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Entry
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- *147670 - INSULIN RECEPTOR; INSR
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*147670</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/147670">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000171105;t=ENST00000302850" 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=3643" 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=147670" 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="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=ENSG00000171105;t=ENST00000302850" 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_000208,NM_001079817,XM_011527988,XM_011527989" 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_000208" 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=147670" 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=00975&isoform_id=00975_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/INSR" 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/33973,186468,186472,186474,186481,307070,386830,463119,546647,553512,553515,914086,29126792,62087302,66275676,68482571,68482624,68482723,83755436,83755438,83755440,83755442,83755444,83755446,83755448,84310407,84310409,84310411,84310413,109658490,118574860,119395736,119395738,119589448,119589449,119589450,119589451,119589452,119589453,145554240,145554242,145554244,145554246,145554248,145554250,145554252,145554254,145559055,164419307,194390640,308153655,1034607804,1034607806,2462565155,2462565157" 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/P06213" 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=3643" 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=ENSG00000171105;t=ENST00000302850" 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=INSR" 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=INSR" 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+3643" 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/INSR" 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:3643" 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/3643" 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=chr19&hgg_gene=ENST00000302850.10&hgg_start=7112265&hgg_end=7294414&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/insr" 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=147670[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><a href="https://www.possumcore.com/nuxeo/nxdoc/default/20a3fb35-3ced-48fd-930c-a467d39e4b27/view_documents?source=omim" class="mim-tip-hint" title="A dysmorphology database of multiple malformations; metabolic, teratogenic, chromosomal, and skeletal syndromes; and their images." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'POSSUM', 'domain': 'possum.net.au'})">POSSUM</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=147670[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/INSR/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/ENSG00000171105" 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=INSR" 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=INSR" 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=INSR" 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=INSR&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/PA202" 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:6091" 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/FBgn0283499.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:96575" 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/INSR#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:96575" 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/3643/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=3643" 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=WBGene00000898;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-020503-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:147670" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</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:3643" 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=INSR&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> 111307005, 237606005, 33559001, 44054006, 48606007, 763325000<br />
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<strong>ICD10CM:</strong> E11<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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147670
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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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INSULIN RECEPTOR; INSR
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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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<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=INSR" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">INSR</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>
|
|
Cytogenetic location: <a href="/geneMap/19/202?start=-3&limit=10&highlight=202">19p13.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:7112265-7294414&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'})">19:7,112,265-7,294,414</a> </span>
|
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</em>
|
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</strong>
|
|
<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;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=610549,246200,609968,262190" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/202?start=-3&limit=10&highlight=202">
|
|
19p13.2
|
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</a>
|
|
</span>
|
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</td>
|
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|
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<td>
|
|
<span class="mim-font">
|
|
Diabetes mellitus, insulin-resistant, with acanthosis nigricans
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/610549"> 610549 </a>
|
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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</span>
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<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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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Insulin receptor is a tetramer of 2 alpha and 2 beta subunits. The alpha and beta subunits are coded by a single gene and are joined by disulfide bonds, a mechanism parallel to that of its ligand, insulin (INS; <a href="/entry/176730">176730</a>) (<a href="#87" class="mim-tip-reference" title="Rubin, C. S. <strong>Personal Communication.</strong> Bronx, N. Y. 12/8/1984."None>Rubin, 1984</a>).</p>
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<p><a href="#106" class="mim-tip-reference" title="Ullrich, A., Bell, J. R., Chen, E. Y., Herrera, R., Petruzzelli, L. M., Dull, T. J., Gray, A., Coussens, L., Liao, Y.-C., Tsubokawa, M., Mason, A., Seeburg, P. H., Grunfeld, C., Rosen, O. M., Ramachandran, J. <strong>Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.</strong> Nature 313: 756-761, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2983222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2983222</a>] [<a href="https://doi.org/10.1038/313756a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2983222">Ullrich et al. (1985)</a> deduced the entire 1,370-amino acid sequence of the insulin receptor from a cDNA clone. The precursor starts with a 27-amino acid signal sequence, followed by the receptor alpha subunit, a precursor processing enzyme cleavage site, then the beta subunit containing a single 23-amino acid transmembrane sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2983222" 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="Caro, J. F., Raju, S. M., Sinha, M. K., Goldfine, I. D., Dohm, G. L. <strong>Heterogeneity of human liver, muscle, and adipose tissue insulin receptor.</strong> Biochem. Biophys. Res. Commun. 151: 123-129, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3279949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3279949</a>] [<a href="https://doi.org/10.1016/0006-291x(88)90567-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3279949">Caro et al. (1988)</a> demonstrated differences in molecular mass, carbohydrate composition, and antigenicity between the insulin receptor alpha subunit in liver and in muscle and adipose tissue, the 2 major peripheral target tissues of insulin. Moreover, the same authors showed that the insulin-stimulated tyrosyl kinase activity is greater in muscle than in liver or adipose tissue. There are sequence homologies to EGF receptor (<a href="/entry/131550">131550</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3279949" 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>Two insulin receptor mRNA transcripts resulting from alternative splicing of exon 11 in the receptor gene are expressed in a highly regulated tissue-specific fashion. <a href="#10" class="mim-tip-reference" title="Benecke, H., Flier, J. S., Moller, D. E. <strong>Alternatively spliced variants of the insulin receptor protein: expression in normal and diabetic human tissues.</strong> J. Clin. Invest. 89: 2066-2070, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1602013/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1602013</a>] [<a href="https://doi.org/10.1172/JCI115819" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1602013">Benecke et al. (1992)</a> studied the relative abundance of these 2 mRNA species in human tissues; the one containing exon 11 shows a marked predominance in liver, whereas the isoform in which exon 11 has been spliced out shows a comparable predominance in leukocytes. Similar amounts of the 2 variants were found in placenta, skeletal muscle, and adipose tissue. No significant differences were found between control and diabetic subjects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1602013" 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="#25" class="mim-tip-reference" title="Due, C., Simonsen, M., Olsson, L. <strong>The major histocompatibility complex class I heavy chain as a structural subunit of the human cell membrane insulin receptor: implications for the range of biological functions of histocompatibility antigens.</strong> Proc. Nat. Acad. Sci. 83: 6007-6011, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3090548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3090548</a>] [<a href="https://doi.org/10.1073/pnas.83.16.6007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3090548">Due et al. (1986)</a> presented evidence that the class I MHC heavy chain (HLA-A, HLA-B, HLA-C; see <a href="/entry/142800">142800</a>) is a structural subunit of the insulin receptor. This broadens the range of biologic functions possible for histocompatibility antigens. Interaction of class I HLA molecules with glucagon receptors (e.g., <a href="/entry/138033">138033</a>) and epidermal growth factor receptors (e.g., <a href="/entry/131550">131550</a>) has also been demonstrated. <a href="#25" class="mim-tip-reference" title="Due, C., Simonsen, M., Olsson, L. <strong>The major histocompatibility complex class I heavy chain as a structural subunit of the human cell membrane insulin receptor: implications for the range of biological functions of histocompatibility antigens.</strong> Proc. Nat. Acad. Sci. 83: 6007-6011, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3090548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3090548</a>] [<a href="https://doi.org/10.1073/pnas.83.16.6007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3090548">Due et al. (1986)</a> favored the hypothesis that the beta-2-microglobulin molecule (B2M; <a href="/entry/109700">109700</a>) is replaced by the insulin receptor when it associates with the MHC class I heavy chain. <a href="#48" class="mim-tip-reference" title="Kittur, D., Shimizu, Y., DeMars, R., Edidin, M. <strong>Insulin binding to human B lymphoblasts is a function of HLA haplotype.</strong> Proc. Nat. Acad. Sci. 84: 1351-1355, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3547409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3547409</a>] [<a href="https://doi.org/10.1073/pnas.84.5.1351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3547409">Kittur et al. (1987)</a> presented evidence for associations between HLA antigens and specific insulin-binding sites on human B lymphocytes. They cited experiments demonstrating coprecipitation of a fraction of insulin receptors with class I and class II MHC antigens. Thus, in addition to other functions of the MHC antigens, they may affect the functioning of, or themselves serve as, cell surface receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3090548+3547409" 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="#112" class="mim-tip-reference" title="Williams, J. F., McClain, D. A., Dull, T. J., Ullrich, A., Olefsky, J. M. <strong>Characterization of an insulin receptor mutant lacking the subunit processing site.</strong> J. Biol. Chem. 265: 8463-8469, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2187866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2187866</a>]" pmid="2187866">Williams et al. (1990)</a> created a mutant form of the INSR gene by site-directed mutagenesis in order to study the effects of mutation on functions of the receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2187866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Christiansen, K., Tranum-Jensen, J., Carlsen, J., Vinten, J. <strong>A model for the quaternary structure of human placental insulin receptor deduced from electron microscopy.</strong> Proc. Nat. Acad. Sci. 88: 249-252, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1986371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1986371</a>] [<a href="https://doi.org/10.1073/pnas.88.1.249" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1986371">Christiansen et al. (1991)</a> used data from electron microscopy to deduce a model for a quaternary structure of the insulin receptor of human placenta. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1986371" 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 a yeast 2-hybrid system, <a href="#24" class="mim-tip-reference" title="Dey, B. R., Furlanetto, R. W., Nissley, S. P. <strong>Cloning of human p55-gamma, a regulatory subunit of phosphatidylinositol 3-kinase, by a yeast two-hybrid library screen with the insulin-like growth factor-I receptor.</strong> Gene 209: 175-183, 1998. Note: Erratum: Gene 212: 155 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9524259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9524259</a>] [<a href="https://doi.org/10.1016/s0378-1119(98)00045-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9524259">Dey et al. (1998)</a> identified a regulatory subunit of phosphatidylinositol 3-kinase, PIK3R3 (<a href="/entry/606076">606076</a>), as a binding partner of INSR. They concluded that PIK3R3 interacts with IGF1R (<a href="/entry/147370">147370</a>) and INSR in a kinase-dependent manner, providing an alternative pathway for the activation of PI3K by these 2 receptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9524259" 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>The protein tyrosine phosphatase PTP1B (<a href="/entry/176885">176885</a>) is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine (ptyr) residues of the INSR kinase activation segment, or IRK. By integrating crystallographic, kinetic, and PTP1B peptide-binding studies, <a href="#88" class="mim-tip-reference" title="Salmeen, A., Andersen, J. N., Myers, M. P., Tonks, N. K., Barford, D. <strong>Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B.</strong> Molec. Cell 6: 1401-1412, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163213</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00137-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163213">Salmeen et al. (2000)</a> defined the molecular specificity of this reaction. Extensive interactions are formed between PTP1B and the IRK sequence encompassing the tandem ptyr residues at positions 1162 and 1163, such that ptyr1162 is selected at the catalytic site and ptyr1163 is located within an adjacent ptyr-recognition site. This selectivity is attributed to the 70-fold greater affinity for tandem ptyr-containing peptides relative to mono-ptyr peptides and predicts a hierarchical dephosphorylation process. Many elements of the PTP1B-IRK interaction are unique to PTP1B, indicating that it may be feasible to generate specific, small molecule inhibitors of this interaction to treat diabetes and obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163213" 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="#56" class="mim-tip-reference" title="Leibiger, B., Leibiger, I. B., Moede, T., Kemper, S., Kulkarni, R. N., Kahn, C. R., de Vargas, L. M., Berggren, P.-O. <strong>Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells.</strong> Molec. Cell 7: 559-570, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11463381/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11463381</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00203-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11463381">Leibiger et al. (2001)</a> showed that insulin activates the transcription of its own gene and that of the beta-cell glucokinase gene (GCK; <a href="/entry/138079">138079</a>) by different mechanisms. Whereas INS gene transcription is promoted by signaling through INSR type A (without exon 11), PI3K class IA (see <a href="/entry/171833">171833</a>), and the 70-kD S6 kinase, insulin stimulates the beta-cell GCK gene by signaling via INSR type B (with exon 11), PI3K class II (see <a href="/entry/602838">602838</a>)-like activity, and protein kinase B (<a href="/entry/164730">164730</a>). These data provided evidence for selectivity in insulin action via the 2 INSR isoforms, the molecular basis being preferential signaling through different PI3K and protein kinases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11463381" 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="#85" class="mim-tip-reference" title="Rajala, R. V. S., Anderson, R. E. <strong>Interaction of the insulin receptor beta-subunit with phosphatidylinositol 3-kinase in bovine ROS.</strong> Invest. Ophthal. Vis. Sci. 42: 3110-3117, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726610/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726610</a>]" pmid="11726610">Rajala and Anderson (2001)</a> sought to identify the tyrosine-phosphorylated protein(s) in the bovine rod outer segments (ROS) that are associated with PI3K. They concluded that tyrosine phosphorylation of the beta subunit of the insulin receptor is involved in the regulation of PI3K activity in the ROS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726610" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By purification and molecular characterization, <a href="#14" class="mim-tip-reference" title="Brunetti, A., Manfioletti, G., Chiefari, E., Goldfine, I. D., Foti, D. <strong>Transcriptional regulation of human insulin receptor gene by the high-mobility group protein HMGI(Y).</strong> FASEB J. 15: 492-500, 2001. Note: Erratum: FASEB J. 15: 1115 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156965</a>] [<a href="https://doi.org/10.1096/fj.00-0190com" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11156965">Brunetti et al. (2001)</a> found that HMGIY (<a href="/entry/600701">600701</a>) bound and activated 2 AT-rich regions in the INSR promoter. Knockdown of HMGIY via antisense RNA reduced surface expression of INSR in 2 human cell lines that normally express high INSR levels. Conversely, transfection of HMGIY elevated surface expression of INSR in 2 cell lines that normally express little INSR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156965" 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>Decreased affinity of numerically normal insulin receptor binding sites has been reported in patients with myotonic dystrophy (<a href="#103" class="mim-tip-reference" title="Tevaarwerk, G. J. M., Strickland, K. P., Lin, C. H., Hudson, A. J. <strong>Studies on insulin resistance and insulin receptor binding in myotonia dystrophica.</strong> J. Clin. Endocr. Metab. 49: 216-222, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/457841/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">457841</a>] [<a href="https://doi.org/10.1210/jcem-49-2-216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="457841">Tevaarwerk et al., 1979</a>). Myotonic dystrophy is often associated with disturbances in insulin response. In muscle from patients with myotonic dystrophy type 1 (DM1; <a href="/entry/160900">160900</a>), altered insulin receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the myotonic dystrophy phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of DM. <a href="#89" class="mim-tip-reference" title="Savkur, R. S., Philips, A. V., Cooper, T. A., Dalton, J. C., Moseley, M. L., Ranum, L. P. W., Day, J. W. <strong>Insulin receptor splicing alteration in myotonic dystrophy type 2.</strong> Am. J. Hum. Genet. 74: 1309-1313, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15114529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15114529</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15114529[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/421528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15114529">Savkur et al. (2004)</a> demonstrated that comparable splicing abnormalities occur in DM2 (<a href="/entry/602668">602668</a>) muscle before the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=457841+15114529" 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="#97" class="mim-tip-reference" title="Song, R., Peng, W., Zhang, Y., Lv, F., Wu, H.-K., Guo, J., Cao, Y., Pi, Y., Zhang, X., Jin, L., Zhang, M., Jiang, P., Liu, F., Meng, S., Zhang, X., Jiang, P., Cao, C.-M., Xiao, R.-P. <strong>Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders.</strong> Nature 494: 375-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23354051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23354051</a>] [<a href="https://doi.org/10.1038/nature11834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23354051">Song et al. (2013)</a> showed in mice that muscle-specific mitsugumin-53 (MG53; <a href="/entry/613288">613288</a>) mediates the degradation of the insulin receptor and insulin receptor substrate-1 (IRS1; <a href="/entry/147545">147545</a>), and when upregulated causes metabolic syndrome featuring insulin resistance, obesity, hypertension, and dyslipidemia. Mg53 expression is markedly elevated in models of insulin resistance, and Mg53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of Mg53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, Irs1, and insulin signaling integrity. Mechanistically, Mg53 acts as an E3 ligase targeting the insulin receptor and Irs1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. <a href="#97" class="mim-tip-reference" title="Song, R., Peng, W., Zhang, Y., Lv, F., Wu, H.-K., Guo, J., Cao, Y., Pi, Y., Zhang, X., Jin, L., Zhang, M., Jiang, P., Liu, F., Meng, S., Zhang, X., Jiang, P., Cao, C.-M., Xiao, R.-P. <strong>Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders.</strong> Nature 494: 375-379, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23354051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23354051</a>] [<a href="https://doi.org/10.1038/nature11834" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23354051">Song et al. (2013)</a> concluded that these findings defined MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23354051" 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="#92" class="mim-tip-reference" title="Seino, S., Seino, M., Nishi, S., Bell, G. I. <strong>Structure of the human insulin receptor gene and characterization of its promoter.</strong> Proc. Nat. Acad. Sci. 86: 114-118, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2911561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2911561</a>] [<a href="https://doi.org/10.1073/pnas.86.1.114" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2911561">Seino et al. (1989)</a> found that the INSR gene spans more than 120 kb and has 22 exons. The 11 exons encoding the alpha subunit are dispersed over more than 90 kb, whereas the 11 exons encoding the beta subunit are located together in a region of about 30 kb. Three transcriptional initiation sites were identified, located 276, 282, and 283 bp upstream of the translation initiation site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2911561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Brunetti, A., Manfioletti, G., Chiefari, E., Goldfine, I. D., Foti, D. <strong>Transcriptional regulation of human insulin receptor gene by the high-mobility group protein HMGI(Y).</strong> FASEB J. 15: 492-500, 2001. Note: Erratum: FASEB J. 15: 1115 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11156965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11156965</a>] [<a href="https://doi.org/10.1096/fj.00-0190com" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11156965">Brunetti et al. (2001)</a> stated that the promoter region of INSR has no TATA or CAAT boxes, but is extremely GC rich. In addition, they identified 2 functional AT-rich sequences in the INSR promoter that were bound and activated by HMGIY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11156965" 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="#66" class="mim-tip-reference" title="McKern, N. M., Lawrence, M. C., Streltsov, V. A., Lou, M.-Z., Adams, T. E., Lovrecz, G. O., Elleman, T. C., Richards, K. M., Bentley, J. D., Pilling, P. A., Hoyne, P. A., Cartledge, K. A., and 11 others. <strong>Structure of the insulin receptor ectodomain reveals a folded-over conformation.</strong> Nature 443: 218-221, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16957736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16957736</a>] [<a href="https://doi.org/10.1038/nature05106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16957736">McKern et al. (2006)</a> presented the crystal structure at 3.8-angstrom resolution of the IR-A ectodomain dimer of the insulin receptor, complexed with 4 antigen-binding fragments (Fabs) from the monoclonal antibodies 83-7 and 83-14, grown in the presence of a fragment of an insulin (<a href="/entry/176730">176730</a>) mimetic peptide. The structure reveals the domain arrangement in the disulfide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is different from previous models. It shows that the 2 L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16957736" 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="#61" class="mim-tip-reference" title="Lou, M., Garrett, T. P. J., McKern, N. M., Hoyne, P. A., Epa, V. C., Bentley, J. D., Lovrecz, G. O., Cosgrove, L. J., Frenkel, M. J., Ward, C. W. <strong>The first three domains of the insulin receptor differ structurally from the insulin-like growth factor 1 receptor in the regions governing ligand specificity.</strong> Proc. Nat. Acad. Sci. 103: 12429-12434, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16894147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16894147</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16894147[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.0605395103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16894147">Lou et al. (2006)</a> reported the crystal structure of the first 3 domains of INSR at 2.3-angstrom resolution and compared it with the structure of the corresponding fragment of IGF1R. They observed notable differences in the regions governing ligand specificity and binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16894147" 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="#67" class="mim-tip-reference" title="Menting, J. G., Whittaker, J., Margetts, M. B., Whittaker, L. J., Kong, G. K.-W., Smith, B. J., Watson, C. J., Zakova, L., Kletvikova, E., Jiracek, J., Chan, S. J., Steiner, D. F., Dodson, G. G., Brzozowski, A. M., Weiss, M. A., Ward, C. W., Lawrence, M. C. <strong>How insulin engages its primary binding site on the insulin receptor.</strong> Nature 493: 241-245, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23302862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23302862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23302862[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/nature11781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23302862">Menting et al. (2013)</a> presented a view of the interaction of insulin with its primary binding site on the insulin receptor on the basis of 4 crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich repeat domain (L1) of insulin receptor is sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alpha-CT) segment, which is itself remodeled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alpha-CT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23302862" 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>With in situ hybridization and Southern blot analysis of somatic cell hybrid DNA, <a href="#114" class="mim-tip-reference" title="Yang-Feng, T. L., Francke, U., Ullrich, A. <strong>Gene for human insulin receptor: localization to site on chromosome 19 involved in pre-B-cell leukemia.</strong> Science 228: 728-731, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3873110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3873110</a>] [<a href="https://doi.org/10.1126/science.3873110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3873110">Yang-Feng et al. (1985)</a> assigned the insulin receptor gene to 19p13.3-p13.2. This site is involved in a nonrandom translocation in pre-B-cell acute leukemia. The t(1;19) was demonstrated by several workers (e.g., <a href="#111" class="mim-tip-reference" title="Williams, D. L., Look, A. T., Melvin, S. L., Roberson, P. K., Dahl, G., Flake, T., Stass, S. <strong>New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia.</strong> Cell 36: 101-109, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6607116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6607116</a>] [<a href="https://doi.org/10.1016/0092-8674(84)90078-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6607116">Williams et al., 1984</a>) in this childhood form of acute lymphoblastic leukemia which responds poorly to treatment. The cells produce cytoplasmic but not cell-surface immunoglobulin heavy chains. <a href="#93" class="mim-tip-reference" title="Shaw, D. J., Meredith, A. L., Brook, J. D., Sarfarazi, M., Harley, H. G., Huson, S. M., Bell, G. I., Harper, P. S. <strong>Linkage relationships of the insulin receptor gene with the complement component 3, LDL receptor, apolipoprotein C2 and myotonic dystrophy loci on chromosome 19.</strong> Hum. Genet. 74: 267-269, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2877934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2877934</a>] [<a href="https://doi.org/10.1007/BF00282546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2877934">Shaw et al. (1986)</a> concluded from linkage studies that INSR is very close to C3 (<a href="/entry/120700">120700</a>) but far from DM (<a href="/entry/160900">160900</a>). By fluorescence in situ hybridization, <a href="#104" class="mim-tip-reference" title="Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. <strong>Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers.</strong> Genomics 15: 133-145, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8432525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8432525</a>] [<a href="https://doi.org/10.1006/geno.1993.1021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8432525">Trask et al. (1993)</a> assigned the INSR gene to 19p13.3. By simultaneous mapping of multiple probes, they were able to achieve a more refined assignment than was possible when a single probe or a few probes were mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6607116+3873110+8432525+2877934" 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="#101" class="mim-tip-reference" title="Taylor, S. I., Marcus-Samuels, B., Ryan-Young, J., Leventhal, S., Elders, M. J. <strong>Genetics of the insulin receptor defect in a patient with extreme insulin resistance.</strong> J. Clin. Endocr. Metab. 62: 1130-1135, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3009519/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3009519</a>] [<a href="https://doi.org/10.1210/jcem-62-6-1130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3009519">Taylor et al. (1986)</a> concluded that a patient with Donohue syndrome (<a href="/entry/246200">246200</a>) and extreme insulin resistance was a genetic compound, i.e., that each parent had transmitted to the proband a different defect of the insulin receptor (see <a href="#0002">147670.0002</a>). The patient, referred to as leprechaun/Ark-1, had an 80 to 90% decrease in the number of insulin receptors in circulating monocytes. Although the receptors on Epstein-Barr virus-transformed lymphocytes from the patient were normal in number, they showed decreased sensitivity to changes in temperature and pH. The father, who had a moderate degree of insulin resistance, resembled the patient in that his monocytes had a 60 to 80% decrease in the number of insulin receptors. Binding of the father's EB virus-transformed lymphocytes was normal. The mother had normal sensitivity to insulin and a normal number of insulin receptors on circulating monocytes. On the other hand, insulin receptors on the mother's EB virus-transformed lymphocytes were qualitatively abnormal, resembling closely the daughter's cultured cells. The father, who was heterozygous for the nonsense mutation, showed a moderate degree of insulin resistance. <a href="#79" class="mim-tip-reference" title="Ojamaa, K., Hedo, J. A., Roberts, C. T., Jr., Moncada, V. Y., Gorden, P., Ullrich, A., Taylor, S. I. <strong>Defects in human insulin receptor gene expression.</strong> Molec. Endocr. 2: 242-247, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2840573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2840573</a>] [<a href="https://doi.org/10.1210/mend-2-3-242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2840573">Ojamaa et al. (1988)</a> found marked reduction in the level of receptor mRNA in a patient with Donohue syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3009519+2840573" 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="#38" class="mim-tip-reference" title="Kadowaki, T., Bevins, C. L., Cama, A., Ojamaa, K., Marcus-Samuels, B., Kadowaki, H., Beitz, L., McKeon, C., Taylor, S. I. <strong>Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance.