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Entry
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- *176730 - INSULIN; INS
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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">*176730</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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<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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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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="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</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/176730">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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</div>
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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=ENSG00000254647;t=ENST00000381330" 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=3630" 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=176730" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000254647;t=ENST00000381330" 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_000207,NM_001185097,NM_001185098,NM_001291897" 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_000207" 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=176730" 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=01455&isoform_id=01455_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/INS" 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/124617,307072,386828,386829,394766,758088,3776078,4557671,13528924,30582455,59036749,114318995,119622893,119622894,297374821,297374823,333826819,389620191,631226408,1883396561,1883396564,1883396566,1883396568,1883396570,1883396572,2385826525" 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/P01308" 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=3630" 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=ENSG00000254647;t=ENST00000381330" 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=INS" 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=INS" 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+3630" 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/INS" 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:3630" 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/3630" 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=chr11&hgg_gene=ENST00000381330.5&hgg_start=2159779&hgg_end=2161209&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6081" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6081" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176730[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176730[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000254647" 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=INS" 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=INS" 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=INS" 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=INS&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/PA201" 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:6081" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/search?q=MGI:96572 MGI:96573" 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/INS#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/batch/summary?idType=MGI&ids=MGI:96572 MGI:96573" 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/3630/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://omia.org/OMIA000279/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3630" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-980526-110" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
|
<span class="small">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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<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:3630" 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=INS&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> 237613005, 609577006<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
176730
|
|
</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>
|
|
<span class="mim-font">
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|
INSULIN; INS
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</span>
|
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</h3>
|
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PROINSULIN
|
|
</span>
|
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</h4>
|
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</div>
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
INS-IGF2 SPLICED READ-THROUGH TRANSCRIPTS, INCLUDED
|
|
</span>
|
|
</div>
|
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|
|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
INSIGF, INCLUDED
|
|
</span>
|
|
</div>
|
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|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=INS" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">INS</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/74?start=-3&limit=10&highlight=74">11p15.5</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:2159779-2161209&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'})">11:2,159,779-2,161,209</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=125852,618858,616214,613370" 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>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/74?start=-3&limit=10&highlight=74">
|
|
11p15.5
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Diabetes mellitus, insulin-dependent, 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/125852"> 125852 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
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</td>
|
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</tr>
|
|
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|
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|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Diabetes mellitus, permanent neonatal 4
