gene: a 1093C-T transition in exon 10 resulting in an arg365-to-ter (R365X) substitution, and a splice site mutation in intron 11 (600073.0007). </p>
|
|
</span>
|
|
</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>.0009 DONNAI-BARROW SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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LRP2, 1-BP DEL, NT12437
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<br />
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|
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SNP: rs786205122,
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|
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ClinVar: RCV000033107
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|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 36-year-old man studied as part of a cohort of individuals with intellectual disability, de Ligt et al. (2012) identified a heterozygous de novo mutation in the LRP2 gene, a 1-bp deletion at position 12437, resulting in a frameshift (Gly4146GlufsTer2). The patient had had seizures from the first day of life and showed developmental delay. As an adult, he was slender but of normal stature and head circumference. Facial dysmorphism included hypertelorism, mild scaphocephaly, deeply set eyes, prominent cheek bones, over-folded helices with bilateral ear tags, broad nasal bridge, and large mouth with downturned corners and a full lower lip; he also had poor vision. The man was diagnosed with Donnai-Barrow syndrome (DBS; 222448) after an additional mutation was detected in the LRP2 gene: a rare, paternally inherited 6160G-A transition, resulting in an asp2054-to-asn (D2054N) substitution (600073.0010). </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>.0010 DONNAI-BARROW SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
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<span class="mim-text-font">
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LRP2, ASP2054ASN
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<br />
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|
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SNP: rs138269726,
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|
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|
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gnomAD: rs138269726,
|
|
|
|
|
|
ClinVar: RCV000033108, RCV001362989
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the asp205-to-asn (D205N) mutation in the LRP2 gene that was found in compound heterozygous state in a patient with Donnai-Barrow syndrome (DBS; 222448) by de Ligt et al. (2012), see 600073.0009. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
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Buc-Caron, M. H., Condamine, H., Kerjaschki, D.
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<strong>Rat Heymann nephritis antigen is closely related to brushin, a glycoprotein present in early mouse embryo epithelia.</strong>
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Ann. Inst. Pasteur Immun. 138: 707-722, 1987.
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[PubMed: 2449897]
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Caruso-Neves, C., Pinheiro, A. A. S., Cai, H., Souza-Menezes, J., Guggino, W. B.
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<strong>PKB and megalin determine the survival or death of renal proximal tubule cells.</strong>
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Chassaing, N., Lacombe, D., Carles, D., Calvas, P., Saura, R., Bieth, E.
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Chatelet, F., Brianti, E., Ronco, P., Roland, J., Verroust, P.
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<strong>Ultrastructural localization by monoclonal antibodies of brush border antigens expressed by glomeruli: II. Extrarenal distribution.</strong>
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Am. J. Path. 122: 512-519, 1986.
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Chowdhary, B. P., Lundgren, S., Johansson, M., Hjalm, G., Akerstrom, G., Gustavsson, I., Rask, L.
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<strong>In situ hybridization mapping of a 500-kDa calcium-sensing protein gene (LRP2) to human chromosome region 2q31-q32.1 and porcine chromosome region 15q22-q24.</strong>
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Cytogenet. Cell Genet. 71: 120-123, 1995.
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de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M.
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<strong>Diagnostic exome sequencing in persons with severe intellectual disability.</strong>
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New Eng. J. Med. 367: 1921-1929, 2012.
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[PubMed: 23033978]
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[Full Text: https://doi.org/10.1056/NEJMoa1206524]
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Devriendt, K., Standaert, L., Van Hole, C., Devlieger, H., Fryns, J.-P.
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<strong>Proteinuria in a patient with the diaphragmatic hernia-hypertelorism-myopia-deafness syndrome: further evidence that the facio-oculo-acoustico-renal syndrome represents the same entity.</strong>
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J. Med. Genet. 35: 70-71, 1998.
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[PubMed: 9475100]
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Donnai, D., Barrow, M.
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<strong>Diaphragmatic hernia, exomphalos, absent corpus callosum, hypertelorism, myopia, and sensorineural deafness: a newly recognized autosomal recessive disorder?</strong>
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Am. J. Med. Genet. 47: 679-682, 1993.
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[PubMed: 8266995]
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Farquhar, M. G., Saito, A., Kerjaschki, D., Orlando, R. A.
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J. Am. Soc. Nephrol. 6: 35-47, 1995.
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Farquhar, M. G.
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J. Clin. Invest. 96: 1184 only, 1995.