</strong> Science 240: 787-790, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2834824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2834824</a>] [<a href="https://doi.org/10.1126/science.2834824" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2834824">Kadowaki et al. (1988)</a> raised the question of whether mutations in the insulin receptor gene may account for the insulin resistance in some patients with noninsulin-dependent diabetes mellitus (NIDDM, T2D; <a href="/entry/125853">125853</a>). <a href="#98" class="mim-tip-reference" title="Taira, M., Taira, M., Hashimoto, N., Shimada, F., Suzuki, Y., Kanatsuka, A., Nakamura, F., Ebina, Y., Tatibana, M., Makino, H., Yoshida, S. <strong>Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor.</strong> Science 245: 63-66, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544997</a>] [<a href="https://doi.org/10.1126/science.2544997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544997">Taira et al. (1989)</a> suggested that many instances of NIDDM may be due to relatively minor mutations of the insulin receptor gene that cause slightly decreased affinity of the receptor for insulin or a slightly decreased kinase activity; in these cases, environmental factors such as obesity may trigger the onset of diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2544997+2834824" 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>Discussing the mechanisms of insulin resistance, <a href="#71" class="mim-tip-reference" title="Moller, D. E., Flier, J. S. <strong>Insulin resistance--mechanisms, syndromes, and implications.</strong> New Eng. J. Med. 325: 938-948, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1881419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1881419</a>] [<a href="https://doi.org/10.1056/NEJM199109263251307" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1881419">Moller and Flier (1991)</a> and <a href="#100" class="mim-tip-reference" title="Taylor, S. I., Cama, A., Accili, D., Barbetti, F., Imano, E., Kadowaki, H., Kadowaki, T. <strong>Genetic basis of endocrine disease 1: molecular genetics of insulin resistant diabetes mellitus.</strong> J. Clin. Endocr. Metab. 73: 1158-1163, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1955495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1955495</a>] [<a href="https://doi.org/10.1210/jcem-73-6-1158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1955495">Taylor et al. (1991)</a> diagrammed the structure of the human insulin receptor and indicated the position of known point mutations. <a href="#100" class="mim-tip-reference" title="Taylor, S. I., Cama, A., Accili, D., Barbetti, F., Imano, E., Kadowaki, H., Kadowaki, T. <strong>Genetic basis of endocrine disease 1: molecular genetics of insulin resistant diabetes mellitus.</strong> J. Clin. Endocr. Metab. 73: 1158-1163, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1955495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1955495</a>] [<a href="https://doi.org/10.1210/jcem-73-6-1158" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1955495">Taylor et al. (1991)</a> divided mutations in the INSR gene into 5 classes: class 1, impaired receptor biosynthesis; class 2, impaired transport of receptors to the cell surface; class 3, decreased affinity of insulin binding; class 4, impaired tyrosine kinase activity; and class 5, accelerated receptor degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1955495+1881419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 22 unrelated women with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism; <a href="/entry/610549">610549</a>), <a href="#69" class="mim-tip-reference" title="Moller, D. E., Cohen, O., Yamaguchi, Y., Assiz, R., Grigorescu, F., Eberle, A., Morrow, L. A., Moses, A. C., Flier, J. S. <strong>Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance.</strong> Diabetes 43: 247-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288049</a>] [<a href="https://doi.org/10.2337/diab.43.2.247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288049">Moller et al. (1994)</a> identified only 1 mutation in the INSR gene: arg1174 to gln (<a href="#0030">147670.0030</a>). <a href="#69" class="mim-tip-reference" title="Moller, D. E., Cohen, O., Yamaguchi, Y., Assiz, R., Grigorescu, F., Eberle, A., Morrow, L. A., Moses, A. C., Flier, J. S. <strong>Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance.</strong> Diabetes 43: 247-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288049</a>] [<a href="https://doi.org/10.2337/diab.43.2.247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288049">Moller et al. (1994)</a> concluded that mutation in the INSR gene is a rare cause of the type A syndrome of extreme insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="'t Hart, L. M., Stolk, R. P., Dekker, J. M., Nijpels, G., Grobbee, D. E., Heine, R. J., Maassen, J. A. <strong>Prevalence of variants in candidate genes for type 2 diabetes mellitus in the Netherlands: the Rotterdam study and the Hoorn study.</strong> J. Clin. Endocr. Metab. 84: 1002-1006, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10084586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10084586</a>] [<a href="https://doi.org/10.1210/jcem.84.3.5563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10084586">'t Hart et al. (1999)</a> studied random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies to determine the prevalence of variants in NIDDM candidate genes. The val985-to-met (<a href="#0029">147670.0029</a>) INSR variant was found at frequencies of 4.4 and 1.8%, respectively, in NIDDM and normoglycemic patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10084586" 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="#65" class="mim-tip-reference" title="McCarthy, L. C., Hosford, D. A., Riley, J. H., Bird, M. I., White, N. J., Hewett, D. R., Peroutka, S. J., Griffiths, L. R., Boyd, P. R., Lea, R. A., Bhatti, S. M., Hosking, L. K., and 28 others. <strong>Single-nucleotide polymorphism alleles in the insulin receptor gene are associated with typical migraine.</strong> Genomics 78: 135-149, 2001. Note: Erratum: Genomics 79: 271 only, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11735220/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11735220</a>] [<a href="https://doi.org/10.1006/geno.2001.6647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11735220">McCarthy et al. (2001)</a> genotyped 24 single-nucleotide polymorphisms (SNPs) within the 19p13 region in a Caucasian population comprising 827 unrelated cases of typical migraine (<a href="/entry/607508">607508</a>). Five SNPs within the insulin receptor gene showed significant association with migraine. Functional studies of the INSR SNPs showed no effect on mRNA levels or splicing in peripheral blood leukocytes or on binding of insulin to mononuclear cells. The authors speculated on possible mechanisms by which the INSR could play a role in the pathogenesis of migraine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11735220" 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="#60" class="mim-tip-reference" title="Longo, N., Wang, Y., Smith, S. A., Langley, S. D., DiMeglio, L. A., Giannella-Neto, D. <strong>Genotype-phenotype correlation in inherited severe insulin resistance.</strong> Hum. Molec. Genet. 11: 1465-1475, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023989</a>] [<a href="https://doi.org/10.1093/hmg/11.12.1465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023989">Longo et al. (2002)</a> reported 6 patients and correlated mutations in the insulin receptor gene with survival. Patients with Donohue syndrome were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor, and their cells had markedly impaired insulin binding (less than 10% of controls). Mutations in their insulin receptor gene inserted premature stop codons resulting in decreased levels of mature mRNA, or alternatively affected the extracellular domain of the receptor. Three patients with Rabson-Mendenhall syndrome had at least 1 missense mutation in the intracellular domain of the insulin receptor. Expression studies in CHO cells indicated that several mutations markedly impaired insulin binding (less than 5% of control), while others retained significant insulin-binding activity. The authors concluded that mutations in the insulin receptor retaining residual insulin-binding activity correlated with prolonged survival in a series of patients with extreme insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12023989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In all affected members of a 3-generation Danish family with hyperinsulinemic hypoglycemia (see HHF5, <a href="/entry/609968">609968</a>), <a href="#36" class="mim-tip-reference" title="Hojlund, K., Hansen, T., Lajer, M., Henriksen, J. E., Levin, K., Lindholm, J., Pedersen, O., Bech-Nielsen, H. <strong>A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.</strong> Diabetes 53: 1592-1593, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15161766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15161766</a>] [<a href="https://doi.org/10.2337/diabetes.53.6.1592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15161766">Hojlund et al. (2004)</a> identified heterozygosity for a point mutation in the insulin receptor gene (<a href="#0030">147670.0030</a>). The mutation was not found in any unaffected family members. The proband's sister, who had moderate symptoms of hypoglycemia, showed mild skin pigmentation in the axillae, increased total and free serum levels of testosterone, and polycystic ovaries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15161766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Foti, D., Chiefari, E., Fedele, M., Iuliano, R., Brunetti, L., Paonessa, F., Manfioletti, G., Barbetti, F., Brunetti, A., Croce, C. M., Fusco, A., Brunetti, A. <strong>Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice.</strong> Nature Med. 11: 765-773, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15924147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15924147</a>] [<a href="https://doi.org/10.1038/nm1254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15924147">Foti et al. (2005)</a> reported 4 patients with insulin resistance and type II diabetes in whom cell-surface insulin receptors were decreased and INSR gene transcription was impaired although the INSR genes were normal. In these individuals, expression of HMGA1 (<a href="/entry/600701">600701</a>) was markedly reduced; restoration of HMGA1 protein expression in their cells enhanced INSR gene transcription and restored cell-surface insulin receptor protein expression and insulin-binding capacity. <a href="#31" class="mim-tip-reference" title="Foti, D., Chiefari, E., Fedele, M., Iuliano, R., Brunetti, L., Paonessa, F., Manfioletti, G., Barbetti, F., Brunetti, A., Croce, C. M., Fusco, A., Brunetti, A. <strong>Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice.</strong> Nature Med. 11: 765-773, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15924147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15924147</a>] [<a href="https://doi.org/10.1038/nm1254" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15924147">Foti et al. (2005)</a> concluded that defects in HMGA1 may cause decreased insulin receptor expression and induce insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15924147" 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 genetically obese mice with insulin resistance, <a href="#55" class="mim-tip-reference" title="Le Marchand-Brustel, Y., Gremeaux, T., Ballotti, R., van Obberghen, E. <strong>Insulin receptor tyrosine kinase is defective in skeletal muscle of insulin-resistant obese mice.</strong> Nature 315: 676-679, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3892304/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3892304</a>] [<a href="https://doi.org/10.1038/315676a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3892304">Le Marchand-Brustel et al. (1985)</a> found a defect in the tyrosine kinase activity of insulin receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3892304" 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>Complete lack of insulin receptors due to mutations of the insulin receptor gene results in severe growth retardation and mild diabetes. In mice, targeted inactivation of insulin receptor substrate-1 (<a href="/entry/147545">147545</a>) leads to inhibition of growth and mild resistance to the metabolic actions of insulin. To address the question of whether both metabolic and growth-promoting actions of insulin are mediated by the insulin receptor, <a href="#3" class="mim-tip-reference" title="Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool, M. H., Salvatore, P., Asico, L. D., Jose, P. A., Taylor, S. I., Westphal, H. <strong>Early neonatal death in mice homozygous for a null allele of the insulin receptor gene.</strong> Nature Genet. 12: 106-109, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528241</a>] [<a href="https://doi.org/10.1038/ng0196-106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528241">Accili et al. (1996)</a> generated mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells. Unlike human patients lacking insulin receptors, mice homozygous for a null allele of the insulin receptor gene were born at term with apparently normal intrauterine growth and development. Within hours of birth, however, homozygous null mice developed severe hyperglycemia and hyperketonemia, and died as a result of diabetic ketoacidosis within 48 to 72 hours. The authors considered the data consistent with a model in which the insulin receptor functions primarily to mediate the metabolic actions of insulin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8528241" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the contribution of muscle insulin resistance to the metabolic phenotype of diabetes, <a href="#16" class="mim-tip-reference" title="Bruning, J. C., Michael, M. D., Winnay, J. N., Hayashi, T., Horsch, D., Accili, D., Goodyear, L. J., Kahn, C. R. <strong>A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance.</strong> Molec. Cell 2: 559-569, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9844629/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9844629</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80155-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9844629">Bruning et al. (1998)</a> used the Cre-loxP system to disrupt the mouse Insr gene in mouse skeletal muscle. The muscle-specific Insr knockout mice exhibited a muscle-specific reduction greater than 95% in receptor content and early signaling events. The mice displayed elevated fat mass, serum triglycerides, and free fatty acids, but blood glucose, serum insulin, and glucose tolerance were normal. Thus, insulin resistance in muscle contributes to the altered fat metabolism associated with type II diabetes, but tissues other than muscle appear to be more involved in insulin-regulated glucose disposal than previously recognized. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9844629" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine whether insulin signaling has a functional role in the pancreatic beta cell, <a href="#52" class="mim-tip-reference" title="Kulkarni, R. N., Bruning, J. C., Winnay, J. N., Postic, C., Magnuson, M. A., Kahn, C. R. <strong>Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes.</strong> Cell 96: 329-339, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10025399/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10025399</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80546-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10025399">Kulkarni et al. (1999)</a> used the Cre-loxP system to specifically inactivate the mouse Insr gene in the beta cells. Expression of Cre using a pancreatic beta cell-specific rat insulin promoter resulted in efficient recombination of a loxP-containing Insr gene in the beta cells. Mice lacking the beta-cell insulin receptor showed a loss of first-phase insulin secretion in response to glucose, but not to arginine, similar to that observed in humans with type II diabetes. These mice also showed a progressively impaired glucose tolerance over 6 months. The data indicated an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggested that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type II diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10025399" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To investigate the effect of the loss of direct insulin action in liver, <a href="#68" class="mim-tip-reference" title="Michael, M. D., Kulkarni, R. N., Postic, C., Previs, S. F., Shulman, G. I., Magnuson, M. A., Kahn, C. R. <strong>Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.</strong> Molec. Cell 6: 87-97, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10949030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10949030</a>]" pmid="10949030">Michael et al. (2000)</a> used the Cre-loxP system to inactivate the Insr gene in hepatocytes. Liver-specific Insr-knockout (LIRKO) mice exhibited dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations were paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the livers of knockout mice exhibited morphologic and functional changes, and the metabolic phenotype became less severe. Thus, the authors concluded that insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10949030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Bruning, J. C., Gautam, D., Burks, D. J., Gillette, J., Schubert, M., Orban, P. C., Klein, R., Krone, W., Muller-Wieland, D., Kahn, C. R. <strong>Role of brain insulin receptor in control of body weight and reproduction.</strong> Science 289: 2122-2125, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11000114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11000114</a>] [<a href="https://doi.org/10.1126/science.289.5487.2122" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11000114">Bruning et al. (2000)</a> created mice with a neuron-specific disruption of the Insr gene (NIRKO). Inactivation of the insulin receptor had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone (see <a href="/entry/152780">152780</a>). Thus, insulin receptor signaling in the central nervous system plays an important role in regulation of energy disposal, fuel metabolism, and reproduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11000114" 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="#9" class="mim-tip-reference" title="Belke, D. D., Betuing, S., Tuttle, M. J., Graveleau, C., Young, M. E., Pham, M., Zhang, D., Cooksey, R. C., McClain, D. A., Litwin, S. E., Taegtmeyer, H., Severson, D., Kahn, C. R., Abel, E. D. <strong>Insulin signaling coordinately regulates cardiac size, metabolism, and contractile protein isoform expression.</strong> J. Clin. Invest. 109: 629-639, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11877471/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11877471</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11877471[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI13946" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11877471">Belke et al. (2002)</a> generated mice with a cardiomyocyte-specific Insr- knockout (CIRKO), using cre/loxP recombination. Hearts of CIRKO mice were 20 to 30% smaller because of decreased postnatal hypertrophy of cardiomyocytes; they had persistent expression of the fetal beta-myosin heavy chain isoform, approximately half the normal expression of glucose transporter-1 (GLUT1; <a href="/entry/138140">138140</a>), and a 2-fold increase in GLUT4 expression. Cardiac glucose uptake was increased in vivo, glycolysis was increased in isolated working hearts, and there was reduced expression of enzymes that catalyze mitochondrial beta-oxidation, leading to decreased fatty acid oxidation rates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11877471" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In brown adipose tissue-specific Insr-knockout mice, <a href="#35" class="mim-tip-reference" title="Guerra, C., Navarro, P., Valverde, A. M., Arribas, M., Bruning, J., Kozak, L. P., Kahn, C. R., Benito, M. <strong>Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance.</strong> J. Clin. Invest. 108: 1205-1213, 2001. Note: Expression of Concern: J. Clin. Invest. 129: 437 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11602628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11602628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11602628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI13103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11602628">Guerra et al. (2001)</a> observed age-dependent profound brown fat atrophy concomitant with the development of fasting hyperglycemia and impaired glucose tolerance. <a href="#35" class="mim-tip-reference" title="Guerra, C., Navarro, P., Valverde, A. M., Arribas, M., Bruning, J., Kozak, L. P., Kahn, C. R., Benito, M. <strong>Brown adipose tissue-specific insulin receptor knockout shows diabetic phenotype without insulin resistance.</strong> J. Clin. Invest. 108: 1205-1213, 2001. Note: Expression of Concern: J. Clin. Invest. 129: 437 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11602628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11602628</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11602628[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI13103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11602628">Guerra et al. (2001)</a> concluded that the insulin receptor plays a direct role in brown fat adipogenesis and suggested that brown adipose tissue is involved in the regulation of insulin secretion and glucose homeostasis. An expression of concern was published for this article because of questions regarding Figure 3, A-C and Figure 4, A and B. The original data supporting these figures was no longer available. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11602628" 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 Cre-loxP system, <a href="#13" class="mim-tip-reference" title="Bluher, M., Michael, M. D., Peroni, O. D., Ueki, K., Carter, N., Kahn, B. B., Kahn, C. R. <strong>Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.</strong> Dev. Cell 3: 25-38, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110165</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00199-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110165">Bluher et al. (2002)</a> generated fat-specific Insr-knockout (FIRKO) mice which they found to have reduced fat mass and loss of the normal relationship between plasma leptin and body weight. The mice were also protected against age-related and hypothalamic lesion-induced obesity and obesity-related glucose intolerance. Using histologic and gene expression studies, <a href="#13" class="mim-tip-reference" title="Bluher, M., Michael, M. D., Peroni, O. D., Ueki, K., Carter, N., Kahn, B. B., Kahn, C. R. <strong>Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.</strong> Dev. Cell 3: 25-38, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110165</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00199-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110165">Bluher et al. (2002)</a> observed that the conditional knockout mice exhibited polarization of adipocytes into populations of large and small cells, which differed in protein expression pattern. <a href="#13" class="mim-tip-reference" title="Bluher, M., Michael, M. D., Peroni, O. D., Ueki, K., Carter, N., Kahn, B. B., Kahn, C. R. <strong>Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.</strong> Dev. Cell 3: 25-38, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110165/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110165</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00199-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110165">Bluher et al. (2002)</a> concluded that insulin signaling in adipocytes is critical for development of obesity and its associated metabolic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12110165" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Bluher, M., Kahn, B. B., Kahn, C. R. <strong>Extended longevity in mice lacking the insulin receptor in adipose tissue.</strong> Science 299: 572-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12543978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12543978</a>] [<a href="https://doi.org/10.1126/science.1078223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12543978">Bluher et al. (2003)</a> generated mice with FIRKO. Growth curves were normal in male and female FIRKO mice from birth to 8 weeks of age. Starting at 3 months of age, FIRKO mice maintained 15 to 25% lower body weights and a 50 to 70% reduction in fat mass throughout life. FIRKO mice were healthy, lacked any of the metabolic abnormalities associated with lipodystrophy, and were protected against age-related deterioration in glucose tolerance, which was observed in all control strains. FIRKO mice maintained low body fat, despite normal food intake. Indeed, because FIRKO mice were leaner, the food intake of FIRKO mice expressed per gram of body weight actually exceeded that of controls by an average of 55%. Both male and female FIRKO mice were found to have an increase in mean life span of about 134 days (18%), with parallel increases in median and maximum life spans. Thus, <a href="#12" class="mim-tip-reference" title="Bluher, M., Kahn, B. B., Kahn, C. R. <strong>Extended longevity in mice lacking the insulin receptor in adipose tissue.</strong> Science 299: 572-574, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12543978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12543978</a>] [<a href="https://doi.org/10.1126/science.1078223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12543978">Bluher et al. (2003)</a> concluded that reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12543978" 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="#96" class="mim-tip-reference" title="Song, J., Wu, L., Chen, Z., Kohanski, R. A., Pick, L. <strong>Axons guided by insulin receptor in Drosophila visual system.</strong> Science 300: 502-505, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12702880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12702880</a>] [<a href="https://doi.org/10.1126/science.1081203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12702880">Song et al. (2003)</a> found that in Drosophila, the insulin receptor functions in axon guidance and is required for photoreceptor cell axons to find their way from the retina to the brain during development of the visual system. The Drosophila insulin receptor functions as a guidance receptor for the adaptor protein Dock/Nck (see <a href="/entry/600508">600508</a>). This function is independent of Chico, the Drosophila insulin receptor substrate homolog. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12702880" 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="#76" class="mim-tip-reference" title="Nef, S., Verma-Kurvari, S., Merenmies, J., Vassalli, J.-D., Efstratiadis, A., Accili, D., Parada, L. F. <strong>Testis determination requires insulin receptor family function in mice.</strong> Nature 426: 291-295, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14628051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14628051</a>] [<a href="https://doi.org/10.1038/nature02059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14628051">Nef et al. (2003)</a> demonstrated that the insulin receptor tyrosine kinase family, comprising INSR, IGF1R (<a href="/entry/147370">147370</a>), and IRR (<a href="/entry/147671">147671</a>), is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry (<a href="/entry/480000">480000</a>) and the early testis-specific marker Sox9 (<a href="/entry/608160">608160</a>) indicated that the insulin signaling pathway is required for male sex determination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14628051" 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="#50" class="mim-tip-reference" title="Kondo, T., Vicent, D., Suzuma, K., Yanagisawa, M., King, G. L., Holzenberger, M., Kahn, C. R. <strong>Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization.</strong> J. Clin. Invest. 111: 1835-1842, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12813019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12813019</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12813019[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI17455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12813019">Kondo et al. (2003)</a> observed that, following relative hypoxia, mice with a vascular endothelial cell-specific Insr knockout (VENIRKO) showed a 57% decrease in retinal neovascularization compared to controls, which was associated with a blunted rise in the vascular mediators VEGF (<a href="/entry/192240">192240</a>), eNOS (NOS3; <a href="/entry/163729">163729</a>), and endothelin-1 (EDN1; <a href="/entry/131240">131240</a>). Mice with a vascular endothelial cell-specific knockout of the Igf1 receptor (VENIFARKO) showed only a 34% reduction in neovascularization and a very modest reduction in mediator generation. <a href="#50" class="mim-tip-reference" title="Kondo, T., Vicent, D., Suzuma, K., Yanagisawa, M., King, G. L., Holzenberger, M., Kahn, C. R. <strong>Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization.</strong> J. Clin. Invest. 111: 1835-1842, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12813019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12813019</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12813019[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI17455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12813019">Kondo et al. (2003)</a> concluded that both insulin and IGF1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with insulin having a greater effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12813019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By mosaic analysis of insulin receptor function in mice, <a href="#47" class="mim-tip-reference" title="Kitamura, T., Kitamura, Y., Nakae, J., Giordano, A., Cinti, S., Kahn, C. R., Efstratiadis, A., Accili, D. <strong>Mosaic analysis of insulin receptor function.</strong> J. Clin. Invest. 113: 209-219, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722613</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14722613[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI17810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722613">Kitamura et al. (2004)</a> demonstrated that insulin regulates growth independently of metabolism and that the number of insulin receptors is an important determinant of the specificity of insulin action. They generated mice with variable cellular mosaicism for null Insr alleles. Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles Donohue syndrome in humans (<a href="/entry/246200">246200</a>). Insr ablation in 98% of cells, although resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia. The growth retardation was associated with a greater than 60-fold increase in the expression of hepatic insulin-like growth factor-binding protein-1 (IGFBP1; <a href="/entry/146730">146730</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis (<a href="#3" class="mim-tip-reference" title="Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool, M. H., Salvatore, P., Asico, L. D., Jose, P. A., Taylor, S. I., Westphal, H. <strong>Early neonatal death in mice homozygous for a null allele of the insulin receptor gene.</strong> Nature Genet. 12: 106-109, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8528241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8528241</a>] [<a href="https://doi.org/10.1038/ng0196-106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8528241">Accili et al., 1996</a>). <a href="#80" class="mim-tip-reference" title="Okamoto, H., Nakae, J., Kitamura, T., Park, B.-C., Dragatsis, I., Accili, D. <strong>Transgenic rescue of insulin receptor-deficient mice.</strong> J. Clin. Invest. 114: 214-223, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15254588[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI21645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254588">Okamoto et al. (2004)</a> showed that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescued Insr knockout mice from neonatal death, prevented diabetes in a majority of animals, and normalized adipose tissue content, life span, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells were rescued from neonatal death, but developed lipoatrophic diabetes and died prematurely. <a href="#80" class="mim-tip-reference" title="Okamoto, H., Nakae, J., Kitamura, T., Park, B.-C., Dragatsis, I., Accili, D. <strong>Transgenic rescue of insulin receptor-deficient mice.</strong> J. Clin. Invest. 114: 214-223, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254588</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15254588[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI21645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254588">Okamoto et al. (2004)</a> concluded that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15254588+8528241" 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="#23" class="mim-tip-reference" title="Corl, A. B., Rodan, A. R., Heberlein, U. <strong>Insulin signaling in the nervous system regulates ethanol intoxication in Drosophila melanogaster.</strong> Nature Neurosci. 8: 18-19, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15592467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15592467</a>] [<a href="https://doi.org/10.1038/nn1363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15592467">Corl et al. (2005)</a> found that specific inhibition of the insulin receptor or its signaling pathways in the nervous system led to increased ethanol sensitivity in Drosophila. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15592467" 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="#105" class="mim-tip-reference" title="Ueki, K., Okada, T., Hu, J., Liew, C. W., Assmann, A., Dahlgren, G. M., Peters, J. L., Shackman, J. G., Zhang, M., Artner, I., Satin, L. S., Stein, R., Holzenberger, M., Kennedy, R. T., Kahn, C. R., Kulkarni, R. N. <strong>Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes.</strong> Nature Genet. 38: 583-588, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16642022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16642022</a>] [<a href="https://doi.org/10.1038/ng1787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16642022">Ueki et al. (2006)</a> created mice lacking both Insr and Igf1r only in pancreatic beta cells. These mice were born with the normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. At 2 weeks of age, normoglycemic beta cell-specific double-knockout mice showed reduced beta cell mass, reduced expression of phosphorylated Akt (<a href="/entry/164730">164730</a>) and the transcription factor MafA (<a href="/entry/610303">610303</a>), increased apoptosis in islets, and severely compromised beta cell function. Analyses of compound knockout showed a dominant role for insulin signaling in regulating beta cell mass. <a href="#105" class="mim-tip-reference" title="Ueki, K., Okada, T., Hu, J., Liew, C. W., Assmann, A., Dahlgren, G. M., Peters, J. L., Shackman, J. G., Zhang, M., Artner, I., Satin, L. S., Stein, R., Holzenberger, M., Kennedy, R. T., Kahn, C. R., Kulkarni, R. N. <strong>Total insulin and IGF-I resistance in pancreatic beta cells causes overt diabetes.</strong> Nature Genet. 38: 583-588, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16642022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16642022</a>] [<a href="https://doi.org/10.1038/ng1787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16642022">Ueki et al. (2006)</a> concluded that insulin- and IGF1-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16642022" 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="Biddinger, S. B., Haas, J. T., Yu, B. B., Bezy, O., Jing, E., Zhang, W., Unterman, T. G., Carey, M. C., Kahn, C. R. <strong>Hepatic insulin resistance directly promotes formation of cholesterol gallstones.</strong> Nature Med. 14: 778-782, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587407[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/nm1785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587407">Biddinger et al. (2008)</a> generated liver-specific Insr-knockout mice (LIRKO) and observed a marked predisposition to cholesterol gallstone formation, with all of the LIRKO mice developing gallstones after 12 weeks on a lithogenic diet. This predisposition was due to at least 2 distinct mechanisms: disinhibition of the Foxo1 gene (<a href="/entry/136533">136533</a>), which increased expression of the biliary cholesterol transporters Abcg5 (<a href="/entry/605459">605459</a>) and Abcg8 (<a href="/entry/605460">605460</a>), resulting in an increase in biliary cholesterol secretion; and decreased expression of the bile acid synthetic enzymes, particularly Cyp7b1 (<a href="/entry/603711">603711</a>), which produced partial resistance to the farnesoid X receptor (NR1H4; <a href="/entry/603826">603826</a>), leading to a lithogenic bile salt profile. <a href="#11" class="mim-tip-reference" title="Biddinger, S. B., Haas, J. T., Yu, B. B., Bezy, O., Jing, E., Zhang, W., Unterman, T. G., Carey, M. C., Kahn, C. R. <strong>Hepatic insulin resistance directly promotes formation of cholesterol gallstones.</strong> Nature Med. 14: 778-782, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18587407/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18587407</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18587407[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/nm1785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18587407">Biddinger et al. (2008)</a> concluded that hepatic insulin resistance provides the link between the metabolic syndrome (<a href="/entry/605552">605552</a>) and increased cholesterol gallstone susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18587407" 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="#84" class="mim-tip-reference" title="Rajala, A., Tanito, M., Le, Y. Z., Kahn, C. R., Rajala, R. V. S. <strong>Loss of neuroprotective survival signal in mice lacking insulin receptor gene in rod photoreceptor cells.</strong> J. Biol. Chem. 283: 19781-19792, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18480052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18480052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18480052[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M802374200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18480052">Rajala et al. (2008)</a> generated rod photoreceptor-specific Insr-knockout mice and found that rods of mutant mice had reduced PI3K and Akt. Mutant mice had a normal phenotype when raised in dim light, but they exhibited significantly reduced retinal function and loss of photoreceptors when exposed to bright light. The authors proposed that INSR may be essential for photoreceptor neuroprotection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18480052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=147670[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3104G-T in exon 17 and results in an amino acid change gly1035 to val (G1035V), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> noted that this mutation has also been referred to as gly1008 to val (G1008V). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a young Japanese male with insulin-resistant diabetes mellitus and acanthosis nigricans (<a href="/entry/610549">610549</a>), in whom impaired tyrosine protein kinase activity had been demonstrated, <a href="#78" class="mim-tip-reference" title="Odawara, M., Kadowaki, T., Yamamoto, R., Shibasaki, Y., Tobe, K., Accili, D., Bevins, C., Mikami, Y., Matsuura, N., Akanuma, Y., Takaku, F., Taylor, S. I., Kasuga, M. <strong>Human diabetes associated with a mutation in the tyrosine kinase domain of the insulin receptor.</strong> Science 245: 66-68, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544998</a>] [<a href="https://doi.org/10.1126/science.2544998" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544998">Odawara et al. (1989)</a> cloned a cDNA for the insulin receptor. One of this person's alleles had a mutation in which valine was substituted for glycine-996 (GLY996VAL), the third glycine in the conserved gly-X-gly-X-X-gly motif in the putative binding site for adenosine triphosphate. Expression of the mutant receptor by transfection into Chinese hamster ovary cells confirmed that the mutation impairs tyrosine kinase activity. The presence of mutant receptors appeared to have negative effects on the activity of the normal receptor. Studies with kinase-deficient insulin receptors transfected into cultured cells show that such receptors function as dominant-negative mutations and suppress the function of endogenous insulin receptors (review by <a href="#44" class="mim-tip-reference" title="Kahn, C. R., Goldstein, B. J. <strong>Molecular defects in insulin action.</strong> Science 245: 13 only, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2662406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2662406</a>] [<a href="https://doi.org/10.1126/science.2662406" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2662406">Kahn and Goldstein, 1989</a>). In most other cases of insulin resistance, the mutation is expressed as a recessive. <a href="#113" class="mim-tip-reference" title="Yamamoto-Honda, R., Koshio, O., Tobe, K., Shibasaki, Y., Momomura, K., Odawara, M., Kadowaki, T., Takaku, F., Akanuma, Y., Kasuga, M. <strong>Phosphorylation state and biological function of a mutant human insulin receptor val(996).</strong> J. Biol. Chem. 265: 14777-14783, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2203761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2203761</a>]" pmid="2203761">Yamamoto-Honda et al. (1990)</a> studied the function of this mutant form of the insulin receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2544998+2662406+2203761" 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">rs121913136 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913136;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=rs121913136" 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=rs121913136" 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=RCV000015794 OR RCV004724744" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015794, RCV004724744" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015794...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1459A-G in exon 6 and results in an amino acid change lys487 to glu (K487E), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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>Donohue syndrome (<a href="/entry/246200">246200</a>) is an autosomal recessive disorder due to a defect in the INSR gene. In the patient leprechaun/Ark-1, <a href="#38" class="mim-tip-reference" title="Kadowaki, T., Bevins, C. L., Cama, A., Ojamaa, K., Marcus-Samuels, B., Kadowaki, H., Beitz, L., McKeon, C., Taylor, S. I. <strong>Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance.</strong> Science 240: 787-790, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2834824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2834824</a>] [<a href="https://doi.org/10.1126/science.2834824" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2834824">Kadowaki et al. (1988)</a> found 2 different mutant alleles of the INSR gene. The patient was a compound heterozygote, with the maternal allele containing a missense mutation (AAG-to-GAG) encoding the substitution of glutamic acid for lysine at position 460 (LYS460GLU, K460E) in the alpha subunit and with the paternal allele having a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit (<a href="#0003">147670.0003</a>), thereby deleting both the transmembrane and the tyrosine kinase domains of the receptor. The mutation was designated leprechaunism Ark-1/allele-1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2834824" 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> rs121913137 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913137;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/rs121913137?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=rs121913137" 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=rs121913137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.2095C-T in exon 10 and results in an amino acid change gln699 to ter (Q699X), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a case of Donohue syndrome (<a href="/entry/246200">246200</a>) due to compound heterozygosity for mutations in the INSR gene, <a href="#38" class="mim-tip-reference" title="Kadowaki, T., Bevins, C. L., Cama, A., Ojamaa, K., Marcus-Samuels, B., Kadowaki, H., Beitz, L., McKeon, C., Taylor, S. I. <strong>Two mutant alleles of the insulin receptor gene in a patient with extreme insulin resistance.</strong> Science 240: 787-790, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2834824/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2834824</a>] [<a href="https://doi.org/10.1126/science.2834824" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2834824">Kadowaki et al. (1988)</a> found that the paternal allele had a nonsense mutation (CAG-to-TAG) causing premature chain termination after amino acid 671 (GLN672TER, Q672X) in the alpha subunit, thereby deleting both the transmembrane and the tyrosine kinase domains of the receptor. This mutation was designated leprechaunism Ark-1 allele-2. The maternal allele carried a missense mutation (<a href="#0001">147670.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2834824" 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">rs121913138 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913138;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=rs121913138" 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=rs121913138" 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=RCV000015798" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015798" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015798</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.2286G-T in exon 12 and results in an amino acid change arg762 to ser (R762S), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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="#46" class="mim-tip-reference" title="Kakehi, T., Hisatomi, A., Kuzuya, H., Yoshimasa, Y., Okamoto, M., Yamada, K., Nishimura, H., Kosaki, A., Nawata, H., Umeda, F., Ibayashi, H., Imura, H. <strong>Defective processing of insulin-receptor precursor in cultured lymphocytes from a patient with extreme insulin resistance.</strong> J. Clin. Invest. 81: 2020-2022, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3384956/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3384956</a>] [<a href="https://doi.org/10.1172/JCI113553" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3384956">Kakehi et al. (1988)</a> found defective processing of the insulin receptor precursor in a 23-year-old Japanese female with extreme insulin resistance, acanthosis nigricans, bilateral polycystic ovaries, and decreased erythrocyte insulin binding (<a href="/entry/610549">610549</a>). Antireceptor antibodies showed the presence of increased amounts of a 210-kD protein but no detectable alpha or beta subunits. It appeared that the 190-kD receptor precursor was synthesized normally and underwent terminal glycosylation and normal intracellular transport to the cell surface, but that proteolytic maturation to alpha and beta subunits did not occur. The mutation could lie either in the INSR gene or in the gene for the receptor-processing enzyme. The former possibility proved to be correct. <a href="#115" class="mim-tip-reference" title="Yoshimasa, Y., Seino, S., Whittaker, J., Kakehi, T., Kosaki, A., Kuzuya, H., Imura, H., Bell, G. I., Steiner, D. F. <strong>Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing.</strong> Science 240: 784-787, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3283938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3283938</a>] [<a href="https://doi.org/10.1126/science.3283938" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3283938">Yoshimasa et al. (1988)</a> found that the insulin receptor gene in this patient had a point mutation within the tetrabasic processing site which was changed from arg-lys-arg-arg to arg-lys-arg-ser. Exon 12 contained a change in codon 735 from AGG-to-AGT (ARG735SER, R735S). Epstein-Barr virus-transformed lymphocytes from this patient synthesized an insulin receptor precursor that was normally glycosylated and inserted into the plasma membrane but was not cleaved to mature alpha and beta subunits. Insulin binding to these cells was severely reduced but could be increased about 5-fold by gentle treatment with trypsin, which was accompanied by appearance of normal alpha subunits. These results indicated that proteolysis of the proreceptor is necessary for its normal full insulin-binding sensitivity and signal-transducing activity and that a cellular protease that is more stringent in its specificity than trypsin is required to process the receptor precursor. The patient was a 23-year-old Japanese woman who was the product of a first-cousin marriage. Diabetes was first recognized at age 6. She showed nonketotic insulin-resistant diabetes mellitus with markedly elevated serum insulin values, acanthosis nigricans, hirsutism, and virilism. Her older sister was similarly affected. In addition, they showed some features not normally considered part of this syndrome, including mental retardation, short stature, and dental dysplasia. The latter 2 features have also been reported in an unrelated subject with Rabson-Mendenhall syndrome (<a href="#83" class="mim-tip-reference" title="Rabson, S. M., Mendenhall, E. N. <strong>Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus.</strong> Am. J. Clin. Path. 26: 283-290, 1956.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13302174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13302174</a>] [<a href="https://doi.org/10.1093/ajcp/26.3.283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13302174">Rabson and Mendenhall, 1956</a>) who expressed an altered insulin receptor (<a href="#102" class="mim-tip-reference" title="Taylor, S. I., Underhill, L. H., Hedo, J. A., Roth, J., Serrano Rios, M., Blizzard, R. M. <strong>Decreased insulin binding to cultured cells from a patient with the Rabson-Mendenhall syndrome: dichotomy between studies with cultured lymphocytes and cultured fibroblasts.</strong> J. Clin. Endocr. Metab. 56: 856-861, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6339538/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6339538</a>] [<a href="https://doi.org/10.1210/jcem-56-4-856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6339538">Taylor et al., 1983</a>). Insulin resistance due to this mutation behaved as a recessive. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13302174+3384956+6339538+3283938" 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="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3680G-C in exon 21 and results in an amino acid change trp1227 to ser (W1227S), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In patient A(2) of the study of <a href="#33" class="mim-tip-reference" title="Grigorescu, F., Flier, J. S., Kahn, C. R. <strong>Characterization of binding and phosphorylation defects of erythrocyte insulin receptors in the type A syndrome of insulin resistance.</strong> Diabetes 35: 127-138, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3510919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3510919</a>] [<a href="https://doi.org/10.2337/diab.35.2.127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3510919">Grigorescu et al. (1986)</a> with insulin-resistant diabetes and acanthosis nigricans (<a href="/entry/610549">610549</a>), <a href="#70" class="mim-tip-reference" title="Moller, D. E., Flier, J. S. <strong>Detection of an alteration in the insulin-receptor gene in a patient with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (type A insulin resistance).</strong> New Eng. J. Med. 319: 1526-1529, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2460770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2460770</a>] [<a href="https://doi.org/10.1056/NEJM198812083192306" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2460770">Moller and Flier (1988)</a> detected a heterozygous point mutation affecting the tyrosine kinase domain of the patient's insulin receptors, such that tryptophan-1200 was replaced by serine (TRP1200SER, W1200S). Hybridization of a mutant allele-specific oligonucleotide to PCR-amplified cDNA confirmed the presence of the mutant allele in the proband and excluded it in her unaffected sister and mother, 18 normal control subjects, and 6 other subjects with insulin resistance. <a href="#72" class="mim-tip-reference" title="Moller, D. E., Yokota, A., Ginsberg-Fellner, F., Flier, J. S. <strong>Functional properties of a naturally occurring trp(1200)-to-ser(1200) mutation of the insulin receptor.</strong> Molec. Endocr. 4: 1183-1191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1963473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1963473</a>] [<a href="https://doi.org/10.1210/mend-4-8-1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1963473">Moller et al. (1990)</a> showed that Chinese hamster ovary cells transfected with mutant cDNA produced a mutant receptor that was functionally severely impaired. The studies demonstrated the importance of trp-1200 to the normal function of the insulin receptor kinase. The observations demonstrated that severe insulin resistance can be caused by the heterozygous state of an INSR mutation. (<a href="#72" class="mim-tip-reference" title="Moller, D. E., Yokota, A., Ginsberg-Fellner, F., Flier, J. S. <strong>Functional properties of a naturally occurring trp(1200)-to-ser(1200) mutation of the insulin receptor.</strong> Molec. Endocr. 4: 1183-1191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1963473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1963473</a>] [<a href="https://doi.org/10.1210/mend-4-8-1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1963473">Moller et al. (1990)</a> used the nucleotide and amino acid numbering system of <a href="#26" class="mim-tip-reference" title="Ebina, Y., Ellis, L., Jarnagin, K., Edery, M., Graf, L., Clauser, E., Ou, J.-H., Masiarz, F., Kan, Y. W., Goldfine, I. D., Roth, R. A., Rutter, W. J. <strong>The human insulin receptor cDNA: the structural basis for hormone activated transmembrane signalling.</strong> Cell 40: 747-758, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2859121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2859121</a>] [<a href="https://doi.org/10.1016/0092-8674(85)90334-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2859121">Ebina et al. (1985)</a>.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1963473+3510919+2460770+2859121" 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 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015799" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015799" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015799</a>
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<p><a href="#98" class="mim-tip-reference" title="Taira, M., Taira, M., Hashimoto, N., Shimada, F., Suzuki, Y., Kanatsuka, A., Nakamura, F., Ebina, Y., Tatibana, M., Makino, H., Yoshida, S. <strong>Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor.</strong> Science 245: 63-66, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544997</a>] [<a href="https://doi.org/10.1126/science.2544997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544997">Taira et al. (1989)</a> studied a 17-year-old Japanese female who exhibited insulin-resistant diabetes, short stature, and acanthosis nigricans (<a href="/entry/610549">610549</a>). The mother had the same phenotype, whereas the father and 2 sibs were unaffected. The proband's maternal uncle and maternal grandfather were also said to be diabetic and of short stature. Erythrocytes and cultured fibroblasts from the proband and her mother had an insulin-binding capacity in the normal range, but cultured fibroblasts from both showed a below-normal rate of 2-deoxyglucose uptake. Therefore, the insulin resistance in this instance seemed to be due to a defect downstream from insulin binding. <a href="#98" class="mim-tip-reference" title="Taira, M., Taira, M., Hashimoto, N., Shimada, F., Suzuki, Y., Kanatsuka, A., Nakamura, F., Ebina, Y., Tatibana, M., Makino, H., Yoshida, S. <strong>Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor.</strong> Science 245: 63-66, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544997</a>] [<a href="https://doi.org/10.1126/science.2544997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544997">Taira et al. (1989)</a> demonstrated that the mutant insulin receptor gene in these 2 subjects lacked almost the entire tyrosine kinase domain. Receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's lymphocytes that had been transformed by Epstein-Barr virus. With the use of several region-specific insulin receptor cDNA probes, <a href="#98" class="mim-tip-reference" title="Taira, M., Taira, M., Hashimoto, N., Shimada, F., Suzuki, Y., Kanatsuka, A., Nakamura, F., Ebina, Y., Tatibana, M., Makino, H., Yoshida, S. <strong>Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor.</strong> Science 245: 63-66, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2544997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2544997</a>] [<a href="https://doi.org/10.1126/science.2544997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2544997">Taira et al. (1989)</a> analyzed the mutation further and demonstrated that it occurred at a nucleotide within the exon just before the codon for lys1030. This amino acid is part of the adenosine triphosphate (ATP)-binding site of the receptor and is required for tyrosine kinase activity. The exon containing the mutation corresponded to exon 17, which encodes the NH(2)-terminal part of the kinase domain. The sequence of the receptor gene was normal on the upstream side of the site of the mutation at nucleotide 145 (of the cloned fragment studied in detail); distal to this site it was entirely different to the point where a stop codon was reached at nucleotide 339. Thus, the putative product from the mutated gene has a new sequence of 65 amino acids at its COOH-terminus. The new sequence of the mutant allele was homologous to the consensus sequence of the Alu family, suggesting that the mutation resulted from recombination between exon 17 of the insulin receptor and an Alu sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2544997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> cataloged this mutation as a complex rearrangement according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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> rs387906538 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906538;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/rs387906538?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=rs387906538" 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=rs387906538" 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=RCV000015800" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015800" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015800</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.2770C-T in exon 14 and results in an amino acid change arg924 to ter (R924X), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Donohue syndrome (<a href="/entry/246200">246200</a>), <a href="#42" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Taylor, S. I. <strong>A nonsense mutation causing decreased levels of insulin receptor mRNA: detection by a simplified technique for direct sequencing of genomic DNA amplified by the polymerase chain reaction.</strong> Proc. Nat. Acad. Sci. 87: 658-662, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2300553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2300553</a>] [<a href="https://doi.org/10.1073/pnas.87.2.658" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2300553">Kadowaki et al. (1990)</a> identified a nonsense mutation at codon 897 (ARG897TER, R897X) in exon 14 in the paternal allele of the patient's insulin receptor gene. In addition, they obtained evidence that the patient's maternal allele contained a cis-acting dominant mutation that, like the paternal allele, caused a decrease in the level of mRNA. The nucleotide sequence of the entire protein-coding domain and the sequences of the intron-exon boundaries of all 22 exons of the maternal allele were normal. This mutation was designated leprechaunism Minn-1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2300553" 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>.0008 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</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">rs121913139 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913139;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=rs121913139" 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=rs121913139" 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=RCV000015801 OR RCV000015802" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015801, RCV000015802" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015801...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3481G-A in exon 19 and results in an amino acid change ala1161 to thr (A1161T), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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="#72" class="mim-tip-reference" title="Moller, D. E., Yokota, A., Ginsberg-Fellner, F., Flier, J. S. <strong>Functional properties of a naturally occurring trp(1200)-to-ser(1200) mutation of the insulin receptor.</strong> Molec. Endocr. 4: 1183-1191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1963473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1963473</a>] [<a href="https://doi.org/10.1210/mend-4-8-1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1963473">Moller et al. (1990)</a> studied a family in which 3 sisters had the type A syndrome of insulin resistance (<a href="/entry/610549">610549</a>), the father was hyperinsulinemic without acanthosis nigricans or other abnormalities (see <a href="/entry/125853">125853</a>), and the mother was normal. The daughters and father were found to be heterozygous for a single base substitution in codon 1134 (GCA to ACA, ala to thr; ALA1134THR, A1134T). Transfection of the mutant insulin receptor gene into CHO cells showed that the protein produced had markedly impaired insulin-stimulated autophosphorylation. The family demonstrates that severe insulin resistance with dominant inheritance can be caused by a missense mutation and can be clinically silent in a male. <a href="#72" class="mim-tip-reference" title="Moller, D. E., Yokota, A., Ginsberg-Fellner, F., Flier, J. S. <strong>Functional properties of a naturally occurring trp(1200)-to-ser(1200) mutation of the insulin receptor.</strong> Molec. Endocr. 4: 1183-1191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1963473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1963473</a>] [<a href="https://doi.org/10.1210/mend-4-8-1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1963473">Moller et al. (1990)</a> studied expression of the ala1134 mutant receptor in Chinese hamster ovary cells. The expressed mutant receptors were processed normally and displayed normal affinity in insulin binding but were markedly deficient in insulin-stimulated autophosphorylation. <a href="#72" class="mim-tip-reference" title="Moller, D. E., Yokota, A., Ginsberg-Fellner, F., Flier, J. S. <strong>Functional properties of a naturally occurring trp(1200)-to-ser(1200) mutation of the insulin receptor.</strong> Molec. Endocr. 4: 1183-1191, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1963473/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1963473</a>] [<a href="https://doi.org/10.1210/mend-4-8-1183" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1963473">Moller et al. (1990)</a> pointed out that alanine-1134 is a highly conserved residue located in a consensus sequence found in most tyrosine kinases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1963473" 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> rs121913141 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913141;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/rs121913141?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=rs121913141" 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=rs121913141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.779T-C in exon 3 and results in an amino acid change leu260 to pro (L260P), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Donohue syndrome (<a href="/entry/246200">246200</a>), the son of parents related as second cousins once removed, coming from the town of Geldeimalsen in the Netherlands, <a href="#49" class="mim-tip-reference" title="Klinkhamer, M. P., Groen, N. A., van der Zon, G. C. M., Lindhout, D., Sandkuyl, L. A., Krans, H. M. J., Moller, W., Maassen, J. A. <strong>A leucine-to-proline mutation in the insulin receptor in a family with insulin resistance.</strong> EMBO J. 8: 2503-2507, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2479553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2479553</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1989.tb08387.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2479553">Klinkhamer et al. (1989)</a> described a leucine-to-proline mutation at position 233 (LEU233PRO; L233P). By DNA amplification, they showed that the patient was homozygous and the parents and 2 of the grandparents from the consanguineous line were heterozygous. All the heterozygotes showed decreased insulin binding to cultured fibroblasts and had mild insulin resistance in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2479553" 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="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1225T-G in exon 5 and results in an amino acid change phe409 to val (F409V), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 women with insulin-resistant diabetes (see <a href="/entry/125853">125853</a>), daughters of first-cousin, Venezuelan Caucasian parents, <a href="#4" class="mim-tip-reference" title="Accili, D., Frapier, C., Mosthaf, L., McKeon, C., Elbein, S. C., Permutt, M. A., Ramos, E., Lander, E., Ullrich, A., Taylor, S. I. <strong>A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.</strong> EMBO J. 8: 2509-2517, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2573522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2573522</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1989.tb08388.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2573522">Accili et al. (1989)</a> identified a T-to-G transversion at position 1273, leading to the substitution of valine for phenylalanine at position 382 in the alpha subunit of the insulin receptor (PHE382VAL; F382V). Inspection of mutant insulin receptor cDNA into NIH 3T3 cells demonstrated that the val382 mutation impaired posttranslational processing and retarded transport of the insulin receptor to the plasma membrane. They used multiple RFLPs to determine haplotypes at the INSR locus and arrived at a lod score of approximately 1.9 to 2.3 for linkage with insulin-resistant diabetes in this family. They pointed out that this lod score exceeds the threshold for declaring linkage when studying a single candidate locus (<a href="#54" class="mim-tip-reference" title="Lander, E. S., Botstein, D. <strong>Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children.</strong> Science 236: 1567-1570, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2884728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2884728</a>] [<a href="https://doi.org/10.1126/science.2884728" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2884728">Lander and Botstein, 1987</a>). The sisters had previously been reported by <a href="#8" class="mim-tip-reference" title="Barnes, N. D., Palumbo, P. J., Hayles, A. B., Folgar, H. <strong>Insulin resistance, skin changes, and virilization: a recessively inherited syndrome possibly due to pineal gland dysfunction.</strong> Diabetologia 10: 285-289, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4413914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4413914</a>] [<a href="https://doi.org/10.1007/BF02627729" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4413914">Barnes et al. (1974)</a> as a case of insulin resistance possibly due to pineal gland dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2573522+4413914+2884728" 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=RCV000015806" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015806" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015806</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.126C-A in exon 2 and results in an amino acid change asn42 to lys (N42K), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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="#41" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Rechler, M. M., Serrano-Rios, M., Roth, J., Gorden, P., Taylor, S. I. <strong>Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.</strong> J. Clin. Invest. 86: 254-264, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2365819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2365819</a>] [<a href="https://doi.org/10.1172/JCI114693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2365819">Kadowaki et al. (1990)</a> studied a patient (RM-1) with Rabson-Mendenhall syndrome (<a href="#75" class="mim-tip-reference" title="Moncada, V. Y., Hedo, J. A., Serrano-Rios, M., Taylor, S. I. <strong>Insulin-receptor biosynthesis in cultured lymphocytes from an insulin-resistant patient (Rabson-Mendenhall syndrome): evidence for defect before insertion of receptor into plasma membrane.</strong> Diabetes 35: 802-807, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3721065/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3721065</a>] [<a href="https://doi.org/10.2337/diab.35.7.802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3721065">Moncada et al., 1986</a>; <a href="/entry/262190">262190</a>) who was found to be a compound heterozygote for 2 mutant alleles of the INSR gene: a missense mutation that substituted lysine for asparagine-15 (AAC to AAA; ASN15LYS, N15K) and a nonsense mutation at codon 1000 (CGA to TGA, ARG1000TER, R1000X; see <a href="#0013">147670.0013</a>). <a href="#39" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Accili, D., Taylor, S. I. <strong>Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor: a mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding.</strong> J. Biol. Chem. 265: 19143-19150, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2121734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2121734</a>]" pmid="2121734">Kadowaki et al. (1990)</a> characterized the lys15-mutant receptor expressed by transfection by mutant cDNA into NIH 3T3 cells. At least 2 defects in insulin receptor function were observed. The mutation retarded posttranslational processing of the receptor and impaired transport of the receptor to the plasma membrane, thereby reducing the number of the receptors on the cell surface. It also caused a 5-fold reduction in the affinity of the receptor for insulin. <a href="#39" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Accili, D., Taylor, S. I. <strong>Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor: a mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding.</strong> J. Biol. Chem. 265: 19143-19150, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2121734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2121734</a>]" pmid="2121734">Kadowaki et al. (1990)</a> suggested that both functional defects were related to distortion of the 3-dimensional structure of the receptor by the mutation. Presumably, the abnormal conformation interfered with the transport of the receptor through the endoplasmic reticulum and Golgi apparatus, and also inhibited the binding of insulin to its binding site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2365819+2121734+3721065" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 RABSON-MENDENHALL SYNDROME</strong>