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618858"> 618858 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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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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<p>Insulin, synthesized by the beta cells of the islets of Langerhans, consists of 2 dissimilar polypeptide chains, A and B, which are linked by 2 disulfide bonds. However, unlike many other proteins, e.g., hemoglobin, made up of structurally distinct subunits, insulin is under the control of a single genetic locus; chains A and B are derived from a 1-chain precursor, proinsulin, which was discovered by <a href="#83" class="mim-tip-reference" title="Steiner, D. F., Oyer, P. E. <strong>The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma.</strong> Proc. Nat. Acad. Sci. 57: 473-480, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16591494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16591494</a>] [<a href="https://doi.org/10.1073/pnas.57.2.473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16591494">Steiner and Oyer (1967)</a>. Proinsulin is converted to insulin by the enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the C (for 'connecting') peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16591494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The human insulin gene contains 3 exons; exon 2 encodes the signal peptide, the B chain, and part of the C-peptide, while exon 3 encodes the remainder of the C-peptide and the A chain (<a href="#83" class="mim-tip-reference" title="Steiner, D. F., Oyer, P. E. <strong>The biosynthesis of insulin and a probable precursor of insulin by a human islet cell adenoma.</strong> Proc. Nat. Acad. Sci. 57: 473-480, 1967.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16591494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16591494</a>] [<a href="https://doi.org/10.1073/pnas.57.2.473" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16591494">Steiner and Oyer, 1967</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16591494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rat, mouse, and at least 3 fish species have 2 insulin genes (<a href="#46" class="mim-tip-reference" title="Lomedico, P., Rosenthal, N., Efstratiadis, A., Gilbert, W., Koladner, R., Tizard, R. <strong>The structure and evolution of the two non-allelic rat preproinsulin genes.</strong> Cell 18: 545-558, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/498284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">498284</a>] [<a href="https://doi.org/10.1016/0092-8674(79)90071-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="498284">Lomedico et al., 1979</a>). The single human insulin gene corresponds to rat gene II; each has 2 introns at corresponding positions. <a href="#16" class="mim-tip-reference" title="Deltour, L., Leduque, P., Blume, N., Madsen, O., Dubois, P., Jami, J., Bucchini, D. <strong>Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo.</strong> Proc. Nat. Acad. Sci. 90: 527-531, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8421685/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8421685</a>] [<a href="https://doi.org/10.1073/pnas.90.2.527" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8421685">Deltour et al. (1993)</a> showed that in the mouse embryo the 2 proinsulin genes are regulated independently, at least in part. The existence of a single insulin gene in man is supported by the findings in patients with mutations. The greatest variation among species is in the C-peptide. Receptor binding parts have been highly conserved. Some of these sites are involved with insulin-like activity, some with growth-factor activity, and some with both. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=498284+8421685" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>INS-IGF2 Spliced Read-Through Transcripts</em></strong></p><p>
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By EST database analysis and RT-PCR, <a href="#53" class="mim-tip-reference" title="Monk, D., Sanches, R., Arnaud, P., Apostolidou, S., Hills, F. A., Abu-Amero, S., Murrell, A., Friess, H., Reik, W., Stanier, P., Constancia, M., Moore, G. E. <strong>Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human.</strong> Hum. Molec. Genet. 15: 1259-1269, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16531418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16531418</a>] [<a href="https://doi.org/10.1093/hmg/ddl041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16531418">Monk et al. (2006)</a> identified 2 read-through transcripts, which they called the INSIGF long and short isoforms, that contain exons from both the INS gene and the downstream IGF2 gene (<a href="/entry/147470">147470</a>). The INSIGF short isoform contains INS exons 1 and 2 fused to IGF2 exons 2, 3, and 4. The deduced 200-amino acid INSIGF protein has an N terminus that includes the insulin leader sequence and B-chain peptide followed by a unique C terminus. The INSIGF long isoform has INS exons 1 and 2 fused to IGF2 exons 2, 3, 7, 8, and 9. This transcript is predicted to be bicistronic and contain reading frames for both INSIGF and IGF2. Sequence alignment between the human and mouse Insigf genomic regions suggested that mouse may expresses Insigf, but the expressed protein is predicted to differ substantially from human INSIGF in its C terminus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16531418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#29" class="mim-tip-reference" title="Harper, M. E., Ullrich, A., Saunders, G. F. <strong>Localization of the human insulin gene to the distal end of the short arm of chromosome 11.</strong> Proc. Nat. Acad. Sci. 78: 4458-4460, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7027261/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7027261</a>] [<a href="https://doi.org/10.1073/pnas.78.7.4458" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7027261">Harper et al. (1981)</a> and <a href="#28" class="mim-tip-reference" title="Harper, M. E., Saunders, G. F. <strong>Chromosomal localization of human insulin gene, placental lactogen-growth hormone genes, and other single copy genes by in situ hybridization. (Abstract)</strong> Am. J. Hum. Genet. 