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Hammes, A., Andreassen, T. K., Spoelgen, R., Raila, J., Hubner, N., Schulz, H., Metzger, J., Schweigert, F. J., Luppa, P. B., Nykjaer, A., Willnow, T. E.
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<strong>Role of endocytosis in cellular uptake of sex steroids.</strong>
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<p class="mim-text-font">
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Hjalm, G., Murray, E., Crumley, G., Harazim, W., Lundgren, S., Onyango, I., Bo, E. K., Larsson, M., Juhlin, C., Hellman, P., Davis, H., Akerstrom, G., Rask, L., Morse, B.
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<strong>Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties.</strong>
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Europ. J. Biochem. 239: 132-137, 1996.
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[PubMed: 8706697]
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[Full Text: https://doi.org/10.1111/j.1432-1033.1996.0132u.x]
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<p class="mim-text-font">
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Kantarci, S., Al-Gazali, L., Hill, R. S., Donnai, D., Black, G. C. M., Bieth, E., Chassaing, N., Lacombe, D., Devriendt, K., Teebi, A., Loscertales, M., Robson, C., Liu, T., MacLaughlin, D. T., Noonan, K. M., Russell, M. K., Walsh, C. A., Donahoe, P. K., Pober, B. R.
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<strong>Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes.</strong>
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Nature Genet. 39: 957-959, 2007.
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[PubMed: 17632512]
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<p class="mim-text-font">
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Kerjaschki, D., Farquhar, M. G.
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<strong>Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats.</strong>
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J. Exp. Med. 157: 667-686, 1983.
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[PubMed: 6337231]
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[Full Text: https://doi.org/10.1084/jem.157.2.667]
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<li>
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<p class="mim-text-font">
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Korenberg, J. R., Argraves, K. M., Chen, X.-N., Tran, H., Strickland, D., Argraves, W. S.
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<strong>Chromosomal localization of human genes for the LDL receptor family member glycoprotein 330 (LRP2) and its associated protein RAP (LRPAP1).</strong>
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Genomics 22: 88-93, 1994.
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[PubMed: 7959795]
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[Full Text: https://doi.org/10.1006/geno.1994.1348]
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<p class="mim-text-font">
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Kounnas, M. Z., Loukinova, E. B., Stefansson, S., Harmony, J. A. K., Brewer, B. H., Strickland, D. K., Argraves, W. S.
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<strong>Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin.</strong>
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J. Biol. Chem. 270: 13070-13075, 1995. Note: Erratum: J. Biol. Chem. 270: 23234 only, 1995.
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[PubMed: 7768901]
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[Full Text: https://doi.org/10.1074/jbc.270.22.13070]
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</p>
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<li>
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<p class="mim-text-font">
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Leheste, J.-R., Rolinski, B., Vorum, H., Hilpert, J., Nykjaer, A., Jacobsen, C., Aucouturier, P., Moskaug, J. O., Otto, A., Christensen, E. I., Willnow, T. E.
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<strong>Megalin knockout mice as an animal model of low molecular weight proteinuria.</strong>
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Am. J. Path. 155: 1361-1370, 1999.
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[PubMed: 10514418]
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[Full Text: https://doi.org/10.1016/S0002-9440(10)65238-8]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Marino, M., Chiovato, L., Friedlander, J. A., Latrofa, F., Pinchera, A., McCluskey, R. T.
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<strong>Serum antibodies against megalin (GP330) in patients with autoimmune thyroiditis.</strong>
|
|
J. Clin. Endocr. Metab. 84: 2468-2474, 1999.
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[PubMed: 10404822]
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[Full Text: https://doi.org/10.1210/jcem.84.7.5837]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
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Moestrup, S. K., Cui, S., Vorum, H., Bregengard, C., Bjorn, S. E., Norris, K., Gliemann, J., Christensen, E. I.
|
|
<strong>Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.</strong>
|
|
J. Clin. Invest. 96: 1404-1413, 1995.
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|
|
|
|
|
[PubMed: 7544804]
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|
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|
|
[Full Text: https://doi.org/10.1172/JCI118176]
|
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</p>
|
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</li>
|
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<li>
|
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<p class="mim-text-font">
|
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Naccache, S. N., Hasson, T., Horowitz, A.
|
|
<strong>Binding of internalized receptors to the PDZ domain of GIPC/synectin recruits myosin VI to endocytic vesicles.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 12735-12740, 2006. Note: Erratum: Proc. Nat. Acad. Sci. 103: 15272 only, 2006.
|
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