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DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS, INCLUDED
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000015807 OR RCV000128412" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015807, RCV000128412" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015807...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3079C-T in exon 17 and results in an amino acid change arg1027 to ter (R1027X), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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>See <a href="#0012">147670.0012</a> and <a href="#39" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Accili, D., Taylor, S. I. <strong>Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor: a mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding.</strong> J. Biol. Chem. 265: 19143-19150, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2121734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2121734</a>]" pmid="2121734">Kadowaki et al. (1990)</a>. See <a href="#0018">147670.0018</a> and <a href="#53" class="mim-tip-reference" title="Kusari, J., Takata, Y., Hatada, E., Freidenberg, G., Kolterman, O., Olefsky, J. M. <strong>Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles.</strong> J. Biol. Chem. 266: 5260-5267, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2002058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2002058</a>]" pmid="2002058">Kusari et al. (1991)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2121734+2002058" 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>.0014 DONOHUE 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> rs121913145 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913145;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/rs121913145?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=rs121913145" 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=rs121913145" 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=RCV000015808" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015808" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015808</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.707A-G in exon 3 and results in an amino acid change his236 to arg (H236R), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a case of Donohue syndrome (<a href="/entry/246200">246200</a>) in a consanguineous Winnipeg pedigree, <a href="#41" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Rechler, M. M., Serrano-Rios, M., Roth, J., Gorden, P., Taylor, S. I. <strong>Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.</strong> J. Clin. Invest. 86: 254-264, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2365819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2365819</a>] [<a href="https://doi.org/10.1172/JCI114693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2365819">Kadowaki et al. (1990)</a> found homozygosity for a CAC-to-CGC mutation resulting in substitution of histidine by arginine (HIS209ARG, H209R). <a href="#40" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Accili, D., Yazaki, Y., Taylor, S. I. <strong>Substitution of arginine for histidine at position 209 in the alpha-subunit of the human insulin receptor: a mutation that impairs receptor dimerization and transport of receptors to the cell surface.</strong> J. Biol. Chem. 266: 21224-21231, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1657953/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1657953</a>]" pmid="1657953">Kadowaki et al. (1991)</a> demonstrated that this mutation impairs receptor dimerization and transport of receptors to the cell surface. The small number of receptors that are transported to the cell surface bind insulin with normal affinity and have normal tyrosine kinase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2365819+1657953" 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>.0015 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</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">rs121913146 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913146;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=rs121913146" 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=rs121913146" 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=RCV000015809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015809</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.479G-A in exon 2 and results in an amino acid change trp160 to ter (W160X), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient (A-1) with insulin-resistant diabetes mellitus and acanthosis nigricans (<a href="/entry/610549">610549</a>), <a href="#41" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Rechler, M. M., Serrano-Rios, M., Roth, J., Gorden, P., Taylor, S. I. <strong>Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.</strong> J. Clin. Invest. 86: 254-264, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2365819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2365819</a>] [<a href="https://doi.org/10.1172/JCI114693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2365819">Kadowaki et al. (1990)</a> found compound heterozygosity for a trp133 (TGG) nonsense mutation (TAG) (TRP133TER, W133X) and a missense mutation (AAT to AGT, ASN462SER, N462S; see <a href="#0016">147670.0016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2365819" 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>.0016 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</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">rs121913147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913147;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=rs121913147" 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=rs121913147" 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=RCV000015810 OR RCV001753417 OR RCV004795417" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015810, RCV001753417, RCV004795417" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015810...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1466A-G in exon 6 and results in an amino acid change asn489 to ser (N489S), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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>See <a href="#0015">147670.0015</a> and <a href="#41" class="mim-tip-reference" title="Kadowaki, T., Kadowaki, H., Rechler, M. M., Serrano-Rios, M., Roth, J., Gorden, P., Taylor, S. I. <strong>Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.</strong> J. Clin. Invest. 86: 254-264, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2365819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2365819</a>] [<a href="https://doi.org/10.1172/JCI114693" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2365819">Kadowaki et al. (1990)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2365819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 16-year-old Japanese girl with type A insulin resistance (hyperinsulinemia, decreased insulin binding, and acanthosis nigricans; <a href="/entry/610549">610549</a>), <a href="#95" class="mim-tip-reference" title="Shimada, F., Taira, M., Suzuki, Y., Hashimoto, N., Nozaki, O., Taira, M., Tatibana, M., Ebina, Y., Tawata, M., Onaya, T., Makino, H., Yoshida, S. <strong>Insulin-resistant diabetes associated with partial deletion of insulin-receptor gene.</strong> Lancet 335: 1179-1181, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1971035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1971035</a>] [<a href="https://doi.org/10.1016/0140-6736(90)92695-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1971035">Shimada et al. (1990)</a> found that 1 LDLR allele, inherited from her mother, contained a 1.2-kb deletion arising from a recombination between 2 Alu elements, one in intron 13 and the other in intron 14, and removing exon 14. The nature of the allele inherited from the father was not determined. The father had borderline impairment of glucose tolerance and mild insulin resistance. <a href="#94" class="mim-tip-reference" title="Shimada, F., Suzuki, Y., Taira, M., Hashimoto, N., Nozaki, O., Makino, H., Yoshida, S. <strong>Abnormal messenger ribonucleic acid (mRNA) transcribed from a mutant insulin receptor gene in a patient with type A insulin resistance.</strong> Diabetologia 35: 639-644, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1644241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1644241</a>] [<a href="https://doi.org/10.1007/BF00400255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1644241">Shimada et al. (1992)</a> extended these studies to demonstrate that the deletion shifted the reading frame, resulting in a termination codon after amino acid 867 (glu), thereby producing a truncated insulin receptor without a transmembrane region and cytoplasmic domain. They also sequenced all 22 exons of the INSR gene and found no mutation in exons except for the deletion of exon 14. Thus the patient was heterozygous for a single mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1644241+1971035" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> cataloged this mutation as a 1.2-kb deletion including exon 14 according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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> rs121913148 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913148;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/rs121913148?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=rs121913148" 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=rs121913148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3059G-A in exon 17 and results in an amino acid change arg1020 to gln (R1020Q), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). According to <a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a>, this mutation has also been known as arg993 to gln (R993Q). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with acanthosis and insulin-resistant diabetes (<a href="/entry/610549">610549</a>) described by <a href="#90" class="mim-tip-reference" title="Scarlett, J. A., Kolterman, O. G., Moore, P., Saekow, M., Insel, J., Griffin, J., Mako, M., Rubenstein, A. H., Olefsky, J. M. <strong>Insulin resistance and diabetes due to a genetic defect in insulin receptors.</strong> J. Clin. Endocr. Metab. 55: 123-132, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7042734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7042734</a>] [<a href="https://doi.org/10.1210/jcem-55-1-123" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7042734">Scarlett et al. (1982)</a>, <a href="#53" class="mim-tip-reference" title="Kusari, J., Takata, Y., Hatada, E., Freidenberg, G., Kolterman, O., Olefsky, J. M. <strong>Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles.</strong> J. Biol. Chem. 266: 5260-5267, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2002058/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2002058</a>]" pmid="2002058">Kusari et al. (1991)</a> found compound heterozygosity at the INSR locus. The parents were not consanguineous. The paternal allele contained a missense mutation encoding the substitution of glutamine for arginine at position 981 (ARG981GLN, R981Q) in the tyrosine kinase domain of the receptor. The maternal allele contained a nonsense mutation causing premature termination after amino acid 988 in the beta subunit (ARG988TER, R988X; <a href="#0013">147670.0013</a>) thereby deleting most of the kinase domain. A CGA-to-CAA mutation was responsible for the first change, and a CGA-to-TGA mutation for the second. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7042734+2002058" 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="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.172G-A in exon 2 and results in an amino acid change gly58 to arg (G58R), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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="#62" class="mim-tip-reference" title="Maassen, J. A., Klinkhamer, M. P., Odink, R. J. H., Sips, H., van der Zon, G. C. M., Wieringa, T., Krans, H. M. J., Moller, W. <strong>Improper expression of insulin receptors on fibroblasts from a leprechaun patient.</strong> Europ. J. Biochem. 172: 725-729, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3280314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3280314</a>] [<a href="https://doi.org/10.1111/j.1432-1033.1988.tb13949.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3280314">Maassen et al. (1988)</a> described a patient named Helmond with Donohue syndrome (<a href="/entry/246200">246200</a>) in whom intact fibroblasts showed markedly reduced insulin binding but significant receptor autophosphorylation when the glycoprotein fraction was used. In this patient, <a href="#108" class="mim-tip-reference" title="van der Vorm, E. R., van der Zon, G. C. M., Moller, W., Krans, H. M. J., Lindhout, D., Maassen, J. A. <strong>An arg for gly substitution at position 31 in the insulin receptor, linked to insulin resistance, inhibits receptor processing and transport.</strong> J. Biol. Chem. 267: 66-71, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1730625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1730625</a>]" pmid="1730625">van der Vorm et al. (1992)</a> demonstrated a GGA-to-AGA change in exon 2 resulting in a gly31-to-arg substitution (GLY31ARG, G31R). The proband was a compound heterozygote. The mutation was present also in heterozygous state in the mother and maternal grandfather. In the mother and grandfather, the mutation was associated with decreased insulin binding to cultured fibroblasts and in vivo hyperinsulinemia after an oral glucose tolerance test. In the paternal line, all subjects had an insulin binding within the normal range and the G31R mutation was absent. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3280314+1730625" 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> rs121913150 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913150;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/rs121913150?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=rs121913150" 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=rs121913150" 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=RCV000015815" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015815" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015815</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3572G-A in exon 20 and results in an amino acid change arg1191 to gln (R1191Q), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> noted that this mutation has also been classified as arg1164 to gln (R1164Q). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with noninsulin-dependent diabetes mellitus (<a href="/entry/125853">125853</a>), <a href="#22" class="mim-tip-reference" title="Cocozza, S., Porcellini, A., Riccardi, G., Monticelli, A., Condorelli, G., Ferrara, A., Pianese, L., Miele, C., Capaldo, B., Beguinot, F., Varrone, S. <strong>NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene.</strong> Diabetes 41: 521-526, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1607076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1607076</a>] [<a href="https://doi.org/10.2337/diab.41.4.521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1607076">Cocozza et al. (1992)</a> identified an abnormality in exon 20 of the INSR gene by denaturing gradient gel electrophoresis (DGGE). Sequencing showed heterozygosity for a change of codon 1152 from CGG to CAG, resulting in replacement of arginine with glutamine (ARG1152GLN, R1152Q). Although autophosphorylation of the purified insulin receptor seemed to be normal and the insulin binding to intact erythrocytes from the patient was in the normal range, the purified insulin receptor showed no detectable activity toward an exogenous substrate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1607076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Esposito, L., Carrera, P., Pontiroli, A. E., Ferrari, M. <strong>Failure to detect Glut4-Ile383 and IR-Gln1152 variants in NIDDM (non-insulin dependent diabetes mellitus) and control subjects in an Italian population.</strong> Hum. Genet. 95: 115-116, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7814014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7814014</a>] [<a href="https://doi.org/10.1007/BF00225088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7814014">Esposito et al. (1995)</a> screened a cohort of 68 Italian NIDDM patients and 65 controls for INSR R1152Q and did not find the variant in any patients or controls. The authors concluded that the R1152Q variant is not involved in the development of NIDDM in the Italian population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7814014" 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> rs121913151 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913151;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/rs121913151?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=rs121913151" 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=rs121913151" 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=RCV000015816 OR RCV000520627" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015816, RCV000520627" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015816...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1195C-T in exon 5 and results in an amino acid change arg399 to ter (R399X), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a black female, the second child of healthy unrelated parents of Hispanic and Afro-American descent, <a href="#58" class="mim-tip-reference" title="Longo, N., Langley, S. D., Griffin, L. D., Elsas, L. J., II. <strong>Reduced mRNA and a nonsense mutation in the insulin-receptor gene produce heritable severe insulin resistance.</strong> Am. J. Hum. Genet. 50: 998-1007, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1315125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1315125</a>]" pmid="1315125">Longo et al. (1992)</a> found the clinical features of Donohue syndrome (<a href="/entry/246200">246200</a>) related to compound heterozygosity for different mutations. The paternally derived mutation, a C-to-T transition at bp 1333, converted arginine-372 to a stop codon (ARG372TER, R372X). The maternally inherited allele had no mutations within the protein-coding region, suggesting that the second mutation was located in a region of the INSR gene involving control of gene expression. The clinical features of the patient were reported by <a href="#77" class="mim-tip-reference" title="Norton, K. I., Glicklich, M., Kupchik, G., Gray, C. E., Ludman, M. <strong>Leprechaunism: a case report with radiographic features.</strong> Dysmorph. Clin. Genet. 4: 57-62, 1990."None>Norton et al. (1990)</a>. The mutation was labeled leprechaunism Mount Sinai. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1315125" 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">rs121913152 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913152;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=rs121913152" 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=rs121913152" 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=RCV000015817" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015817" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015817</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.164T-C in exon 2 and results in an amino acid change val55 to ala (V55A), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Barbetti, F., Gejman, P. V., Taylor, S. I., Raben, N., Cama, A., Bonora, E., Pizzo, P., Moghetti, P., Muggeo, M., Roth, J. <strong>Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis.</strong> Diabetes 41: 408-415, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1607067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1607067</a>] [<a href="https://doi.org/10.2337/diab.41.4.408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1607067">Barbetti et al. (1992)</a> used denaturing gradient gel electrophoresis (DGGE) to identify compound heterozygosity for 2 different mutations in the INSR gene in a patient labeled leprechaun/Verona-1. The patient was a white female whose appearance suggested Donohue syndrome (<a href="/entry/246200">246200</a>) at birth (characteristic facies, hirsutism, clitoromegaly). Immediately after birth, she developed hypoglycemia during fasting. In addition, she became hyperglycemic after meals. Her peak immunoreactive insulin during an oral glucose tolerance test was very high. At age 6.5 years, pelvic sonogram demonstrated polycystic ovaries, and abdominal sonogram showed bilateral medullary sponge kidneys. The INSR allele inherited from the father had a mutation substituting alanine for valine-28 (VAL28ALA, V28A); in the allele inherited from the mother, arginine was substituted for glycine-366 (GLY366ARG, G366R). <a href="#7" class="mim-tip-reference" title="Barbetti, F., Gejman, P. V., Taylor, S. I., Raben, N., Cama, A., Bonora, E., Pizzo, P., Moghetti, P., Muggeo, M., Roth, J. <strong>Detection of mutations in insulin receptor gene by denaturing gradient gel electrophoresis.</strong> Diabetes 41: 408-415, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1607067/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1607067</a>] [<a href="https://doi.org/10.2337/diab.41.4.408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1607067">Barbetti et al. (1992)</a> applied the DGGE method also to several other cases of Donohue syndrome in whom the genetic defect had previously been identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1607067" 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>.0024 DONOHUE 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">rs267607184 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607184;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=rs267607184" 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=rs267607184" 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=RCV000015795" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015795" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015795</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1177G-A in exon 5 and results in an amino acid change gly393 to arg (G393R), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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>See <a href="#0023">147670.0023</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> rs121913153 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913153;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/rs121913153?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=rs121913153" 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=rs121913153" 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=RCV000015818" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015818" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015818</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.338G-C in exon 2 and results in an amino acid change arg113 to pro (R113P), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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>Fibroblasts cultured from a patient with Donohue syndrome (<a href="/entry/246200">246200</a>) with intrauterine growth retardation and severe insulin resistance (designated leprechaun Atlanta (Atl)-1) had normal amounts of insulin receptor protein and defective insulin binding but constitutive activation of insulin-receptor autophosphorylation and kinase activity and of glucose transport (<a href="#59" class="mim-tip-reference" title="Longo, N., Langley, S. D., Griffin, L. D., Elsas, L. J. <strong>Activation of glucose transport by a natural mutation in the human insulin receptor.</strong> Proc. Nat. Acad. Sci. 90: 60-64, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8419945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8419945</a>] [<a href="https://doi.org/10.1073/pnas.90.1.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8419945">Longo et al., 1993</a>). In the same fibroblasts, growth was impaired. Homozygosity for a mutation in the INSR gene was suspected, since he inherited identical DNA haplotypes for this gene from the parents who were blood relatives. <a href="#59" class="mim-tip-reference" title="Longo, N., Langley, S. D., Griffin, L. D., Elsas, L. J. <strong>Activation of glucose transport by a natural mutation in the human insulin receptor.</strong> Proc. Nat. Acad. Sci. 90: 60-64, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8419945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8419945</a>] [<a href="https://doi.org/10.1073/pnas.90.1.60" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8419945">Longo et al. (1993)</a> found that indeed the proband was homozygous and both parents were heterozygous for a G-to-C transversion at nucleotide 476 of the INSR cDNA converting arginine-86 to proline (ARG86PRO, R86P). Expression of this mutation in CHO cells duplicated the natural mutation by activating glucose transport without increasing insulin binding or insulin-stimulated cellular growth. The R86P substitution is contiguous to the hydrophobic beta-sheet of the receptor alpha subunit implicated in the binding of aromatic residues of the insulin molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8419945" 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">rs121913154 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913154;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=rs121913154" 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=rs121913154" 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=RCV000015819" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015819" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015819</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3485C-A in exon 19 and results in an amino acid change ala1162 to glu (A1162E), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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="Cama, A., de la Luz Sierra, M., Quon, M. J., Ottini, L., Gorden, P., Taylor, S. I. <strong>Substitution of glutamic acid for alanine 1135 in the putative 'catalytic loop' of the tyrosine kinase domain of the human insulin receptor: a mutation that impairs proteolytic processing into subunits and inhibits receptor tyrosine kinase activity.</strong> J. Biol. Chem. 268: 8060-8069, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096518</a>]" pmid="8096518">Cama et al. (1993)</a> described the molecular findings in a 32-year-old woman with insulin resistance. She had presented to medical attention at the age of 11 with features of type A insulin resistance including acanthosis nigricans and virilization (<a href="/entry/610549">610549</a>). Subsequently, her acanthosis nigricans disappeared and she began to ovulate spontaneously, became pregnant without medical intervention, and had an apparently normal daughter. Using oligonucleotides complementary to sequences in introns 18 and 19, <a href="#18" class="mim-tip-reference" title="Cama, A., de la Luz Sierra, M., Quon, M. J., Ottini, L., Gorden, P., Taylor, S. I. <strong>Substitution of glutamic acid for alanine 1135 in the putative 'catalytic loop' of the tyrosine kinase domain of the human insulin receptor: a mutation that impairs proteolytic processing into subunits and inhibits receptor tyrosine kinase activity.</strong> J. Biol. Chem. 268: 8060-8069, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8096518/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8096518</a>]" pmid="8096518">Cama et al. (1993)</a> used PCR to amplify exon 19 of the insulin receptor gene. By direct sequencing of the amplified genomic DNA, they demonstrated that codon 1135 was mutated from GCG (ala) to GAG (glu) (ALA1135GLU, A1135E). Neither parent had the mutation, which was heterozygous in the proposita. Like previously described mutations in the tyrosine kinase domain, the glu1135 mutation impaired receptor tyrosine kinase activity and inhibited the ability of insulin to stimulate thymidine incorporation and receptor endocytosis. However, unlike previously described mutations in the intracellular domain of the receptor, the new mutation impaired proteolytic cleavage of the proreceptor into separate subunits and impaired the transport of the receptor to the cell surface. The latter defect accounted for the decrease in number of receptors on the cell surface of the patient's circulating monocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8096518" 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">rs121913155 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913155;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=rs121913155" 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=rs121913155" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.442A-T in exon 2 and results in an amino acid change lys148 to ter (K148X), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an offspring of consanguineous parents of Pakistani origin, <a href="#51" class="mim-tip-reference" title="Krook, A., Brueton, L., O'Rahilly, S. <strong>Homozygous nonsense mutation in the insulin receptor gene in infant with leprechaunism.</strong> Lancet 342: 277-278, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8101305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8101305</a>] [<a href="https://doi.org/10.1016/0140-6736(93)91820-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8101305">Krook et al. (1993)</a> observed Donohue syndrome (<a href="/entry/246200">246200</a>) resulting from homozygosity for a nonsense mutation, lys121 to ter (LYS121TER, K121X). Severe intrauterine growth retardation had been evident throughout pregnancy and at birth the baby had a wasted appearance with a distended abdomen, lack of subcutaneous fat, and decreased muscle mass. The facies was gaunt with pronounced hirsutism, protuberant ears, and gum hypertrophy. There was generalized hypertrichosis. Both parents were heterozygous for a mutation in codon 121 of the INSR gene that changed AAG (lysine) to TAG (stop). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8101305" 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="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> cataloged this mutation as a deletion of the entire INSR gene according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 15-month-old boy with Donohue syndrome (<a href="/entry/246200">246200</a>), an offspring of first-cousin parents, <a href="#110" class="mim-tip-reference" title="Wertheimer, E., Lu, S.-P., Backeljauw, P. F., Davenport, M. L., Taylor, S. I. <strong>Homozygous deletion of the human insulin receptor gene results in leprechaunism.</strong> Nature Genet. 5: 71-73, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7693131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7693131</a>] [<a href="https://doi.org/10.1038/ng0993-71" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7693131">Wertheimer et al. (1993)</a> found homozygous deletion of the INSR gene. Thus, contrary to previous predictions, complete absence of the INSR gene is compatible with life. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7693131" 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> rs1799816 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1799816;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/rs1799816?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=rs1799816" 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=rs1799816" 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=RCV000015822 OR RCV000175131 OR RCV000344820 OR RCV000445519 OR RCV000515071 OR RCV001132183 OR RCV001132184 OR RCV001258250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015822, RCV000175131, RCV000344820, RCV000445519, RCV000515071, RCV001132183, RCV001132184, RCV001258250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015822...</a>