33: 105A, 1981."None>Harper and Saunders (1981)</a> assigned the insulin gene to chromosome 11p15.5 by in situ hybridization. They used 10% dextran sulfate to enhance labeling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7027261" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#44" class="mim-tip-reference" title="Lebo, R. V., Kan, Y. W., Cheung, M. C., Cordell, B., Goodman, H. M., Law, M. L., Jones, C., Kao, F. T. <strong>Assignment of the human insulin gene to chromosome 11 band p11 and linkage analysis with the beta-globin locus. (Abstract)</strong> Am. J. Hum. Genet. 33: 150A, 1981."None>Lebo et al. (1981)</a> studied the linkage between 2 restriction polymorphisms, the HpaI polymorphism on the 3-prime side of the beta-globin gene (HBB; <a href="/entry/141900">141900</a>) and the SacI polymorphism on the 5-prime side of the insulin gene. They found 4 recombinants in 34 meioses (12%), giving 90% confidence limits for the interval as 6-22 cM. Given that the HBB globin gene is on 11p12 and the insulin gene on 11p15, that chromosome 11 represents about 4.8% of the genetic length of the genome, and that the total genetic length is 3,000 cM, then one would expect an interval of 29-42 cM. <a href="#43" class="mim-tip-reference" title="Lebo, R. V., Kan, Y. W., Cheung, M. C., Carrano, A. V., Yu, L.-C., Chang, J. C., Cordell, B., Goodman, H. M. <strong>Assigning the polymorphic human insulin gene to the short arm of chromosome 11 by chromosome sorting.</strong> Hum. Genet. 60: 10-15, 1982.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6281170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6281170</a>] [<a href="https://doi.org/10.1007/BF00281255" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6281170">Lebo et al. (1982)</a> determined the regional location of the insulin gene by restriction endonuclease analysis of DNA isolated from metaphase chromosomes, sorted according to relative Hoechst fluorescence intensity by the fluorescence activated chromosome sorter. They showed that the 2 restriction fragments represent insulin gene polymorphism and not duplicate gene loci such as those found in 2 rodent and 2 fish species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6281170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 deletion mapping, <a href="#32" class="mim-tip-reference" title="Huerre, C., Gilgenkrantz, S., Leonard, C., Pictet, R., Kaplan, J. C., Junien, C. <strong>Regional assignment of the structural gene for insulin to 11p15.1-11p15.5 by deletion mapping. (Abstract)</strong> Cytogenet. Cell Genet. 37: 495, 1984."None>Huerre et al. (1984)</a> assigned the insulin gene to 11p15.5-p15.1. By in situ hybridization of meiotic pachytene bivalents, <a href="#8" class="mim-tip-reference" title="Chaganti, R. S. K., Jhanwar, S. C., Antonarakis, S. E., Hayward, W. S. <strong>Germ-line chromosomal localization of genes in chromosome 11p linkage; parathyroid hormone, beta-globin, c-Ha-ras-1, and insulin.</strong> Somat. Cell Molec. Genet. 11: 197-202, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3885418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3885418</a>] [<a href="https://doi.org/10.1007/BF01534708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3885418">Chaganti et al. (1985)</a> arrived at the following localizations: PTH, 11p11.21; HBB, 11p11.22; HRAS, 11p14.1; INS, 11p14.1. <a href="#50" class="mim-tip-reference" title="Meyers, D. A., Beaty, T. H., Maestri, N. E., Antonarakis, S. E., Kazazian, H. H., Jr. <strong>Multipoint mapping studies of the beta-globin, insulin and C-HA-RAS-1 loci on 11p. (Letter)</strong> Am. J. Hum. Genet. 39: 539-541, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3532775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3532775</a>]" pmid="3532775">Meyers et al. (1986)</a> concluded that the Utah database (<a href="#98" class="mim-tip-reference" title="White, R., Leppert, M., Bishop, D. T., Barker, D., Berkowitz, J., Brown, C., Callahan, P., Holm, T., Jerominski, L. <strong>Construction of linkage maps with DNA markers for human chromosomes.</strong> Nature 313: 101-105, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2981412/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2981412</a>] [<a href="https://doi.org/10.1038/313101a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2981412">White et al., 1985</a>) provides greater support for the conclusion that the HRAS1 locus (<a href="/entry/190020">190020</a>) is distal to the INS locus. The beta-hemoglobin cluster is about 10 cM centromeric from this pair of loci; INS and HRAS1 are separated by about 2 to 4 cM. <a href="#45" class="mim-tip-reference" title="Lichter, P., Tang, C. C., Call, K., Hermanson, G., Evans, G. A., Housman, D., Ward, D. C. <strong>High-resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones.</strong> Science 247: 64-69, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2294592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2294592</a>] [<a href="https://doi.org/10.1126/science.2294592" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2294592">Lichter et al. (1990)</a> presented a method for high resolution fluorescence in situ hybridization. By hybridizing 3 or more cosmids simultaneously, gene order on the chromosome could be established unequivocally. The map coordinates established by in situ hybridization studies of chromosome 11 showed a 1-to-1 correspondence with those determined by Southern blot analysis of hybrid cell lines containing fragments of chromosome 11. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3532775+2294592+2981412+3885418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rat insulin I and II genes are on chromosome 1 about 100,000 kb apart. In the mouse, they lie on different chromosomes, no. 6 and no. 7; the mouse Hbb gene is also on chromosome 7. The insulin gene duplication-transposition obviously preceded separation of rat and mouse in the evolutionary process. The preproinsulin gene I in rat and mouse has lost 1 of the 2 introns present in gene II, is flanked by a long (41-base) direct repeat, and has a remnant of a polydeoxyadenylate acid tract preceding the downstream direct repeat. These structural features suggested to <a href="#80" class="mim-tip-reference" title="Soares, M. B., Schon, E., Henderson, A., Karathanasis, S. K., Cate, R., Zeitlin, S., Chirgwin, J., Efstratiadis, A. <strong>RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon.</strong> Molec. Cell. Biol. 5: 2090-2103, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2427930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2427930</a>] [<a href="https://doi.org/10.1128/mcb.5.8.2090-2103.1985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2427930">Soares et al. (1985)</a> that gene I is a functional transposon, i.e., was generated by an RNA-mediated duplication-transposition event involving a transcript of gene II that was initiated upstream from the normal capping site. Gene I has a single intron. <a href="#89" class="mim-tip-reference" title="Todd, S., Yoshida, M. C., Fang, X. E., McDonald, L., Jacobs, J., Heinrich, G., Bell, G. I., Naylor, S. L., Sakaguchi, A. Y. <strong>Genes for insulin I and II, parathyroid hormone, and calcitonin are on rat chromosome 1.</strong> Biochem. Biophys. Res. Commun. 131: 1175-1180, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3902019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3902019</a>] [<a href="https://doi.org/10.1016/0006-291x(85)90214-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3902019">Todd et al. (1985)</a> found that in the rat, the parathyroid hormone and calcitonin genes are, like the insulin genes I and II, on chromosome 1. <a href="#35" class="mim-tip-reference" title="Jones, J. M., Meisler, M. H., Seldin, M. F., Lee, B. K., Eicher, E. M. <strong>Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7.</strong> Genomics 14: 197-199, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1358794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1358794</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80308-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1358794">Jones et al. (1992)</a> localized Ins2, one of the 2 insulin genes of the mouse, to a specific region of chromosome 7 within a human-mouse conserved linkage group. They also demonstrated that the obesity mutant tubby (tub) is a locus distinct from Ins2. The tub gene was found to lie 2.4 cM from the Hbb gene. <a href="#35" class="mim-tip-reference" title="Jones, J. M., Meisler, M. H., Seldin, M. F., Lee, B. K., Eicher, E. M. <strong>Localization of insulin-2 (Ins-2) and the obesity mutant tubby (tub) to distinct regions of mouse chromosome 7.</strong> Genomics 14: 197-199, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1358794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1358794</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80308-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1358794">Jones et al. (1992)</a> suggested that the human homolog of 'tubby' resides in 11p15 and that the HBB locus in the human could be used as a linkage marker for studies of familial obesity in humans. Contradictory mapping results were obtained by <a href="#14" class="mim-tip-reference" title="Davies, P. O., Poirier, C., Deltour, L., Montagutelli, X. <strong>Genetic reassignment of the insulin-1 (Ins1) gene to distal mouse chromosome 19.</strong> Genomics 21: 665-667, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959751</a>] [<a href="https://doi.org/10.1006/geno.1994.1334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959751">Davies et al. (1994)</a>. Experiments using 3 different PCR primer pairs in 2 independent interspecific murine crosses conclusively localized the murine Ins1 gene to distal chromosome 19. They raised the question of chromosomal rearrangements having occurred in the cell lines used in the previous chromosomal assignments to mouse chromosome 6 through RFLP analysis of mouse/hamster somatic cell hybrids. They suggested that the use of polymorphisms detectable between murine strains or between various mouse species for genetic linkage analysis remains a more reliable method for determining the chromosomal location of genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7959751+3902019+2427930+1358794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Fasting Insulin Level Quantitative Trait Loci</em></strong></p><p>
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With a genome screen for genetic control of fasting insulin level in the Hutterites, <a href="#1" class="mim-tip-reference" title="Abney, M., Ober, C., McPeek, M. S. <strong>Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites.</strong> Am. J. Hum. Genet. 70: 920-934, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11880950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11880950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11880950[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/10.1086/339705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11880950">Abney et al. (2002)</a> illustrated methods for linkage and association mapping of quantitative traits in a founder population with a large, known genealogy. They detected linkage to quantitative-trait loci (QTLs) through a multipoint homozygosity-mapping method. They proposed 2 association methods, one of which is multipoint and uses homozygosity by descent for a particular allele. Applied to fasting insulin level, the methods found significant linkage on chromosome 19 and suggestive evidence of QTLs on chromosomes 1 and 16. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11880950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Dandona, P., Aljada, A., Mohanty, P., Ghanim, H., Hamouda, W., Assian, E., Ahmad, S. <strong>Insulin inhibits intranuclear nuclear factor kappa-B and stimulates I-kappa-B in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?</strong> J. Clin. Endocr. Metab. 