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<p>This variant, formerly titled DIABETES MELLITUS, NONINSULIN-DEPENDENT, has been reclassified based on the report of <a href="#57" class="mim-tip-reference" title="Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. <strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong> Nature 536: 285-291, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[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/nature19057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27535533">Lek et al. (2016)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27535533" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3034G-A in exon 17 and results in an amino acid change val1012 to met (V1012M), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In studies of 11 familial NIDDM pedigrees (<a href="/entry/125853">125853</a>), <a href="#28" class="mim-tip-reference" title="Elbein, S. C., Sorensen, L. K., Schumacher, M. C. <strong>Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM.</strong> Diabetes 42: 429-434, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8432414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8432414</a>] [<a href="https://doi.org/10.2337/diab.42.3.429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8432414">Elbein et al. (1993)</a> found 1 in which some members had a val985-to-met substitution in exon 17 (VAL985MET, V985M). The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was absent in 1 affected individual and was present in some nondiabetic pedigree members. Nondiabetic carriers of the mutation were found to have significantly higher glucose levels when compared with 266 members of other pedigrees, after correction for age, weight, and sex. <a href="#28" class="mim-tip-reference" title="Elbein, S. C., Sorensen, L. K., Schumacher, M. C. <strong>Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM.</strong> Diabetes 42: 429-434, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8432414/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8432414</a>] [<a href="https://doi.org/10.2337/diab.42.3.429" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8432414">Elbein et al. (1993)</a> suggested that although the val985-to-met substitution does not result in severe insulin resistance and has low penetrance with respect to expression of the NIDDM phenotype, it may represent a modifying factor collaborating with other loci predisposing to diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8432414" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a population-based Rotterdam study, <a href="#2" class="mim-tip-reference" title="'t Hart, L. M., Stolk, R. P., Heine, R. J., Grobbee, D. E., van der Does, F. E. E., Maassen, J. A. <strong>Association of the insulin-receptor variant met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study.</strong> Am. J. Hum. Genet. 59: 1119-1125, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900242</a>]" pmid="8900242">'t Hart et al. (1996)</a> examined 161 individuals with NIDDM and 538 healthy controls for the presence of mutations in the INSR gene, using SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, the findings indicated a relative risk for diabetes of 4.49 for met985 carriers. When the total study group was analyzed, <a href="#2" class="mim-tip-reference" title="'t Hart, L. M., Stolk, R. P., Heine, R. J., Grobbee, D. E., van der Does, F. E. E., Maassen, J. A. <strong>Association of the insulin-receptor variant met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study.</strong> Am. J. Hum. Genet. 59: 1119-1125, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8900242/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8900242</a>]" pmid="8900242">'t Hart et al. (1996)</a> found that the prevalence of the mutation increased with increasing serum glucose levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8900242" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies, <a href="#1" class="mim-tip-reference" title="'t Hart, L. M., Stolk, R. P., Dekker, J. M., Nijpels, G., Grobbee, D. E., Heine, R. J., Maassen, J. A. <strong>Prevalence of variants in candidate genes for type 2 diabetes mellitus in the Netherlands: the Rotterdam study and the Hoorn study.</strong> J. Clin. Endocr. Metab. 84: 1002-1006, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10084586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10084586</a>] [<a href="https://doi.org/10.1210/jcem.84.3.5563" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10084586">'t Hart et al. (1999)</a> found the val985-to-met INSR variant at frequencies of 4.4 and 1.8%, respectively, in NIDDM and normoglycemic patients. Inclusion of data from 2 other studies yielded a summarized odds ratio of 1.87. The authors concluded that the association between the val985-to-met variant in the INSR gene and type II diabetes, previously reported in the Rotterdam study, is supported by the joint analysis with a second population-based study and other studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10084586" 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="#57" class="mim-tip-reference" title="Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O'Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., and 68 others. <strong>Analysis of protein-coding genetic variation in 60,706 humans.</strong> Nature 536: 285-291, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27535533/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27535533</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27535533[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/nature19057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27535533">Lek et al. (2016)</a> noted that the V1012M variant has a high allele frequency (0.0225) in the South Asian population in the ExAC database, suggesting that it is not pathogenic. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27535533" 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=RCV000015823 OR RCV000125461 OR RCV001818162" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015823, RCV000125461, RCV001818162" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015823...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3602G-A in exon 20 and results in an amino acid change arg1201 to gln (R1201Q), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Among 22 unrelated women with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (manifested by hyperandrogenemia, oligoamenorrhea, and hirsutism; <a href="/entry/610549">610549</a>), <a href="#69" class="mim-tip-reference" title="Moller, D. E., Cohen, O., Yamaguchi, Y., Assiz, R., Grigorescu, F., Eberle, A., Morrow, L. A., Moses, A. C., Flier, J. S. <strong>Prevalence of mutations in the insulin receptor gene in subjects with features of the type A syndrome of insulin resistance.</strong> Diabetes 43: 247-255, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288049</a>] [<a href="https://doi.org/10.2337/diab.43.2.247" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288049">Moller et al. (1994)</a> found heterozygosity for a CGG-to-CAG transition in exon 20 of the INSR gene, resulting in an arg1174-to-gln (ARG1174GLN, R1174Q) amino acid substitution. The mutation involved the intracellular receptor beta subunit. The mutation was found in an affected sister, whereas it was absent in the unaffected mother. It was probably present in 2 paternal aunts who were reportedly affected. Thus, arg1174 to gln, involving the insulin receptor tyrosine kinase domain, is a cause of dominantly inherited insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In all affected members of a 3-generation Danish family with hyperinsulinemic hypoglycemia (<a href="/entry/609968">609968</a>), <a href="#36" class="mim-tip-reference" title="Hojlund, K., Hansen, T., Lajer, M., Henriksen, J. E., Levin, K., Lindholm, J., Pedersen, O., Bech-Nielsen, H. <strong>A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene.</strong> Diabetes 53: 1592-1593, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15161766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15161766</a>] [<a href="https://doi.org/10.2337/diabetes.53.6.1592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15161766">Hojlund et al. (2004)</a> identified heterozygosity for a G-A transition at codon 1174 in exon 20 of the INSR gene, resulting in an arg1174-to-gln (R1174Q) substitution. The mutation was not found in any unaffected family members. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15161766" 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">rs121913157 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913157;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=rs121913157" 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=rs121913157" 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=RCV000015824 OR RCV001851881" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015824, RCV001851881" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015824...</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.3540G-A in exon 20 and results in an amino acid change met1180 to ile (M1180I), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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 met1153-to-ile mutation (MET1153ILE, M1153I) in the INSR gene was demonstrated to be the cause of insulin resistance by Cama et al. (<a href="#17" class="mim-tip-reference" title="Cama, A., de la Luz Sierra, M., Ottini, L., Kadowaki, T., Gorden, P., Imperato-McGinley, J., Taylor, S. I. <strong>A mutation in the tyrosine kinase domain of the insulin receptor associated with insulin resistance in an obese woman.</strong> J. Clin. Endocr. Metab. 73: 894-901, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1890161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1890161</a>] [<a href="https://doi.org/10.1210/jcem-73-4-894" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1890161">1991</a>, <a href="#19" class="mim-tip-reference" title="Cama, A., Quon, M. J., de la Luz Sierra, M., Taylor, S. I. <strong>Substitution of isoleucine for methionine at position 1153 in the beta-subunit of the human insulin receptor.</strong> J. Biol. Chem. 267: 8383-8389, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314826</a>]" pmid="1314826">1992</a>). The mutation caused a defect in receptor internalization relative to normal receptors. Insulin resistance in the patient showed a fluctuating clinical course, suggesting that the ratio of normal receptors to mutant receptors on the surface of the patient's cells may change depending on factors that promote or inhibit receptor endocytosis, such as hyperinsulinemia and obesity. <a href="#82" class="mim-tip-reference" title="Quon, M. J., Guerre-Millo, M., Zarnowski, M. J., Butte, A. J., Em, M., Cushman, S. W., Taylor, S. I. <strong>Tyrosine kinase-deficient mutant human insulin receptors (met1153-to-ile) overexpressed in transfected rat adipose cells fail to mediate translocation of epitope-tagged GLUT4.</strong> Proc. Nat. Acad. Sci. 91: 5587-5591, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8202531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8202531</a>] [<a href="https://doi.org/10.1073/pnas.91.12.5587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8202531">Quon et al. (1994)</a> applied to the study of this mutation a physiologically relevant system for dissecting the molecular mechanisms of insulin signal transduction related to glucose transport. The method involved transfection of DNA into rat adipose cells in primary culture. As a reporter gene, they used cDNA coding for GLUT4 (<a href="/entry/138190">138190</a>) with an epitope tag in the first exofacial loop so that GLUT4 translocation could be studied exclusively in transfected cells. Insulin stimulated a 4.3-fold recruitment of transfected epitope-tagged GLUT4 to the cell surface. Cells cotransfected with the reporter gene and the human insulin receptor gene showed an increase in cell surface GLUT4 in the basal state (no insulin) to levels comparable to those seen with maximal insulin stimulation of cells transfected with the reporter gene alone. In contrast, cells overexpressing the met1153-to-ile mutation showed no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. In contrast, cells overexpressing the met1163-to-ile mutation showed no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. The results were interpreted as indicating that insulin receptor tyrosine kinase activity is essential in insulin-stimulated glucose transport in adipose cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1314826+8202531+1890161" 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">rs121913158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913158;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=rs121913158" 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=rs121913158" 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=RCV000015825" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015825" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015825</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1316G-C in exon 6 and results in an amino acid change trp439 to ser (W439S), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a child with Donohue syndrome (<a href="/entry/246200">246200</a>), the offspring of consanguineous Turkish parents, <a href="#107" class="mim-tip-reference" title="van der Vorm, E. R., Kuipers, A., Kielkopf-Renner, S., Krans, H. M. J., Moller, W., Maassen, J. A. <strong>A mutation in the insulin receptor that impairs proreceptor processing but not insulin binding.</strong> J. Biol. Chem. 269: 14297-14302, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8188715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8188715</a>]" pmid="8188715">van der Vorm et al. (1994)</a> found a trp412-to-ser mutation (TRP412SER, W412S) in the INSR gene. The mutant receptor was expressed stably in CHO cells and transiently in COS-1 cells where it was found that the mutant was not cleaved into alpha- and beta-subunits but remained as a 210-kD proreceptor at an intracellular site. Cross-linking experiments showed that the mutant proreceptor was able to bind insulin with an affinity comparable to that of the wildtype alpha chain. Despite its capacity to bind insulin, the mutant receptor was not autophosphorylated. Impaired transport of the proreceptor to the cell surface appeared to be the primary cause for the binding defect observed in intact cells. The patient was thought to be homozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8188715" 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> rs121913159 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121913159;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/rs121913159?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=rs121913159" 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=rs121913159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.438C-G in exon 2 and results in an amino acid change ile146 to met (I146M), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Al-Gazali, L. I., Khalil, M., Devadas, K. <strong>A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents.</strong> J. Med. Genet. 30: 470-475, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8326490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8326490</a>] [<a href="https://doi.org/10.1136/jmg.30.6.470" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8326490">Al-Gazali et al. (1993)</a> described a 'mild' variant of Donohue syndrome (<a href="/entry/246200">246200</a>) in 5 infants from an inbred family. Using denaturing gradient gel electrophoresis and subsequent sequence of selected exons, <a href="#37" class="mim-tip-reference" title="Hone, J., Accili, D., Al-Gazali, L. I., Lestringant, G., Orban, T., Taylor, S. I. <strong>Homozygosity for a new mutation (ile119-to-met) in the insulin receptor gene in five sibs with familial insulin resistance.</strong> J. Med. Genet. 31: 715-716, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7815442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7815442</a>] [<a href="https://doi.org/10.1136/jmg.31.9.715" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7815442">Hone et al. (1994)</a> identified a homozygous mutation resulting from an ile119-to-met (ILE119MET, I119M) substitution in exon 2 of the INSR gene in this family. Mutation in the insulin binding domain predicts ineffective insulin signal transduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7815442+8326490" 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">rs587776819 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776819;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=rs587776819" 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=rs587776819" 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=RCV000015827" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015827" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015827</a>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> cataloged this mutation as c.1124-2A-G according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an English patient with Rabson-Mendenhall syndrome (<a href="/entry/262190">262190</a>), <a href="#99" class="mim-tip-reference" title="Takahashi, Y., Kadowaki, H., Ando, A., Quin, J. D., MacCuish, A. C., Yazaki, Y., Akanuma, Y., Kadowaki, T. <strong>Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall's syndrome.</strong> J. Clin. Invest. 101: 588-594, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9449692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9449692</a>] [<a href="https://doi.org/10.1172/JCI1283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9449692">Takahashi et al. (1998)</a> found compound heterozygosity for novel mutations in the INSR gene. One was an A-to-G transition at the 3-prime splice acceptor site of intron 4, and the other was an 8-bp deletion in exon 12. Both decreased mRNA expression in a cis-dominant manner, and were predicted to produce severely truncated proteins. Unexpectedly, nearly normal insulin receptor levels were expressed in the patient's lymphocytes, although the level of expression assessed by immunoblot was approximately 10% of the control cells. Insulin-binding affinity was markedly reduced, but insulin-dependent tyrosine kinase activity was present. On analysis of INSR mRNA of lymphocytes by RT-PCR, aberrant splicing caused by activation of a cryptic splice site in exon 5, resulting in a 4-amino acid deletion and 1-amino acid substitution, but restoring an open reading frame, was found. Skipped exon 5, another aberrant splicing, was found in both the patient and the mother who was heterozygous for the mutation, whereas activation of the cryptic splice site occurred almost exclusively in the patient. <a href="#99" class="mim-tip-reference" title="Takahashi, Y., Kadowaki, H., Ando, A., Quin, J. D., MacCuish, A. C., Yazaki, Y., Akanuma, Y., Kadowaki, T. <strong>Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall's syndrome.</strong> J. Clin. Invest. 101: 588-594, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9449692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9449692</a>] [<a href="https://doi.org/10.1172/JCI1283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9449692">Takahashi et al. (1998)</a> speculated that the mutant receptor may have been involved in the relatively long survival of the patient by rescuing an otherwise more severe phenotype resulting from the complete lack of functional insulin receptors. The patient, previously reported by <a href="#81" class="mim-tip-reference" title="Quin, J. D., Fisher, B. M., Paterson, K. R., Inoue, A., Beastall, G. H., MacCuish, A. C. <strong>Acute response to recombinant insulin-like growth factor-I in a patient with Mendenhall's syndrome.</strong> New Eng. J. Med. 323: 1425-1426, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2233914/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2233914</a>] [<a href="https://doi.org/10.1056/NEJM199011153232016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2233914">Quin et al. (1990)</a>, had severe insulin-resistant diabetes and intermittent ketonuria, and was treated successfully with recombinant insulinlike growth factor 1 (IGF1; <a href="/entry/147440">147440</a>). Although other therapeutic agents were unsuccessful, the patient lived to age 13, when he began subcutaneous IGF1 injections. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2233914+9449692" 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">rs587776820 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776820;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=rs587776820" 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=rs587776820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> cataloged this mutation as c.2480_2487del8 in exon 12 according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" 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>See <a href="#0034">147670.0034</a> and <a href="#99" class="mim-tip-reference" title="Takahashi, Y., Kadowaki, H., Ando, A., Quin, J. D., MacCuish, A. C., Yazaki, Y., Akanuma, Y., Kadowaki, T. <strong>Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall's syndrome.</strong> J. Clin. Invest. 101: 588-594, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9449692/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9449692</a>] [<a href="https://doi.org/10.1172/JCI1283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9449692">Takahashi et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9449692" 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="#6" class="mim-tip-reference" title="Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R. <strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong> Molec. Genet. Metab. Rep. 1: 71-84, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27896077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27896077</a>] [<a href="https://doi.org/10.1016/j.ymgmr.2013.12.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27896077">Ardon et al. (2014)</a> stated that this mutation is c.1372A-G in exon 6 and results in an amino acid change asn458 to asp (N458D), according to a revised INSR sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=NC_000019" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">NC_000019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27896077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Scottish Caucasian male with Donohue syndrome (<a href="/entry/246200">246200</a>) who died at 3 months of age, <a href="#63" class="mim-tip-reference" title="Maassen, J. A., Tobias, E. S., Kayserilli, H., Tukel, T., Yuksel-Apak, M., D'Haens, E., Kleijer, W. J., Fery, F., van der Zon, G. C. M. <strong>Identification and functional assessment of novel and known insulin receptor mutations in five patients with syndromes of severe insulin resistance.</strong> J. Clin. Endocr. Metab. 88: 4251-4257, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12970295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12970295</a>] [<a href="https://doi.org/10.1210/jc.2003-030034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12970295">Maassen et al. (2003)</a> detected a novel homozygous A-to-G transition in the INSR gene that resulted in an asn431-to-asp (ASN431ASP, N431D) amino acid change. The N431D mutation only partially reduced insulin proreceptor processing and activation of signaling cascades. The correlation between fibroblast insulin binding and duration of patient survival reported by <a href="#60" class="mim-tip-reference" title="Longo, N., Wang, Y., Smith, S. A., Langley, S. D., DiMeglio, L. A., Giannella-Neto, D. <strong>Genotype-phenotype correlation in inherited severe insulin resistance.</strong> Hum. Molec. Genet. 11: 1465-1475, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12023989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12023989</a>] [<a href="https://doi.org/10.1093/hmg/11.12.1465" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12023989">Longo et al. (2002)</a> was not observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12023989+12970295" 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="#Elbein1986" class="mim-tip-reference" title="Elbein, S. C., Corsetti, L., Ullrich, A., Permutt, M. A. <strong>Multiple restriction fragment length polymorphisms at the insulin receptor locus: a highly informative marker for linkage analysis.</strong> Proc. Nat. Acad. Sci. 83: 5223-5227, 1986.">Elbein et al. (1986)</a>; <a href="#Ferrannini1982" class="mim-tip-reference" title="Ferrannini, E., Muggeo, M., Navalesi, R., Pilo, A. <strong>Impaired insulin degradation in a patient with insulin resistance and acanthosis nigricans.</strong> Am. J. Med. 73: 148-154, 1982.">Ferrannini et al. (1982)</a>; <a href="#Grigorescu1984" class="mim-tip-reference" title="Grigorescu, F., Flier, J. S., Kahn, C. R. <strong>Defect in insulin receptor phosphorylation in erythrocytes and fibroblasts associated with severe insulin resistance.</strong> J. Biol. Chem. 259: 15003-15006, 1984.">Grigorescu et al.
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(1984)</a>; <a href="#Grunberger1984" class="mim-tip-reference" title="Grunberger, G., Zick, Y., Gordon, G. <strong>Defect in phosphorylation of insulin receptors in cells from an insulin-resistant patient with normal insulin binding.</strong> Science 223: 932-934, 1984.">Grunberger et al. (1984)</a>; <a href="#Kahn1976" class="mim-tip-reference" title="Kahn, C. R., Flier, J. S., Bar, R. S., Archer, J. A., Gorden, P., Martin, M. M., Roth, J. <strong>The syndromes of insulin resistance and acanthosis nigricans: insulin receptor disorders in man.</strong> New Eng. J. Med. 294: 739-745, 1976.">Kahn et al. (1976)</a>; <a href="#Kahn1988" class="mim-tip-reference" title="Kahn, C. R., White, M. F. <strong>The insulin receptor and the molecular mechanism of insulin action.</strong> J. Clin. Invest. 82: 1151-1156, 1988.">Kahn and White
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(1988)</a>; <a href="#Mariani1982" class="mim-tip-reference" title="Mariani, S., Pedone, A., Meschi, F., Di Natale, B., Caputo, R., Broggi, U., Chiumello, G. <strong>Insulin resistance in a child with acanthosis nigricans type A.</strong> Acta Paediat. Scand. 71: 667-670, 1982.">Mariani et al. (1982)</a>; <a href="#Moller1990" class="mim-tip-reference" title="Moller, D. E., Yokota, A., White, M. F., Pazianos, A. G., Flier, J. S. <strong>A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance.</strong> J. Biol. Chem. 265: 14979-14985, 1990.">Moller et al. (1990)</a>; <a href="#Moller1990" class="mim-tip-reference" title="Moller, D. E., Yokota, A., White, M. F., Pazianos, A. G., Flier, J. S. <strong>A naturally occurring mutation of insulin receptor alanine 1134 impairs tyrosine kinase function and is associated with dominantly inherited insulin resistance.</strong> J. Biol. Chem. 265: 14979-14985, 1990.">Moller et al.
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(1990)</a>; <a href="#Roth1983" class="mim-tip-reference" title="Roth, R. A., Cassell, D. J. <strong>Insulin receptor: evidence that it is a protein kinase.</strong> Science 219: 299-301, 1983.">Roth and Cassell (1983)</a>; <a href="#Schwenk1986" class="mim-tip-reference" title="Schwenk, W. F., Rizza, R. A., Mandarino, L. J., Gerich, J. E., Hayles, A. B., Haymond, M. W. <strong>Familial insulin resistance and acanthosis nigricans: presence of a postbinding defect.</strong> Diabetes 35: 33-37, 1986.">Schwenk et al. (1986)</a>; <a href="#Ward1986" class="mim-tip-reference" title="Ward, G. M., Harrison, L. C. <strong>Structure of the human erythrocyte insulin receptor.</strong> Diabetes 35: 101-105, 1986.">Ward and
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<strong>Prevalence of variants in candidate genes for type 2 diabetes mellitus in the Netherlands: the Rotterdam study and the Hoorn study.</strong>
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J. Clin. Endocr. Metab. 84: 1002-1006, 1999.
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[<a href="https://doi.org/10.1136/jmg.30.6.470" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.88.1.249" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.41.4.521" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nn1363" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0378-1119(98)00045-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.83.16.6007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.42.3.429" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.35.2.127" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem-49-2-216" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1021" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16642022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16642022</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16642022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1787" target="_blank">Full Text</a>]
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<a id="Ullrich1985" class="mim-anchor"></a>
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Ullrich, A., Bell, J. R., Chen, E. Y., Herrera, R., Petruzzelli, L. M., Dull, T. J., Gray, A., Coussens, L., Liao, Y.-C., Tsubokawa, M., Mason, A., Seeburg, P. H., Grunfeld, C., Rosen, O. M., Ramachandran, J.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2983222/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2983222</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2983222" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/313756a0" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1730625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1730625</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1730625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ward, G. M., Harrison, L. C.
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<strong>Structure of the human erythrocyte insulin receptor.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3510133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3510133</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3510133" 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/10.2337/diab.35.1.101" target="_blank">Full Text</a>]
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<strong>Homozygous deletion of the human insulin receptor gene results in leprechaunism.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7693131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7693131</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7693131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng0993-71" target="_blank">Full Text</a>]
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Williams, D. L., Look, A. T., Melvin, S. L., Roberson, P. K., Dahl, G., Flake, T., Stass, S.
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<strong>New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6607116/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6607116</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6607116" 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/10.1016/0092-8674(84)90078-3" target="_blank">Full Text</a>]
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Williams, J. F., McClain, D. A., Dull, T. J., Ullrich, A., Olefsky, J. M.
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<strong>Characterization of an insulin receptor mutant lacking the subunit processing site.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2187866/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2187866</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2187866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2203761/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2203761</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2203761" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Yang-Feng, T. L., Francke, U., Ullrich, A.
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<strong>Gene for human insulin receptor: localization to site on chromosome 19 involved in pre-B-cell leukemia.</strong>
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Science 228: 728-731, 1985.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3873110/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3873110</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3873110" 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.3873110" target="_blank">Full Text</a>]
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Yoshimasa, Y., Seino, S., Whittaker, J., Kakehi, T., Kosaki, A., Kuzuya, H., Imura, H., Bell, G. I., Steiner, D. F.
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<strong>Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3283938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3283938</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3283938" 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.3283938" target="_blank">Full Text</a>]
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Alan F. Scott - updated : 05/02/2022
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Ada Hamosh - updated : 12/02/2016<br>Marla J. F. O'Neill - updated : 6/6/2014<br>Ada Hamosh - updated : 5/16/2013<br>Ada Hamosh - updated : 3/21/2013<br>Patricia A. Hartz - updated : 11/5/2012<br>Marla J. F. O'Neill - updated : 7/25/2008<br>Paul J. Converse - updated : 11/9/2006<br>Ada Hamosh - updated : 11/7/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Marla J. F. O'Neill - updated : 3/16/2006<br>Marla J. F. O'Neill - updated : 3/13/2006<br>Marla J. F. O'Neill - updated : 7/27/2005<br>John A. Phillips, III - updated : 7/6/2005<br>Marla J. F. O'Neill - updated : 3/16/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 11/19/2004<br>Victor A. McKusick - updated : 9/15/2004<br>Victor A. McKusick - updated : 5/27/2004<br>Victor A. McKusick - updated : 2/10/2004<br>Ada Hamosh - updated : 12/1/2003<br>Ada Hamosh - updated : 4/22/2003<br>George E. Tiller - updated : 4/11/2003<br>Dawn Watkins-Chow - updated : 2/26/2003<br>Ada Hamosh - updated : 2/3/2003<br>Cassandra L. Kniffin - updated : 1/24/2003<br>Deborah L. Stone - updated : 9/12/2002<br>Jane Kelly - updated : 7/2/2002<br>Dawn Watkins-Chow - updated : 6/28/2001<br>Stylianos E. Antonarakis - updated : 4/17/2001<br>Stylianos E. Antonarakis - updated : 1/11/2001<br>Ada Hamosh - updated : 10/23/2000<br>Stylianos E. Antonarakis - updated : 9/11/2000<br>John A. Phillips, III - updated : 11/24/1999<br>Stylianos E. Antonarakis - updated : 2/16/1999<br>Stylianos E. Antonarakis - updated : 2/9/1999<br>Iosif W. Lurie - updated : 1/23/1997
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Victor A. McKusick : 6/2/1986
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carol : 12/10/2021<br>carol : 09/02/2020<br>carol : 05/09/2019<br>carol : 05/08/2019<br>carol : 12/05/2016<br>alopez : 12/02/2016<br>carol : 08/17/2016<br>carol : 08/08/2014<br>alopez : 6/24/2014<br>carol : 6/18/2014<br>carol : 6/17/2014<br>carol : 6/16/2014<br>mcolton : 6/6/2014<br>carol : 10/1/2013<br>alopez : 5/16/2013<br>carol : 4/22/2013<br>carol : 4/12/2013<br>alopez : 4/2/2013<br>terry : 3/21/2013<br>mgross : 11/9/2012<br>terry : 11/5/2012<br>wwang : 1/21/2010<br>wwang : 4/20/2009<br>wwang : 7/28/2008<br>terry : 7/25/2008<br>wwang : 5/15/2007<br>carol : 4/18/2007<br>mgross : 11/10/2006<br>terry : 11/9/2006<br>alopez : 11/7/2006<br>carol : 11/6/2006<br>carol : 11/6/2006<br>mgross : 8/9/2006<br>wwang : 5/4/2006<br>wwang : 4/27/2006<br>carol : 3/16/2006<br>carol : 3/13/2006<br>wwang : 8/3/2005<br>terry : 7/27/2005<br>alopez : 7/6/2005<br>alopez : 7/6/2005<br>wwang : 3/17/2005<br>wwang : 3/16/2005<br>wwang : 3/8/2005<br>ckniffin : 3/1/2005<br>tkritzer : 11/19/2004<br>tkritzer : 9/16/2004<br>terry : 9/15/2004<br>alopez : 5/27/2004<br>carol : 3/17/2004<br>tkritzer : 2/16/2004<br>terry : 2/10/2004<br>alopez : 12/2/2003<br>alopez : 12/2/2003<br>terry : 12/1/2003<br>cwells : 11/7/2003<br>alopez : 4/22/2003<br>terry : 4/22/2003<br>cwells : 4/11/2003<br>tkritzer : 2/26/2003<br>tkritzer : 2/26/2003<br>alopez : 2/4/2003<br>terry : 2/3/2003<br>carol : 2/3/2003<br>ckniffin : 1/24/2003<br>carol : 9/12/2002<br>mgross : 7/2/2002<br>mgross : 6/28/2001<br>mgross : 4/17/2001<br>mgross : 1/11/2001<br>alopez : 10/25/2000<br>terry : 10/23/2000<br>mgross : 9/11/2000<br>carol : 12/22/1999<br>alopez : 11/24/1999<br>mgross : 2/16/1999<br>mgross : 2/16/1999<br>carol : 2/10/1999<br>mgross : 2/9/1999<br>dkim : 7/23/1998<br>alopez : 3/25/1998<br>terry : 3/20/1998<br>mark : 1/5/1998<br>joanna : 12/17/1997<br>terry : 1/23/1997<br>terry : 1/23/1997<br>carol : 1/23/1997<br>carol : 7/5/1996<br>mark : 1/8/1996<br>terry : 1/4/1996<br>mimadm : 11/5/1994<br>jason : 6/27/1994<br>carol : 5/27/1994<br>terry : 5/13/1994<br>pfoster : 4/25/1994<br>warfield : 4/12/1994
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 147670
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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INSULIN RECEPTOR; INSR
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</span>
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</h3>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: INSR</em></strong>
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</span>
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</p>
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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> 111307005, 237606005, 33559001, 44054006, 48606007, 763325000;
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<strong>ICD10CM:</strong> E11;
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</p>
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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: 19p13.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:7,112,265-7,294,414 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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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>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>
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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="4">
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<span class="mim-font">
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19p13.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Diabetes mellitus, insulin-resistant, with acanthosis nigricans
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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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610549
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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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</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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<td>
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<span class="mim-font">
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Donohue 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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246200
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</span>
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<td>
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<span class="mim-font">
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Autosomal recessive
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Hyperinsulinemic hypoglycemia, familial, 5
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</td>
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<td>
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<span class="mim-font">
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609968
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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 dominant
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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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<tr>
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<td>
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<span class="mim-font">
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Rabson-Mendenhall 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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262190
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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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</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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<br />
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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>Insulin receptor is a tetramer of 2 alpha and 2 beta subunits. The alpha and beta subunits are coded by a single gene and are joined by disulfide bonds, a mechanism parallel to that of its ligand, insulin (INS; 176730) (Rubin, 1984).</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>Ullrich et al. (1985) deduced the entire 1,370-amino acid sequence of the insulin receptor from a cDNA clone. The precursor starts with a 27-amino acid signal sequence, followed by the receptor alpha subunit, a precursor processing enzyme cleavage site, then the beta subunit containing a single 23-amino acid transmembrane sequence. </p><p>Caro et al. (1988) demonstrated differences in molecular mass, carbohydrate composition, and antigenicity between the insulin receptor alpha subunit in liver and in muscle and adipose tissue, the 2 major peripheral target tissues of insulin. Moreover, the same authors showed that the insulin-stimulated tyrosyl kinase activity is greater in muscle than in liver or adipose tissue. There are sequence homologies to EGF receptor (131550). </p><p>Two insulin receptor mRNA transcripts resulting from alternative splicing of exon 11 in the receptor gene are expressed in a highly regulated tissue-specific fashion. Benecke et al. (1992) studied the relative abundance of these 2 mRNA species in human tissues; the one containing exon 11 shows a marked predominance in liver, whereas the isoform in which exon 11 has been spliced out shows a comparable predominance in leukocytes. Similar amounts of the 2 variants were found in placenta, skeletal muscle, and adipose tissue. No significant differences were found between control and diabetic subjects. </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>Due et al. (1986) presented evidence that the class I MHC heavy chain (HLA-A, HLA-B, HLA-C; see 142800) is a structural subunit of the insulin receptor. This broadens the range of biologic functions possible for histocompatibility antigens. Interaction of class I HLA molecules with glucagon receptors (e.g., 138033) and epidermal growth factor receptors (e.g., 131550) has also been demonstrated. Due et al. (1986) favored the hypothesis that the beta-2-microglobulin molecule (B2M; 109700) is replaced by the insulin receptor when it associates with the MHC class I heavy chain. Kittur et al. (1987) presented evidence for associations between HLA antigens and specific insulin-binding sites on human B lymphocytes. They cited experiments demonstrating coprecipitation of a fraction of insulin receptors with class I and class II MHC antigens. Thus, in addition to other functions of the MHC antigens, they may affect the functioning of, or themselves serve as, cell surface receptors. </p><p>Williams et al. (1990) created a mutant form of the INSR gene by site-directed mutagenesis in order to study the effects of mutation on functions of the receptor. </p><p>Christiansen et al. (1991) used data from electron microscopy to deduce a model for a quaternary structure of the insulin receptor of human placenta. </p><p>Using a yeast 2-hybrid system, Dey et al. (1998) identified a regulatory subunit of phosphatidylinositol 3-kinase, PIK3R3 (606076), as a binding partner of INSR. They concluded that PIK3R3 interacts with IGF1R (147370) and INSR in a kinase-dependent manner, providing an alternative pathway for the activation of PI3K by these 2 receptors. </p><p>The protein tyrosine phosphatase PTP1B (176885) is responsible for negatively regulating insulin signaling by dephosphorylating the phosphotyrosine (ptyr) residues of the INSR kinase activation segment, or IRK. By integrating crystallographic, kinetic, and PTP1B peptide-binding studies, Salmeen et al. (2000) defined the molecular specificity of this reaction. Extensive interactions are formed between PTP1B and the IRK sequence encompassing the tandem ptyr residues at positions 1162 and 1163, such that ptyr1162 is selected at the catalytic site and ptyr1163 is located within an adjacent ptyr-recognition site. This selectivity is attributed to the 70-fold greater affinity for tandem ptyr-containing peptides relative to mono-ptyr peptides and predicts a hierarchical dephosphorylation process. Many elements of the PTP1B-IRK interaction are unique to PTP1B, indicating that it may be feasible to generate specific, small molecule inhibitors of this interaction to treat diabetes and obesity. </p><p>Leibiger et al. (2001) showed that insulin activates the transcription of its own gene and that of the beta-cell glucokinase gene (GCK; 138079) by different mechanisms. Whereas INS gene transcription is promoted by signaling through INSR type A (without exon 11), PI3K class IA (see 171833), and the 70-kD S6 kinase, insulin stimulates the beta-cell GCK gene by signaling via INSR type B (with exon 11), PI3K class II (see 602838)-like activity, and protein kinase B (164730). These data provided evidence for selectivity in insulin action via the 2 INSR isoforms, the molecular basis being preferential signaling through different PI3K and protein kinases. </p><p>Rajala and Anderson (2001) sought to identify the tyrosine-phosphorylated protein(s) in the bovine rod outer segments (ROS) that are associated with PI3K. They concluded that tyrosine phosphorylation of the beta subunit of the insulin receptor is involved in the regulation of PI3K activity in the ROS. </p><p>By purification and molecular characterization, Brunetti et al. (2001) found that HMGIY (600701) bound and activated 2 AT-rich regions in the INSR promoter. Knockdown of HMGIY via antisense RNA reduced surface expression of INSR in 2 human cell lines that normally express high INSR levels. Conversely, transfection of HMGIY elevated surface expression of INSR in 2 cell lines that normally express little INSR. </p><p>Decreased affinity of numerically normal insulin receptor binding sites has been reported in patients with myotonic dystrophy (Tevaarwerk et al., 1979). Myotonic dystrophy is often associated with disturbances in insulin response. In muscle from patients with myotonic dystrophy type 1 (DM1; 160900), altered insulin receptor splicing to the nonmuscle isoform corresponds to the insulin insensitivity and diabetes that are part of the myotonic dystrophy phenotype; because of insulin-receptor species differences, this effect is not seen in mouse models of DM. Savkur et al. (2004) demonstrated that comparable splicing abnormalities occur in DM2 (602668) muscle before the development of muscle histopathology, thus demonstrating an early pathogenic effect of RNA expansions. </p><p>Song et al. (2013) showed in mice that muscle-specific mitsugumin-53 (MG53; 613288) mediates the degradation of the insulin receptor and insulin receptor substrate-1 (IRS1; 147545), and when upregulated causes metabolic syndrome featuring insulin resistance, obesity, hypertension, and dyslipidemia. Mg53 expression is markedly elevated in models of insulin resistance, and Mg53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of Mg53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, Irs1, and insulin signaling integrity. Mechanistically, Mg53 acts as an E3 ligase targeting the insulin receptor and Irs1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. Song et al. (2013) concluded that these findings defined MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications. </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 Structure</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>Seino et al. (1989) found that the INSR gene spans more than 120 kb and has 22 exons. The 11 exons encoding the alpha subunit are dispersed over more than 90 kb, whereas the 11 exons encoding the beta subunit are located together in a region of about 30 kb. Three transcriptional initiation sites were identified, located 276, 282, and 283 bp upstream of the translation initiation site. </p><p>Brunetti et al. (2001) stated that the promoter region of INSR has no TATA or CAAT boxes, but is extremely GC rich. In addition, they identified 2 functional AT-rich sequences in the INSR promoter that were bound and activated by HMGIY. </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>Biochemical Features</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><strong><em>Crystal Structure</em></strong></p><p>
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McKern et al. (2006) presented the crystal structure at 3.8-angstrom resolution of the IR-A ectodomain dimer of the insulin receptor, complexed with 4 antigen-binding fragments (Fabs) from the monoclonal antibodies 83-7 and 83-14, grown in the presence of a fragment of an insulin (176730) mimetic peptide. The structure reveals the domain arrangement in the disulfide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is different from previous models. It shows that the 2 L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding. </p><p>Lou et al. (2006) reported the crystal structure of the first 3 domains of INSR at 2.3-angstrom resolution and compared it with the structure of the corresponding fragment of IGF1R. They observed notable differences in the regions governing ligand specificity and binding. </p><p>Menting et al. (2013) presented a view of the interaction of insulin with its primary binding site on the insulin receptor on the basis of 4 crystal structures of insulin bound to truncated insulin receptor constructs. The direct interaction of insulin with the first leucine-rich repeat domain (L1) of insulin receptor is sparse, the hormone instead engaging the insulin receptor carboxy-terminal alpha-chain (alpha-CT) segment, which is itself remodeled on the face of L1 upon insulin binding. Contact between insulin and L1 is restricted to insulin B-chain residues. The alpha-CT segment displaces the B-chain C-terminal beta-strand away from the hormone core, revealing the mechanism of a long-proposed conformational switch in insulin upon receptor engagement. This mode of hormone-receptor recognition is novel within the broader family of receptor tyrosine kinases. </p>
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</span>
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<div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>With in situ hybridization and Southern blot analysis of somatic cell hybrid DNA, Yang-Feng et al. (1985) assigned the insulin receptor gene to 19p13.3-p13.2. This site is involved in a nonrandom translocation in pre-B-cell acute leukemia. The t(1;19) was demonstrated by several workers (e.g., Williams et al., 1984) in this childhood form of acute lymphoblastic leukemia which responds poorly to treatment. The cells produce cytoplasmic but not cell-surface immunoglobulin heavy chains. Shaw et al. (1986) concluded from linkage studies that INSR is very close to C3 (120700) but far from DM (160900). By fluorescence in situ hybridization, Trask et al. (1993) assigned the INSR gene to 19p13.3. By simultaneous mapping of multiple probes, they were able to achieve a more refined assignment than was possible when a single probe or a few probes were mapped. </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>Taylor et al. (1986) concluded that a patient with Donohue syndrome (246200) and extreme insulin resistance was a genetic compound, i.e., that each parent had transmitted to the proband a different defect of the insulin receptor (see 147670.0002). The patient, referred to as leprechaun/Ark-1, had an 80 to 90% decrease in the number of insulin receptors in circulating monocytes. Although the receptors on Epstein-Barr virus-transformed lymphocytes from the patient were normal in number, they showed decreased sensitivity to changes in temperature and pH. The father, who had a moderate degree of insulin resistance, resembled the patient in that his monocytes had a 60 to 80% decrease in the number of insulin receptors. Binding of the father's EB virus-transformed lymphocytes was normal. The mother had normal sensitivity to insulin and a normal number of insulin receptors on circulating monocytes. On the other hand, insulin receptors on the mother's EB virus-transformed lymphocytes were qualitatively abnormal, resembling closely the daughter's cultured cells. The father, who was heterozygous for the nonsense mutation, showed a moderate degree of insulin resistance. Ojamaa et al. (1988) found marked reduction in the level of receptor mRNA in a patient with Donohue syndrome. </p><p>Kadowaki et al. (1988) raised the question of whether mutations in the insulin receptor gene may account for the insulin resistance in some patients with noninsulin-dependent diabetes mellitus (NIDDM, T2D; 125853). Taira et al. (1989) suggested that many instances of NIDDM may be due to relatively minor mutations of the insulin receptor gene that cause slightly decreased affinity of the receptor for insulin or a slightly decreased kinase activity; in these cases, environmental factors such as obesity may trigger the onset of diabetes. </p><p>Discussing the mechanisms of insulin resistance, Moller and Flier (1991) and Taylor et al. (1991) diagrammed the structure of the human insulin receptor and indicated the position of known point mutations. Taylor et al. (1991) divided mutations in the INSR gene into 5 classes: class 1, impaired receptor biosynthesis; class 2, impaired transport of receptors to the cell surface; class 3, decreased affinity of insulin binding; class 4, impaired tyrosine kinase activity; and class 5, accelerated receptor degradation. </p><p>Among 22 unrelated women with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism; 610549), Moller et al. (1994) identified only 1 mutation in the INSR gene: arg1174 to gln (147670.0030). Moller et al. (1994) concluded that mutation in the INSR gene is a rare cause of the type A syndrome of extreme insulin resistance. </p><p>'t Hart et al. (1999) studied random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies to determine the prevalence of variants in NIDDM candidate genes. The val985-to-met (147670.0029) INSR variant was found at frequencies of 4.4 and 1.8%, respectively, in NIDDM and normoglycemic patients. </p><p>McCarthy et al. (2001) genotyped 24 single-nucleotide polymorphisms (SNPs) within the 19p13 region in a Caucasian population comprising 827 unrelated cases of typical migraine (607508). Five SNPs within the insulin receptor gene showed significant association with migraine. Functional studies of the INSR SNPs showed no effect on mRNA levels or splicing in peripheral blood leukocytes or on binding of insulin to mononuclear cells. The authors speculated on possible mechanisms by which the INSR could play a role in the pathogenesis of migraine. </p><p>Longo et al. (2002) reported 6 patients and correlated mutations in the insulin receptor gene with survival. Patients with Donohue syndrome were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor, and their cells had markedly impaired insulin binding (less than 10% of controls). Mutations in their insulin receptor gene inserted premature stop codons resulting in decreased levels of mature mRNA, or alternatively affected the extracellular domain of the receptor. Three patients with Rabson-Mendenhall syndrome had at least 1 missense mutation in the intracellular domain of the insulin receptor. Expression studies in CHO cells indicated that several mutations markedly impaired insulin binding (less than 5% of control), while others retained significant insulin-binding activity. The authors concluded that mutations in the insulin receptor retaining residual insulin-binding activity correlated with prolonged survival in a series of patients with extreme insulin resistance. </p><p>In all affected members of a 3-generation Danish family with hyperinsulinemic hypoglycemia (see HHF5, 609968), Hojlund et al. (2004) identified heterozygosity for a point mutation in the insulin receptor gene (147670.0030). The mutation was not found in any unaffected family members. The proband's sister, who had moderate symptoms of hypoglycemia, showed mild skin pigmentation in the axillae, increased total and free serum levels of testosterone, and polycystic ovaries. </p><p>Foti et al. (2005) reported 4 patients with insulin resistance and type II diabetes in whom cell-surface insulin receptors were decreased and INSR gene transcription was impaired although the INSR genes were normal. In these individuals, expression of HMGA1 (600701) was markedly reduced; restoration of HMGA1 protein expression in their cells enhanced INSR gene transcription and restored cell-surface insulin receptor protein expression and insulin-binding capacity. Foti et al. (2005) concluded that defects in HMGA1 may cause decreased insulin receptor expression and induce insulin resistance. </p>
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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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<p>In genetically obese mice with insulin resistance, Le Marchand-Brustel et al. (1985) found a defect in the tyrosine kinase activity of insulin receptor. </p><p>Complete lack of insulin receptors due to mutations of the insulin receptor gene results in severe growth retardation and mild diabetes. In mice, targeted inactivation of insulin receptor substrate-1 (147545) leads to inhibition of growth and mild resistance to the metabolic actions of insulin. To address the question of whether both metabolic and growth-promoting actions of insulin are mediated by the insulin receptor, Accili et al. (1996) generated mice lacking insulin receptors by targeted mutagenesis in embryo-derived stem (ES) cells. Unlike human patients lacking insulin receptors, mice homozygous for a null allele of the insulin receptor gene were born at term with apparently normal intrauterine growth and development. Within hours of birth, however, homozygous null mice developed severe hyperglycemia and hyperketonemia, and died as a result of diabetic ketoacidosis within 48 to 72 hours. The authors considered the data consistent with a model in which the insulin receptor functions primarily to mediate the metabolic actions of insulin. </p><p>To determine the contribution of muscle insulin resistance to the metabolic phenotype of diabetes, Bruning et al. (1998) used the Cre-loxP system to disrupt the mouse Insr gene in mouse skeletal muscle. The muscle-specific Insr knockout mice exhibited a muscle-specific reduction greater than 95% in receptor content and early signaling events. The mice displayed elevated fat mass, serum triglycerides, and free fatty acids, but blood glucose, serum insulin, and glucose tolerance were normal. Thus, insulin resistance in muscle contributes to the altered fat metabolism associated with type II diabetes, but tissues other than muscle appear to be more involved in insulin-regulated glucose disposal than previously recognized. </p><p>To determine whether insulin signaling has a functional role in the pancreatic beta cell, Kulkarni et al. (1999) used the Cre-loxP system to specifically inactivate the mouse Insr gene in the beta cells. Expression of Cre using a pancreatic beta cell-specific rat insulin promoter resulted in efficient recombination of a loxP-containing Insr gene in the beta cells. Mice lacking the beta-cell insulin receptor showed a loss of first-phase insulin secretion in response to glucose, but not to arginine, similar to that observed in humans with type II diabetes. These mice also showed a progressively impaired glucose tolerance over 6 months. The data indicated an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggested that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type II diabetes. </p><p>To investigate the effect of the loss of direct insulin action in liver, Michael et al. (2000) used the Cre-loxP system to inactivate the Insr gene in hepatocytes. Liver-specific Insr-knockout (LIRKO) mice exhibited dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations were paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the livers of knockout mice exhibited morphologic and functional changes, and the metabolic phenotype became less severe. Thus, the authors concluded that insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function. </p><p>Bruning et al. (2000) created mice with a neuron-specific disruption of the Insr gene (NIRKO). Inactivation of the insulin receptor had no impact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet-sensitive obesity with increases in body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone (see 152780). Thus, insulin receptor signaling in the central nervous system plays an important role in regulation of energy disposal, fuel metabolism, and reproduction. </p><p>Belke et al. (2002) generated mice with a cardiomyocyte-specific Insr- knockout (CIRKO), using cre/loxP recombination. Hearts of CIRKO mice were 20 to 30% smaller because of decreased postnatal hypertrophy of cardiomyocytes; they had persistent expression of the fetal beta-myosin heavy chain isoform, approximately half the normal expression of glucose transporter-1 (GLUT1; 138140), and a 2-fold increase in GLUT4 expression. Cardiac glucose uptake was increased in vivo, glycolysis was increased in isolated working hearts, and there was reduced expression of enzymes that catalyze mitochondrial beta-oxidation, leading to decreased fatty acid oxidation rates. </p><p>In brown adipose tissue-specific Insr-knockout mice, Guerra et al. (2001) observed age-dependent profound brown fat atrophy concomitant with the development of fasting hyperglycemia and impaired glucose tolerance. Guerra et al. (2001) concluded that the insulin receptor plays a direct role in brown fat adipogenesis and suggested that brown adipose tissue is involved in the regulation of insulin secretion and glucose homeostasis. An expression of concern was published for this article because of questions regarding Figure 3, A-C and Figure 4, A and B. The original data supporting these figures was no longer available. </p><p>Using the Cre-loxP system, Bluher et al. (2002) generated fat-specific Insr-knockout (FIRKO) mice which they found to have reduced fat mass and loss of the normal relationship between plasma leptin and body weight. The mice were also protected against age-related and hypothalamic lesion-induced obesity and obesity-related glucose intolerance. Using histologic and gene expression studies, Bluher et al. (2002) observed that the conditional knockout mice exhibited polarization of adipocytes into populations of large and small cells, which differed in protein expression pattern. Bluher et al. (2002) concluded that insulin signaling in adipocytes is critical for development of obesity and its associated metabolic abnormalities. </p><p>Bluher et al. (2003) generated mice with FIRKO. Growth curves were normal in male and female FIRKO mice from birth to 8 weeks of age. Starting at 3 months of age, FIRKO mice maintained 15 to 25% lower body weights and a 50 to 70% reduction in fat mass throughout life. FIRKO mice were healthy, lacked any of the metabolic abnormalities associated with lipodystrophy, and were protected against age-related deterioration in glucose tolerance, which was observed in all control strains. FIRKO mice maintained low body fat, despite normal food intake. Indeed, because FIRKO mice were leaner, the food intake of FIRKO mice expressed per gram of body weight actually exceeded that of controls by an average of 55%. Both male and female FIRKO mice were found to have an increase in mean life span of about 134 days (18%), with parallel increases in median and maximum life spans. Thus, Bluher et al. (2003) concluded that reduction of fat mass without caloric restriction can be associated with increased longevity in mice, possibly through effects on insulin signaling. </p><p>Song et al. (2003) found that in Drosophila, the insulin receptor functions in axon guidance and is required for photoreceptor cell axons to find their way from the retina to the brain during development of the visual system. The Drosophila insulin receptor functions as a guidance receptor for the adaptor protein Dock/Nck (see 600508). This function is independent of Chico, the Drosophila insulin receptor substrate homolog. </p><p>Nef et al. (2003) demonstrated that the insulin receptor tyrosine kinase family, comprising INSR, IGF1R (147370), and IRR (147671), is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that were mutant for all 3 receptors developed ovaries and showed a completely female phenotype. Reduced expression of both Sry (480000) and the early testis-specific marker Sox9 (608160) indicated that the insulin signaling pathway is required for male sex determination. </p><p>Kondo et al. (2003) observed that, following relative hypoxia, mice with a vascular endothelial cell-specific Insr knockout (VENIRKO) showed a 57% decrease in retinal neovascularization compared to controls, which was associated with a blunted rise in the vascular mediators VEGF (192240), eNOS (NOS3; 163729), and endothelin-1 (EDN1; 131240). Mice with a vascular endothelial cell-specific knockout of the Igf1 receptor (VENIFARKO) showed only a 34% reduction in neovascularization and a very modest reduction in mediator generation. Kondo et al. (2003) concluded that both insulin and IGF1 signaling in endothelium play a role in retinal neovascularization through the expression of vascular mediators, with insulin having a greater effect. </p><p>By mosaic analysis of insulin receptor function in mice, Kitamura et al. (2004) demonstrated that insulin regulates growth independently of metabolism and that the number of insulin receptors is an important determinant of the specificity of insulin action. They generated mice with variable cellular mosaicism for null Insr alleles. Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles Donohue syndrome in humans (246200). Insr ablation in 98% of cells, although resulting in similar growth retardation and lipoatrophy, caused diabetes without beta-cell hyperplasia. The growth retardation was associated with a greater than 60-fold increase in the expression of hepatic insulin-like growth factor-binding protein-1 (IGFBP1; 146730). </p><p>In mice, genetic ablation of insulin receptors causes early postnatal death from diabetic ketoacidosis (Accili et al., 1996). Okamoto et al. (2004) showed that combined restoration of insulin receptor function in brain, liver, and pancreatic beta cells rescued Insr knockout mice from neonatal death, prevented diabetes in a majority of animals, and normalized adipose tissue content, life span, and reproductive function. In contrast, mice with insulin receptor expression limited to brain or liver and pancreatic beta cells were rescued from neonatal death, but developed lipoatrophic diabetes and died prematurely. Okamoto et al. (2004) concluded that insulin receptor signaling in noncanonical insulin target tissues is sufficient to maintain fuel homeostasis and prevent diabetes. </p><p>Corl et al. (2005) found that specific inhibition of the insulin receptor or its signaling pathways in the nervous system led to increased ethanol sensitivity in Drosophila. </p><p>Ueki et al. (2006) created mice lacking both Insr and Igf1r only in pancreatic beta cells. These mice were born with the normal complement of islet cells, but 3 weeks after birth, they developed diabetes, in contrast to mild phenotypes observed in single mutants. At 2 weeks of age, normoglycemic beta cell-specific double-knockout mice showed reduced beta cell mass, reduced expression of phosphorylated Akt (164730) and the transcription factor MafA (610303), increased apoptosis in islets, and severely compromised beta cell function. Analyses of compound knockout showed a dominant role for insulin signaling in regulating beta cell mass. Ueki et al. (2006) concluded that insulin- and IGF1-dependent pathways are not critical for development of beta cells but that a loss of action of these hormones in beta cells leads to diabetes. </p><p>Biddinger et al. (2008) generated liver-specific Insr-knockout mice (LIRKO) and observed a marked predisposition to cholesterol gallstone formation, with all of the LIRKO mice developing gallstones after 12 weeks on a lithogenic diet. This predisposition was due to at least 2 distinct mechanisms: disinhibition of the Foxo1 gene (136533), which increased expression of the biliary cholesterol transporters Abcg5 (605459) and Abcg8 (605460), resulting in an increase in biliary cholesterol secretion; and decreased expression of the bile acid synthetic enzymes, particularly Cyp7b1 (603711), which produced partial resistance to the farnesoid X receptor (NR1H4; 603826), leading to a lithogenic bile salt profile. Biddinger et al. (2008) concluded that hepatic insulin resistance provides the link between the metabolic syndrome (605552) and increased cholesterol gallstone susceptibility. </p><p>Rajala et al. (2008) generated rod photoreceptor-specific Insr-knockout mice and found that rods of mutant mice had reduced PI3K and Akt. Mutant mice had a normal phenotype when raised in dim light, but they exhibited significantly reduced retinal function and loss of photoreceptors when exposed to bright light. The authors proposed that INSR may be essential for photoreceptor neuroprotection. </p>
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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>37 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
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INSR, GLY1035VAL
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SNP: rs121913135,
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ClinVar: RCV000015793
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<p>Ardon et al. (2014) stated that this mutation is c.3104G-T in exon 17 and results in an amino acid change gly1035 to val (G1035V), according to a revised INSR sequence (GenBank NC_000019). Ardon et al. (2014) noted that this mutation has also been referred to as gly1008 to val (G1008V). </p><p>In a young Japanese male with insulin-resistant diabetes mellitus and acanthosis nigricans (610549), in whom impaired tyrosine protein kinase activity had been demonstrated, Odawara et al. (1989) cloned a cDNA for the insulin receptor. One of this person's alleles had a mutation in which valine was substituted for glycine-996 (GLY996VAL), the third glycine in the conserved gly-X-gly-X-X-gly motif in the putative binding site for adenosine triphosphate. Expression of the mutant receptor by transfection into Chinese hamster ovary cells confirmed that the mutation impairs tyrosine kinase activity. The presence of mutant receptors appeared to have negative effects on the activity of the normal receptor. Studies with kinase-deficient insulin receptors transfected into cultured cells show that such receptors function as dominant-negative mutations and suppress the function of endogenous insulin receptors (review by Kahn and Goldstein, 1989). In most other cases of insulin resistance, the mutation is expressed as a recessive. Yamamoto-Honda et al. (1990) studied the function of this mutant form of the insulin receptor. </p>
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<span class="mim-font">
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<strong>.0002 DONOHUE SYNDROME</strong>
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INSR, LYS487GLU
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SNP: rs121913136,
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ClinVar: RCV000015794, RCV004724744
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<p>Ardon et al. (2014) stated that this mutation is c.1459A-G in exon 6 and results in an amino acid change lys487 to glu (K487E), according to a revised INSR sequence (GenBank NC_000019). </p><p>Donohue syndrome (246200) is an autosomal recessive disorder due to a defect in the INSR gene. In the patient leprechaun/Ark-1, Kadowaki et al. (1988) found 2 different mutant alleles of the INSR gene. The patient was a compound heterozygote, with the maternal allele containing a missense mutation (AAG-to-GAG) encoding the substitution of glutamic acid for lysine at position 460 (LYS460GLU, K460E) in the alpha subunit and with the paternal allele having a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit (147670.0003), thereby deleting both the transmembrane and the tyrosine kinase domains of the receptor. The mutation was designated leprechaunism Ark-1/allele-1. </p>
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<span class="mim-font">
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<strong>.0003 DONOHUE SYNDROME</strong>
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INSR, GLN699TER
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SNP: rs121913137,
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gnomAD: rs121913137,
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ClinVar: RCV000015796
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<p>Ardon et al. (2014) stated that this mutation is c.2095C-T in exon 10 and results in an amino acid change gln699 to ter (Q699X), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a case of Donohue syndrome (246200) due to compound heterozygosity for mutations in the INSR gene, Kadowaki et al. (1988) found that the paternal allele had a nonsense mutation (CAG-to-TAG) causing premature chain termination after amino acid 671 (GLN672TER, Q672X) in the alpha subunit, thereby deleting both the transmembrane and the tyrosine kinase domains of the receptor. This mutation was designated leprechaunism Ark-1 allele-2. The maternal allele carried a missense mutation (147670.0001). </p>
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<h4>
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<span class="mim-font">
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<strong>.0004 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
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</span>
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INSR, ARG762SER
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SNP: rs121913138,
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ClinVar: RCV000015798
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<p>Ardon et al. (2014) stated that this mutation is c.2286G-T in exon 12 and results in an amino acid change arg762 to ser (R762S), according to a revised INSR sequence (GenBank NC_000019). </p><p>Kakehi et al. (1988) found defective processing of the insulin receptor precursor in a 23-year-old Japanese female with extreme insulin resistance, acanthosis nigricans, bilateral polycystic ovaries, and decreased erythrocyte insulin binding (610549). Antireceptor antibodies showed the presence of increased amounts of a 210-kD protein but no detectable alpha or beta subunits. It appeared that the 190-kD receptor precursor was synthesized normally and underwent terminal glycosylation and normal intracellular transport to the cell surface, but that proteolytic maturation to alpha and beta subunits did not occur. The mutation could lie either in the INSR gene or in the gene for the receptor-processing enzyme. The former possibility proved to be correct. Yoshimasa et al. (1988) found that the insulin receptor gene in this patient had a point mutation within the tetrabasic processing site which was changed from arg-lys-arg-arg to arg-lys-arg-ser. Exon 12 contained a change in codon 735 from AGG-to-AGT (ARG735SER, R735S). Epstein-Barr virus-transformed lymphocytes from this patient synthesized an insulin receptor precursor that was normally glycosylated and inserted into the plasma membrane but was not cleaved to mature alpha and beta subunits. Insulin binding to these cells was severely reduced but could be increased about 5-fold by gentle treatment with trypsin, which was accompanied by appearance of normal alpha subunits. These results indicated that proteolysis of the proreceptor is necessary for its normal full insulin-binding sensitivity and signal-transducing activity and that a cellular protease that is more stringent in its specificity than trypsin is required to process the receptor precursor. The patient was a 23-year-old Japanese woman who was the product of a first-cousin marriage. Diabetes was first recognized at age 6. She showed nonketotic insulin-resistant diabetes mellitus with markedly elevated serum insulin values, acanthosis nigricans, hirsutism, and virilism. Her older sister was similarly affected. In addition, they showed some features not normally considered part of this syndrome, including mental retardation, short stature, and dental dysplasia. The latter 2 features have also been reported in an unrelated subject with Rabson-Mendenhall syndrome (Rabson and Mendenhall, 1956) who expressed an altered insulin receptor (Taylor et al., 1983). Insulin resistance due to this mutation behaved as a recessive. </p>
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<h4>
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<span class="mim-font">
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<strong>.0005 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
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INSR, TRP1227SER
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ClinVar: RCV000015797
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<p>Ardon et al. (2014) stated that this mutation is c.3680G-C in exon 21 and results in an amino acid change trp1227 to ser (W1227S), according to a revised INSR sequence (GenBank NC_000019). </p><p>In patient A(2) of the study of Grigorescu et al. (1986) with insulin-resistant diabetes and acanthosis nigricans (610549), Moller and Flier (1988) detected a heterozygous point mutation affecting the tyrosine kinase domain of the patient's insulin receptors, such that tryptophan-1200 was replaced by serine (TRP1200SER, W1200S). Hybridization of a mutant allele-specific oligonucleotide to PCR-amplified cDNA confirmed the presence of the mutant allele in the proband and excluded it in her unaffected sister and mother, 18 normal control subjects, and 6 other subjects with insulin resistance. Moller et al. (1990) showed that Chinese hamster ovary cells transfected with mutant cDNA produced a mutant receptor that was functionally severely impaired. The studies demonstrated the importance of trp-1200 to the normal function of the insulin receptor kinase. The observations demonstrated that severe insulin resistance can be caused by the heterozygous state of an INSR mutation. (Moller et al. (1990) used the nucleotide and amino acid numbering system of Ebina et al. (1985).) </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>.0006 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</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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INSR, EX17, ALU
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<br />
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ClinVar: RCV000015799
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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>Taira et al. (1989) studied a 17-year-old Japanese female who exhibited insulin-resistant diabetes, short stature, and acanthosis nigricans (610549). The mother had the same phenotype, whereas the father and 2 sibs were unaffected. The proband's maternal uncle and maternal grandfather were also said to be diabetic and of short stature. Erythrocytes and cultured fibroblasts from the proband and her mother had an insulin-binding capacity in the normal range, but cultured fibroblasts from both showed a below-normal rate of 2-deoxyglucose uptake. Therefore, the insulin resistance in this instance seemed to be due to a defect downstream from insulin binding. Taira et al. (1989) demonstrated that the mutant insulin receptor gene in these 2 subjects lacked almost the entire tyrosine kinase domain. Receptor autophosphorylation and tyrosine kinase activity toward an exogenous substrate were reduced in partially purified insulin receptors from the proband's lymphocytes that had been transformed by Epstein-Barr virus. With the use of several region-specific insulin receptor cDNA probes, Taira et al. (1989) analyzed the mutation further and demonstrated that it occurred at a nucleotide within the exon just before the codon for lys1030. This amino acid is part of the adenosine triphosphate (ATP)-binding site of the receptor and is required for tyrosine kinase activity. The exon containing the mutation corresponded to exon 17, which encodes the NH(2)-terminal part of the kinase domain. The sequence of the receptor gene was normal on the upstream side of the site of the mutation at nucleotide 145 (of the cloned fragment studied in detail); distal to this site it was entirely different to the point where a stop codon was reached at nucleotide 339. Thus, the putative product from the mutated gene has a new sequence of 65 amino acids at its COOH-terminus. The new sequence of the mutant allele was homologous to the consensus sequence of the Alu family, suggesting that the mutation resulted from recombination between exon 17 of the insulin receptor and an Alu sequence. </p><p>Ardon et al. (2014) cataloged this mutation as a complex rearrangement according to a revised INSR sequence (GenBank NC_000019). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 DONOHUE 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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INSR, ARG924TER
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<br />
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SNP: rs387906538,
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gnomAD: rs387906538,
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ClinVar: RCV000015800
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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>Ardon et al. (2014) stated that this mutation is c.2770C-T in exon 14 and results in an amino acid change arg924 to ter (R924X), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a patient with Donohue syndrome (246200), Kadowaki et al. (1990) identified a nonsense mutation at codon 897 (ARG897TER, R897X) in exon 14 in the paternal allele of the patient's insulin receptor gene. In addition, they obtained evidence that the patient's maternal allele contained a cis-acting dominant mutation that, like the paternal allele, caused a decrease in the level of mRNA. The nucleotide sequence of the entire protein-coding domain and the sequences of the intron-exon boundaries of all 22 exons of the maternal allele were normal. This mutation was designated leprechaunism Minn-1. </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 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
|
|
</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">
|
|
INSULIN RESISTANCE, INCLUDED
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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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INSR, ALA1161THR
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<br />
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SNP: rs121913139,
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ClinVar: RCV000015801, RCV000015802
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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>Ardon et al. (2014) stated that this mutation is c.3481G-A in exon 19 and results in an amino acid change ala1161 to thr (A1161T), according to a revised INSR sequence (GenBank NC_000019). </p><p>Moller et al. (1990) studied a family in which 3 sisters had the type A syndrome of insulin resistance (610549), the father was hyperinsulinemic without acanthosis nigricans or other abnormalities (see 125853), and the mother was normal. The daughters and father were found to be heterozygous for a single base substitution in codon 1134 (GCA to ACA, ala to thr; ALA1134THR, A1134T). Transfection of the mutant insulin receptor gene into CHO cells showed that the protein produced had markedly impaired insulin-stimulated autophosphorylation. The family demonstrates that severe insulin resistance with dominant inheritance can be caused by a missense mutation and can be clinically silent in a male. Moller et al. (1990) studied expression of the ala1134 mutant receptor in Chinese hamster ovary cells. The expressed mutant receptors were processed normally and displayed normal affinity in insulin binding but were markedly deficient in insulin-stimulated autophosphorylation. Moller et al. (1990) pointed out that alanine-1134 is a highly conserved residue located in a consensus sequence found in most tyrosine kinases. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0009 MOVED TO 147670.0005</strong>
|
|
</span>
|
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</h4>
|
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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 DONOHUE SYNDROME</strong>
|
|
</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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|
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|
INSR, LEU260PRO
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<br />
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|
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SNP: rs121913141,
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|
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gnomAD: rs121913141,
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|
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|
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ClinVar: RCV000015804
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|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.779T-C in exon 3 and results in an amino acid change leu260 to pro (L260P), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a patient with Donohue syndrome (246200), the son of parents related as second cousins once removed, coming from the town of Geldeimalsen in the Netherlands, Klinkhamer et al. (1989) described a leucine-to-proline mutation at position 233 (LEU233PRO; L233P). By DNA amplification, they showed that the patient was homozygous and the parents and 2 of the grandparents from the consanguineous line were heterozygous. All the heterozygotes showed decreased insulin binding to cultured fibroblasts and had mild insulin resistance in vivo. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 DIABETES MELLITUS, INSULIN-RESISTANT</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, PHE409VAL
|
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|
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<br />
|
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|
|
SNP: rs121913142,
|
|
|
|
|
|
|
|
ClinVar: RCV000015805
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.1225T-G in exon 5 and results in an amino acid change phe409 to val (F409V), according to a revised INSR sequence (GenBank NC_000019). </p><p>In 2 women with insulin-resistant diabetes (see 125853), daughters of first-cousin, Venezuelan Caucasian parents, Accili et al. (1989) identified a T-to-G transversion at position 1273, leading to the substitution of valine for phenylalanine at position 382 in the alpha subunit of the insulin receptor (PHE382VAL; F382V). Inspection of mutant insulin receptor cDNA into NIH 3T3 cells demonstrated that the val382 mutation impaired posttranslational processing and retarded transport of the insulin receptor to the plasma membrane. They used multiple RFLPs to determine haplotypes at the INSR locus and arrived at a lod score of approximately 1.9 to 2.3 for linkage with insulin-resistant diabetes in this family. They pointed out that this lod score exceeds the threshold for declaring linkage when studying a single candidate locus (Lander and Botstein, 1987). The sisters had previously been reported by Barnes et al. (1974) as a case of insulin resistance possibly due to pineal gland dysfunction. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 RABSON-MENDENHALL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, ASN42LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913143,
|
|
|
|
|
|
|
|
ClinVar: RCV000015806
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.126C-A in exon 2 and results in an amino acid change asn42 to lys (N42K), according to a revised INSR sequence (GenBank NC_000019). </p><p>Kadowaki et al. (1990) studied a patient (RM-1) with Rabson-Mendenhall syndrome (Moncada et al., 1986; 262190) who was found to be a compound heterozygote for 2 mutant alleles of the INSR gene: a missense mutation that substituted lysine for asparagine-15 (AAC to AAA; ASN15LYS, N15K) and a nonsense mutation at codon 1000 (CGA to TGA, ARG1000TER, R1000X; see 147670.0013). Kadowaki et al. (1990) characterized the lys15-mutant receptor expressed by transfection by mutant cDNA into NIH 3T3 cells. At least 2 defects in insulin receptor function were observed. The mutation retarded posttranslational processing of the receptor and impaired transport of the receptor to the plasma membrane, thereby reducing the number of the receptors on the cell surface. It also caused a 5-fold reduction in the affinity of the receptor for insulin. Kadowaki et al. (1990) suggested that both functional defects were related to distortion of the 3-dimensional structure of the receptor by the mutation. Presumably, the abnormal conformation interfered with the transport of the receptor through the endoplasmic reticulum and Golgi apparatus, and also inhibited the binding of insulin to its binding site. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 RABSON-MENDENHALL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, ARG1027TER
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000015807, RCV000128412
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.3079C-T in exon 17 and results in an amino acid change arg1027 to ter (R1027X), according to a revised INSR sequence (GenBank NC_000019). </p><p>See 147670.0012 and Kadowaki et al. (1990). See 147670.0018 and Kusari et al. (1991). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 DONOHUE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, HIS236ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913145,
|
|
|
|
|
|
gnomAD: rs121913145,
|
|
|
|
|
|
ClinVar: RCV000015808
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.707A-G in exon 3 and results in an amino acid change his236 to arg (H236R), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a case of Donohue syndrome (246200) in a consanguineous Winnipeg pedigree, Kadowaki et al. (1990) found homozygosity for a CAC-to-CGC mutation resulting in substitution of histidine by arginine (HIS209ARG, H209R). Kadowaki et al. (1991) demonstrated that this mutation impairs receptor dimerization and transport of receptors to the cell surface. The small number of receptors that are transported to the cell surface bind insulin with normal affinity and have normal tyrosine kinase activity. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, TRP160TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913146,
|
|
|
|
|
|
|
|
ClinVar: RCV000015809
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.479G-A in exon 2 and results in an amino acid change trp160 to ter (W160X), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a patient (A-1) with insulin-resistant diabetes mellitus and acanthosis nigricans (610549), Kadowaki et al. (1990) found compound heterozygosity for a trp133 (TGG) nonsense mutation (TAG) (TRP133TER, W133X) and a missense mutation (AAT to AGT, ASN462SER, N462S; see 147670.0016). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, ASN489SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913147,
|
|
|
|
|
|
|
|
ClinVar: RCV000015810, RCV001753417, RCV004795417
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.1466A-G in exon 6 and results in an amino acid change asn489 to ser (N489S), according to a revised INSR sequence (GenBank NC_000019). </p><p>See 147670.0015 and Kadowaki et al. (1990). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, EX14DEL
|
|
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<br />
|
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|
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|
|
|
|
ClinVar: RCV000015811
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old Japanese girl with type A insulin resistance (hyperinsulinemia, decreased insulin binding, and acanthosis nigricans; 610549), Shimada et al. (1990) found that 1 LDLR allele, inherited from her mother, contained a 1.2-kb deletion arising from a recombination between 2 Alu elements, one in intron 13 and the other in intron 14, and removing exon 14. The nature of the allele inherited from the father was not determined. The father had borderline impairment of glucose tolerance and mild insulin resistance. Shimada et al. (1992) extended these studies to demonstrate that the deletion shifted the reading frame, resulting in a termination codon after amino acid 867 (glu), thereby producing a truncated insulin receptor without a transmembrane region and cytoplasmic domain. They also sequenced all 22 exons of the INSR gene and found no mutation in exons except for the deletion of exon 14. Thus the patient was heterozygous for a single mutant allele. </p><p>Ardon et al. (2014) cataloged this mutation as a 1.2-kb deletion including exon 14 according to a revised INSR sequence (GenBank NC_000019). </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>.0018 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</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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INSR, ARG1020GLN
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<br />
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SNP: rs121913148,
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gnomAD: rs121913148,
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ClinVar: RCV000015812, RCV002496377
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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>Ardon et al. (2014) stated that this mutation is c.3059G-A in exon 17 and results in an amino acid change arg1020 to gln (R1020Q), according to a revised INSR sequence (GenBank NC_000019). According to Ardon et al. (2014), this mutation has also been known as arg993 to gln (R993Q). </p><p>In a patient with acanthosis and insulin-resistant diabetes (610549) described by Scarlett et al. (1982), Kusari et al. (1991) found compound heterozygosity at the INSR locus. The parents were not consanguineous. The paternal allele contained a missense mutation encoding the substitution of glutamine for arginine at position 981 (ARG981GLN, R981Q) in the tyrosine kinase domain of the receptor. The maternal allele contained a nonsense mutation causing premature termination after amino acid 988 in the beta subunit (ARG988TER, R988X; 147670.0013) thereby deleting most of the kinase domain. A CGA-to-CAA mutation was responsible for the first change, and a CGA-to-TGA mutation for the second. </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-text-font">
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<strong>.0019 MOVED TO 147670.0013</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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<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>.0020 DONOHUE 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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INSR, GLY58ARG
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<br />
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SNP: rs52836744,
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ClinVar: RCV000015814
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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>Ardon et al. (2014) stated that this mutation is c.172G-A in exon 2 and results in an amino acid change gly58 to arg (G58R), according to a revised INSR sequence (GenBank NC_000019). </p><p>Maassen et al. (1988) described a patient named Helmond with Donohue syndrome (246200) in whom intact fibroblasts showed markedly reduced insulin binding but significant receptor autophosphorylation when the glycoprotein fraction was used. In this patient, van der Vorm et al. (1992) demonstrated a GGA-to-AGA change in exon 2 resulting in a gly31-to-arg substitution (GLY31ARG, G31R). The proband was a compound heterozygote. The mutation was present also in heterozygous state in the mother and maternal grandfather. In the mother and grandfather, the mutation was associated with decreased insulin binding to cultured fibroblasts and in vivo hyperinsulinemia after an oral glucose tolerance test. In the paternal line, all subjects had an insulin binding within the normal range and the G31R mutation was absent. </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>.0021 TYPE 2 DIABETES MELLITUS</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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INSR, ARG1191GLN
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<br />
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SNP: rs121913150,
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gnomAD: rs121913150,
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ClinVar: RCV000015815
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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>Ardon et al. (2014) stated that this mutation is c.3572G-A in exon 20 and results in an amino acid change arg1191 to gln (R1191Q), according to a revised INSR sequence (GenBank NC_000019). Ardon et al. (2014) noted that this mutation has also been classified as arg1164 to gln (R1164Q). </p><p>In a patient with noninsulin-dependent diabetes mellitus (125853), Cocozza et al. (1992) identified an abnormality in exon 20 of the INSR gene by denaturing gradient gel electrophoresis (DGGE). Sequencing showed heterozygosity for a change of codon 1152 from CGG to CAG, resulting in replacement of arginine with glutamine (ARG1152GLN, R1152Q). Although autophosphorylation of the purified insulin receptor seemed to be normal and the insulin binding to intact erythrocytes from the patient was in the normal range, the purified insulin receptor showed no detectable activity toward an exogenous substrate. </p><p>Esposito et al. (1995) screened a cohort of 68 Italian NIDDM patients and 65 controls for INSR R1152Q and did not find the variant in any patients or controls. The authors concluded that the R1152Q variant is not involved in the development of NIDDM in the Italian population. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0022 DONOHUE SYNDROME</strong>
|
|
</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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INSR, ARG399TER
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<br />
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SNP: rs121913151,
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gnomAD: rs121913151,
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ClinVar: RCV000015816, RCV000520627
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|
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|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.1195C-T in exon 5 and results in an amino acid change arg399 to ter (R399X), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a black female, the second child of healthy unrelated parents of Hispanic and Afro-American descent, Longo et al. (1992) found the clinical features of Donohue syndrome (246200) related to compound heterozygosity for different mutations. The paternally derived mutation, a C-to-T transition at bp 1333, converted arginine-372 to a stop codon (ARG372TER, R372X). The maternally inherited allele had no mutations within the protein-coding region, suggesting that the second mutation was located in a region of the INSR gene involving control of gene expression. The clinical features of the patient were reported by Norton et al. (1990). The mutation was labeled leprechaunism Mount Sinai. </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>.0023 DONOHUE SYNDROME</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, VAL55ALA
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<br />
|
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|
|
SNP: rs121913152,
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|
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|
|
ClinVar: RCV000015817
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.164T-C in exon 2 and results in an amino acid change val55 to ala (V55A), according to a revised INSR sequence (GenBank NC_000019). </p><p>Barbetti et al. (1992) used denaturing gradient gel electrophoresis (DGGE) to identify compound heterozygosity for 2 different mutations in the INSR gene in a patient labeled leprechaun/Verona-1. The patient was a white female whose appearance suggested Donohue syndrome (246200) at birth (characteristic facies, hirsutism, clitoromegaly). Immediately after birth, she developed hypoglycemia during fasting. In addition, she became hyperglycemic after meals. Her peak immunoreactive insulin during an oral glucose tolerance test was very high. At age 6.5 years, pelvic sonogram demonstrated polycystic ovaries, and abdominal sonogram showed bilateral medullary sponge kidneys. The INSR allele inherited from the father had a mutation substituting alanine for valine-28 (VAL28ALA, V28A); in the allele inherited from the mother, arginine was substituted for glycine-366 (GLY366ARG, G366R). Barbetti et al. (1992) applied the DGGE method also to several other cases of Donohue syndrome in whom the genetic defect had previously been identified. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 DONOHUE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, GLY393ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607184,
|
|
|
|
|
|
|
|
ClinVar: RCV000015795
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.1177G-A in exon 5 and results in an amino acid change gly393 to arg (G393R), according to a revised INSR sequence (GenBank NC_000019). </p><p>See 147670.0023.</p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 DONOHUE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, ARG113PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913153,
|
|
|
|
|
|
gnomAD: rs121913153,
|
|
|
|
|
|
ClinVar: RCV000015818
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.338G-C in exon 2 and results in an amino acid change arg113 to pro (R113P), according to a revised INSR sequence (GenBank NC_000019). </p><p>Fibroblasts cultured from a patient with Donohue syndrome (246200) with intrauterine growth retardation and severe insulin resistance (designated leprechaun Atlanta (Atl)-1) had normal amounts of insulin receptor protein and defective insulin binding but constitutive activation of insulin-receptor autophosphorylation and kinase activity and of glucose transport (Longo et al., 1993). In the same fibroblasts, growth was impaired. Homozygosity for a mutation in the INSR gene was suspected, since he inherited identical DNA haplotypes for this gene from the parents who were blood relatives. Longo et al. (1993) found that indeed the proband was homozygous and both parents were heterozygous for a G-to-C transversion at nucleotide 476 of the INSR cDNA converting arginine-86 to proline (ARG86PRO, R86P). Expression of this mutation in CHO cells duplicated the natural mutation by activating glucose transport without increasing insulin binding or insulin-stimulated cellular growth. The R86P substitution is contiguous to the hydrophobic beta-sheet of the receptor alpha subunit implicated in the binding of aromatic residues of the insulin molecule. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
|
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, ALA1162GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121913154,
|
|
|
|
|
|
|
|
ClinVar: RCV000015819
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.3485C-A in exon 19 and results in an amino acid change ala1162 to glu (A1162E), according to a revised INSR sequence (GenBank NC_000019). </p><p>Cama et al. (1993) described the molecular findings in a 32-year-old woman with insulin resistance. She had presented to medical attention at the age of 11 with features of type A insulin resistance including acanthosis nigricans and virilization (610549). Subsequently, her acanthosis nigricans disappeared and she began to ovulate spontaneously, became pregnant without medical intervention, and had an apparently normal daughter. Using oligonucleotides complementary to sequences in introns 18 and 19, Cama et al. (1993) used PCR to amplify exon 19 of the insulin receptor gene. By direct sequencing of the amplified genomic DNA, they demonstrated that codon 1135 was mutated from GCG (ala) to GAG (glu) (ALA1135GLU, A1135E). Neither parent had the mutation, which was heterozygous in the proposita. Like previously described mutations in the tyrosine kinase domain, the glu1135 mutation impaired receptor tyrosine kinase activity and inhibited the ability of insulin to stimulate thymidine incorporation and receptor endocytosis. However, unlike previously described mutations in the intracellular domain of the receptor, the new mutation impaired proteolytic cleavage of the proreceptor into separate subunits and impaired the transport of the receptor to the cell surface. The latter defect accounted for the decrease in number of receptors on the cell surface of the patient's circulating monocytes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 DONOHUE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, LYS148TER
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|
|
|
<br />
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|
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SNP: rs121913155,
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|
|
ClinVar: RCV000015820
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.442A-T in exon 2 and results in an amino acid change lys148 to ter (K148X), according to a revised INSR sequence (GenBank NC_000019). </p><p>In an offspring of consanguineous parents of Pakistani origin, Krook et al. (1993) observed Donohue syndrome (246200) resulting from homozygosity for a nonsense mutation, lys121 to ter (LYS121TER, K121X). Severe intrauterine growth retardation had been evident throughout pregnancy and at birth the baby had a wasted appearance with a distended abdomen, lack of subcutaneous fat, and decreased muscle mass. The facies was gaunt with pronounced hirsutism, protuberant ears, and gum hypertrophy. There was generalized hypertrichosis. Both parents were heterozygous for a mutation in codon 121 of the INSR gene that changed AAG (lysine) to TAG (stop). </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>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0028 DONOHUE 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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|
|
INSR, DEL
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<br />
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|
|
ClinVar: RCV000015821
|
|
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|
|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) cataloged this mutation as a deletion of the entire INSR gene according to a revised INSR sequence (GenBank NC_000019). </p><p>In a 15-month-old boy with Donohue syndrome (246200), an offspring of first-cousin parents, Wertheimer et al. (1993) found homozygous deletion of the INSR gene. Thus, contrary to previous predictions, complete absence of the INSR gene is compatible with life. </p>
|
|
</span>
|
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0029 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
INSR, VAL1012MET
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs1799816,
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|
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|
|
|
gnomAD: rs1799816,
|
|
|
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|
|
ClinVar: RCV000015822, RCV000175131, RCV000344820, RCV000445519, RCV000515071, RCV001132183, RCV001132184, RCV001258250
|
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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>This variant, formerly titled DIABETES MELLITUS, NONINSULIN-DEPENDENT, has been reclassified based on the report of Lek et al. (2016). </p><p>Ardon et al. (2014) stated that this mutation is c.3034G-A in exon 17 and results in an amino acid change val1012 to met (V1012M), according to a revised INSR sequence (GenBank NC_000019). </p><p>In studies of 11 familial NIDDM pedigrees (125853), Elbein et al. (1993) found 1 in which some members had a val985-to-met substitution in exon 17 (VAL985MET, V985M). The substitution was present in 3 NIDDM individuals in 3 generations, including a lean individual with onset at age 24. The substitution was absent in 1 affected individual and was present in some nondiabetic pedigree members. Nondiabetic carriers of the mutation were found to have significantly higher glucose levels when compared with 266 members of other pedigrees, after correction for age, weight, and sex. Elbein et al. (1993) suggested that although the val985-to-met substitution does not result in severe insulin resistance and has low penetrance with respect to expression of the NIDDM phenotype, it may represent a modifying factor collaborating with other loci predisposing to diabetes. </p><p>In a population-based Rotterdam study, 't Hart et al. (1996) examined 161 individuals with NIDDM and 538 healthy controls for the presence of mutations in the INSR gene, using SSCP. A heterozygous mutation changing valine-985 into methionine was detected in 5.6% of diabetic subjects and in 1.3% of individuals with normal oral glucose tolerance test. Adjusted for age, gender, and body-mass index, the findings indicated a relative risk for diabetes of 4.49 for met985 carriers. When the total study group was analyzed, 't Hart et al. (1996) found that the prevalence of the mutation increased with increasing serum glucose levels. </p><p>In a study of random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies, 't Hart et al. (1999) found the val985-to-met INSR variant at frequencies of 4.4 and 1.8%, respectively, in NIDDM and normoglycemic patients. Inclusion of data from 2 other studies yielded a summarized odds ratio of 1.87. The authors concluded that the association between the val985-to-met variant in the INSR gene and type II diabetes, previously reported in the Rotterdam study, is supported by the joint analysis with a second population-based study and other studies. </p><p>Lek et al. (2016) noted that the V1012M variant has a high allele frequency (0.0225) in the South Asian population in the ExAC database, suggesting that it is not pathogenic. </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>.0030 DIABETES MELLITUS, INSULIN-RESISTANT, WITH ACANTHOSIS NIGRICANS</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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HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 5, INCLUDED
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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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INSR, ARG1201GLN
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<br />
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ClinVar: RCV000015823, RCV000125461, RCV001818162
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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>Ardon et al. (2014) stated that this mutation is c.3602G-A in exon 20 and results in an amino acid change arg1201 to gln (R1201Q), according to a revised INSR sequence (GenBank NC_000019). </p><p>Among 22 unrelated women with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (manifested by hyperandrogenemia, oligoamenorrhea, and hirsutism; 610549), Moller et al. (1994) found heterozygosity for a CGG-to-CAG transition in exon 20 of the INSR gene, resulting in an arg1174-to-gln (ARG1174GLN, R1174Q) amino acid substitution. The mutation involved the intracellular receptor beta subunit. The mutation was found in an affected sister, whereas it was absent in the unaffected mother. It was probably present in 2 paternal aunts who were reportedly affected. Thus, arg1174 to gln, involving the insulin receptor tyrosine kinase domain, is a cause of dominantly inherited insulin resistance. </p><p>In all affected members of a 3-generation Danish family with hyperinsulinemic hypoglycemia (609968), Hojlund et al. (2004) identified heterozygosity for a G-A transition at codon 1174 in exon 20 of the INSR gene, resulting in an arg1174-to-gln (R1174Q) substitution. The mutation was not found in any unaffected family members. </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>.0031 INSULIN RESISTANCE</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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INSR, MET1180ILE
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<br />
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SNP: rs121913157,
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ClinVar: RCV000015824, RCV001851881
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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>Ardon et al. (2014) stated that this mutation is c.3540G-A in exon 20 and results in an amino acid change met1180 to ile (M1180I), according to a revised INSR sequence (GenBank NC_000019). </p><p>A met1153-to-ile mutation (MET1153ILE, M1153I) in the INSR gene was demonstrated to be the cause of insulin resistance by Cama et al. (1991, 1992). The mutation caused a defect in receptor internalization relative to normal receptors. Insulin resistance in the patient showed a fluctuating clinical course, suggesting that the ratio of normal receptors to mutant receptors on the surface of the patient's cells may change depending on factors that promote or inhibit receptor endocytosis, such as hyperinsulinemia and obesity. Quon et al. (1994) applied to the study of this mutation a physiologically relevant system for dissecting the molecular mechanisms of insulin signal transduction related to glucose transport. The method involved transfection of DNA into rat adipose cells in primary culture. As a reporter gene, they used cDNA coding for GLUT4 (138190) with an epitope tag in the first exofacial loop so that GLUT4 translocation could be studied exclusively in transfected cells. Insulin stimulated a 4.3-fold recruitment of transfected epitope-tagged GLUT4 to the cell surface. Cells cotransfected with the reporter gene and the human insulin receptor gene showed an increase in cell surface GLUT4 in the basal state (no insulin) to levels comparable to those seen with maximal insulin stimulation of cells transfected with the reporter gene alone. In contrast, cells overexpressing the met1153-to-ile mutation showed no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. In contrast, cells overexpressing the met1163-to-ile mutation showed no increase in the basal cell surface GLUT4 and no shift in the insulin dose-response curve relative to cells transfected with the reporter gene alone. The results were interpreted as indicating that insulin receptor tyrosine kinase activity is essential in insulin-stimulated glucose transport in adipose cells. </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>.0032 DONOHUE 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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INSR, TRP439SER
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<br />
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SNP: rs121913158,
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ClinVar: RCV000015825
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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>Ardon et al. (2014) stated that this mutation is c.1316G-C in exon 6 and results in an amino acid change trp439 to ser (W439S), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a child with Donohue syndrome (246200), the offspring of consanguineous Turkish parents, van der Vorm et al. (1994) found a trp412-to-ser mutation (TRP412SER, W412S) in the INSR gene. The mutant receptor was expressed stably in CHO cells and transiently in COS-1 cells where it was found that the mutant was not cleaved into alpha- and beta-subunits but remained as a 210-kD proreceptor at an intracellular site. Cross-linking experiments showed that the mutant proreceptor was able to bind insulin with an affinity comparable to that of the wildtype alpha chain. Despite its capacity to bind insulin, the mutant receptor was not autophosphorylated. Impaired transport of the proreceptor to the cell surface appeared to be the primary cause for the binding defect observed in intact cells. The patient was thought to be homozygous for the mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0033 DONOHUE 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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INSR, ILE146MET
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<br />
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SNP: rs121913159,
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gnomAD: rs121913159,
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ClinVar: RCV000015826
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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>Ardon et al. (2014) stated that this mutation is c.438C-G in exon 2 and results in an amino acid change ile146 to met (I146M), according to a revised INSR sequence (GenBank NC_000019). </p><p>Al-Gazali et al. (1993) described a 'mild' variant of Donohue syndrome (246200) in 5 infants from an inbred family. Using denaturing gradient gel electrophoresis and subsequent sequence of selected exons, Hone et al. (1994) identified a homozygous mutation resulting from an ile119-to-met (ILE119MET, I119M) substitution in exon 2 of the INSR gene in this family. Mutation in the insulin binding domain predicts ineffective insulin signal transduction. </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>.0034 RABSON-MENDENHALL 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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INSR, IVS4AS, A-G, -2
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<br />
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|
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SNP: rs587776819,
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|
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ClinVar: RCV000015827
|
|
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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>Ardon et al. (2014) cataloged this mutation as c.1124-2A-G according to a revised INSR sequence (GenBank NC_000019). </p><p>In an English patient with Rabson-Mendenhall syndrome (262190), Takahashi et al. (1998) found compound heterozygosity for novel mutations in the INSR gene. One was an A-to-G transition at the 3-prime splice acceptor site of intron 4, and the other was an 8-bp deletion in exon 12. Both decreased mRNA expression in a cis-dominant manner, and were predicted to produce severely truncated proteins. Unexpectedly, nearly normal insulin receptor levels were expressed in the patient's lymphocytes, although the level of expression assessed by immunoblot was approximately 10% of the control cells. Insulin-binding affinity was markedly reduced, but insulin-dependent tyrosine kinase activity was present. On analysis of INSR mRNA of lymphocytes by RT-PCR, aberrant splicing caused by activation of a cryptic splice site in exon 5, resulting in a 4-amino acid deletion and 1-amino acid substitution, but restoring an open reading frame, was found. Skipped exon 5, another aberrant splicing, was found in both the patient and the mother who was heterozygous for the mutation, whereas activation of the cryptic splice site occurred almost exclusively in the patient. Takahashi et al. (1998) speculated that the mutant receptor may have been involved in the relatively long survival of the patient by rescuing an otherwise more severe phenotype resulting from the complete lack of functional insulin receptors. The patient, previously reported by Quin et al. (1990), had severe insulin-resistant diabetes and intermittent ketonuria, and was treated successfully with recombinant insulinlike growth factor 1 (IGF1; 147440). Although other therapeutic agents were unsuccessful, the patient lived to age 13, when he began subcutaneous IGF1 injections. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0035 RABSON-MENDENHALL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
INSR, 8-BP DEL, NT2480
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<br />
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|
|
SNP: rs587776820,
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|
|
ClinVar: RCV000015828
|
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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>Ardon et al. (2014) cataloged this mutation as c.2480_2487del8 in exon 12 according to a revised INSR sequence (GenBank NC_000019). </p><p>See 147670.0034 and Takahashi et al. (1998). </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>.0036 DONOHUE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
INSR, ASN458ASP
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|
|
|
<br />
|
|
|
|
SNP: rs121913160,
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|
|
ClinVar: RCV000015829
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Ardon et al. (2014) stated that this mutation is c.1372A-G in exon 6 and results in an amino acid change asn458 to asp (N458D), according to a revised INSR sequence (GenBank NC_000019). </p><p>In a Scottish Caucasian male with Donohue syndrome (246200) who died at 3 months of age, Maassen et al. (2003) detected a novel homozygous A-to-G transition in the INSR gene that resulted in an asn431-to-asp (ASN431ASP, N431D) amino acid change. The N431D mutation only partially reduced insulin proreceptor processing and activation of signaling cascades. The correlation between fibroblast insulin binding and duration of patient survival reported by Longo et al. (2002) was not observed. </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-text-font">
|
|
<strong>.0037 MOVED TO 147670.0030</strong>
|
|
</span>
|
|
</h4>
|
|
</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>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Elbein et al. (1986); Ferrannini et al. (1982); Grigorescu et al.
|
|
(1984); Grunberger et al. (1984); Kahn et al. (1976); Kahn and White
|
|
(1988); Mariani et al. (1982); Moller et al. (1990); Moller et al.
|
|
(1990); Roth and Cassell (1983); Schwenk et al. (1986); Ward and
|
|
Harrison (1986)
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
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<div>
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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't Hart, L. M., Stolk, R. P., Dekker, J. M., Nijpels, G., Grobbee, D. E., Heine, R. J., Maassen, J. A.
|
|
<strong>Prevalence of variants in candidate genes for type 2 diabetes mellitus in the Netherlands: the Rotterdam study and the Hoorn study.</strong>
|
|
J. Clin. Endocr. Metab. 84: 1002-1006, 1999.
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|
[PubMed: 10084586]
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[Full Text: https://doi.org/10.1210/jcem.84.3.5563]
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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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't Hart, L. M., Stolk, R. P., Heine, R. J., Grobbee, D. E., van der Does, F. E. E., Maassen, J. A.
|
|
<strong>Association of the insulin-receptor variant met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study.</strong>
|
|
Am. J. Hum. Genet. 59: 1119-1125, 1996.
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[PubMed: 8900242]
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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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Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool, M. H., Salvatore, P., Asico, L. D., Jose, P. A., Taylor, S. I., Westphal, H.
|
|
<strong>Early neonatal death in mice homozygous for a null allele of the insulin receptor gene.</strong>
|
|
Nature Genet. 12: 106-109, 1996.
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[PubMed: 8528241]
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[Full Text: https://doi.org/10.1038/ng0196-106]
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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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Accili, D., Frapier, C., Mosthaf, L., McKeon, C., Elbein, S. C., Permutt, M. A., Ramos, E., Lander, E., Ullrich, A., Taylor, S. I.
|
|
<strong>A mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrane and causes insulin-resistant diabetes.</strong>
|
|
EMBO J. 8: 2509-2517, 1989.
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[PubMed: 2573522]
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[Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb08388.x]
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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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Al-Gazali, L. I., Khalil, M., Devadas, K.
|
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<strong>A syndrome of insulin resistance resembling leprechaunism in five sibs of consanguineous parents.</strong>
|
|
J. Med. Genet. 30: 470-475, 1993.
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[PubMed: 8326490]
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[Full Text: https://doi.org/10.1136/jmg.30.6.470]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ardon, O., Procter, M., Tvrdik, T., Longo, N., Mao, R.
|
|
<strong>Sequencing analysis of insulin receptor defects and detection of two novel mutations in INSR gene.</strong>
|
|
Molec. Genet. Metab. Rep. 1: 71-84, 2014.
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[PubMed: 27896077]
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[Full Text: https://doi.org/10.1016/j.ymgmr.2013.12.006]
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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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</p>
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Wertheimer, E., Lu, S.-P., Backeljauw, P. F., Davenport, M. L., Taylor, S. I.
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<strong>Homozygous deletion of the human insulin receptor gene results in leprechaunism.</strong>
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Williams, D. L., Look, A. T., Melvin, S. L., Roberson, P. K., Dahl, G., Flake, T., Stass, S.
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<strong>New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia.</strong>
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Williams, J. F., McClain, D. A., Dull, T. J., Ullrich, A., Olefsky, J. M.
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Yamamoto-Honda, R., Koshio, O., Tobe, K., Shibasaki, Y., Momomura, K., Odawara, M., Kadowaki, T., Takaku, F., Akanuma, Y., Kasuga, M.
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Yang-Feng, T. L., Francke, U., Ullrich, A.
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<strong>Gene for human insulin receptor: localization to site on chromosome 19 involved in pre-B-cell leukemia.</strong>
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Yoshimasa, Y., Seino, S., Whittaker, J., Kakehi, T., Kosaki, A., Kuzuya, H., Imura, H., Bell, G. I., Steiner, D. F.
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<strong>Insulin-resistant diabetes due to a point mutation that prevents insulin proreceptor processing.</strong>
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[PubMed: 3283938]
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Contributors:
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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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Alan F. Scott - updated : 05/02/2022<br>Ada Hamosh - updated : 12/02/2016<br>Marla J. F. O'Neill - updated : 6/6/2014<br>Ada Hamosh - updated : 5/16/2013<br>Ada Hamosh - updated : 3/21/2013<br>Patricia A. Hartz - updated : 11/5/2012<br>Marla J. F. O'Neill - updated : 7/25/2008<br>Paul J. Converse - updated : 11/9/2006<br>Ada Hamosh - updated : 11/7/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Marla J. F. O'Neill - updated : 3/16/2006<br>Marla J. F. O'Neill - updated : 3/13/2006<br>Marla J. F. O'Neill - updated : 7/27/2005<br>John A. Phillips, III - updated : 7/6/2005<br>Marla J. F. O'Neill - updated : 3/16/2005<br>Cassandra L. Kniffin - updated : 3/1/2005<br>Marla J. F. O'Neill - updated : 11/19/2004<br>Victor A. McKusick - updated : 9/15/2004<br>Victor A. McKusick - updated : 5/27/2004<br>Victor A. McKusick - updated : 2/10/2004<br>Ada Hamosh - updated : 12/1/2003<br>Ada Hamosh - updated : 4/22/2003<br>George E. Tiller - updated : 4/11/2003<br>Dawn Watkins-Chow - updated : 2/26/2003<br>Ada Hamosh - updated : 2/3/2003<br>Cassandra L. Kniffin - updated : 1/24/2003<br>Deborah L. Stone - updated : 9/12/2002<br>Jane Kelly - updated : 7/2/2002<br>Dawn Watkins-Chow - updated : 6/28/2001<br>Stylianos E. Antonarakis - updated : 4/17/2001<br>Stylianos E. Antonarakis - updated : 1/11/2001<br>Ada Hamosh - updated : 10/23/2000<br>Stylianos E. Antonarakis - updated : 9/11/2000<br>John A. Phillips, III - updated : 11/24/1999<br>Stylianos E. Antonarakis - updated : 2/16/1999<br>Stylianos E. Antonarakis - updated : 2/9/1999<br>Iosif W. Lurie - updated : 1/23/1997
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Victor A. McKusick : 6/2/1986
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