86: 3257-3265, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11443198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11443198</a>] [<a href="https://doi.org/10.1210/jcem.86.7.7623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11443198">Dandona et al. (2001)</a> infused insulin intravenously into obese subjects to investigate the potential antiinflammatory effects of insulin. NF-kappa-B (NFKB; see <a href="/entry/164011">164011</a>) in mononuclear cells fell at 2 hours and further at 4 hours, reverting toward the baseline at 6 hours. IKB (see <a href="/entry/164008">164008</a>) increased significantly at 2 hours, increasing further at 4 hours and remaining elevated at 6 hours. Reactive oxygen species generation by mononuclear cells fell significantly at 2 hours and fell further at 4 hours. The authors concluded that insulin has a potent acute antiinflammatory effect, including a reduction in intranuclear NFKB, an increase in IKB, and decreases in the generation of reactive oxygen species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11443198" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rats, <a href="#56" class="mim-tip-reference" title="Obici, S., Zhang, B. B., Karkanias, G., Rossetti, L. <strong>Hypothalamic insulin signaling is required for inhibition of glucose production.</strong> Nature Med. 8: 1376-1382, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12426561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12426561</a>] [<a href="https://doi.org/10.1038/nm1202-798" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12426561">Obici et al. (2002)</a> found that infusion of insulin into the third cerebral ventricle, with access to the hypothalamus, suppressed glucose production independent of circulating levels of insulin or of other glucoregulatory hormones, whereas central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. The findings indicated that the hypothalamus is a site of insulin action in the regulation of glucose production. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12426561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#53" class="mim-tip-reference" title="Monk, D., Sanches, R., Arnaud, P., Apostolidou, S., Hills, F. A., Abu-Amero, S., Murrell, A., Friess, H., Reik, W., Stanier, P., Constancia, M., Moore, G. E. <strong>Imprinting of IGF2 P0 transcript and novel alternatively spliced INS-IGF2 isoforms show differences between mouse and human.</strong> Hum. Molec. Genet. 15: 1259-1269, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16531418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16531418</a>] [<a href="https://doi.org/10.1093/hmg/ddl041" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16531418">Monk et al. (2006)</a> found that the INSIGF read-through transcript were monoallelically/parentally expressed in adult and fetal eye and limb, but pancreas showed biallelic expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16531418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Frosig, C., Rose, A. J., Treebak, J. T., Kiens, B., Richter, E. A., Wojtaszewski, J. F. P. <strong>Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160.</strong> Diabetes 56: 2093-2102, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17513702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17513702</a>] [<a href="https://doi.org/10.2337/db06-1698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17513702">Frosig et al. (2007)</a> studied insulin-related responses in 8 healthy men who performed 3 weeks of 1-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was about 60% higher in trained compared with untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies obtained before and after training as well as after 10 and 20 minutes of insulin stimulation showed increased protein content of AKT1 (<a href="/entry/164730">164730</a>)/AKT2 (<a href="/entry/164731">164731</a>), AS160 (TBC1D4; <a href="/entry/612465">612465</a>), GLUT4 (SLC2A4; <a href="/entry/138190">138190</a>), HK2 (<a href="/entry/601125">601125</a>), and LNPEP (<a href="/entry/151300">151300</a>) in response to training. Training improved insulin action on thigh blood flow, and in both basal and insulin-stimulated muscle tissue, activities of AKT1 and GYS1 (<a href="/entry/138570">138570</a>) and phosphorylation of AS160 increased with training. In contrast, training reduced IRS1 (<a href="/entry/147545">147545</a>)-associated PI3K (see <a href="/entry/601232">601232</a>) activity in both basal and insulin-stimulated muscle tissue. <a href="#20" class="mim-tip-reference" title="Frosig, C., Rose, A. J., Treebak, J. T., Kiens, B., Richter, E. A., Wojtaszewski, J. F. P. <strong>Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160.</strong> Diabetes 56: 2093-2102, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17513702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17513702</a>] [<a href="https://doi.org/10.2337/db06-1698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17513702">Frosig et al. (2007)</a> concluded that improved insulin-stimulated glucose uptake after endurance training results from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17513702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Gene-Environment Interaction</em></strong></p><p>
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Prenatal famine in humans has been associated with various consequences in later life, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. <a href="#88" class="mim-tip-reference" title="Tobi, E. W., Lumey, L. H., Talens, R. P., Kremer, D., Putter, H., Stein, A. D., Slagboom, P. E., Heijmans, B. T. <strong>DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific.</strong> Hum. Molec. Genet. 18: 4046-4053, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656776</a>] [<a href="https://doi.org/10.1093/hmg/ddp353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19656776">Tobi et al. (2009)</a> investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to war-time famine in the Netherlands from 1944 to 1945. Methylation of INSIGF, the alternately spliced read-through transcript of INS and IGF2 (<a href="/entry/147470">147470</a>), was lower among 60 individuals who were periconceptionally exposed to the famine compared to 60 of their unexposed same-sex sibs, whereas methylation of IL10 (<a href="/entry/124092">124092</a>), LEP (<a href="/entry/164160">164160</a>), ABCA1 (<a href="/entry/600046">600046</a>), GNASAS (<a href="/entry/610540">610540</a>) and MEG3 (<a href="/entry/605636">605636</a>) was higher than control. A significant interaction with sex was observed for INSIGF, LEP, and GNASAS. When methylation of 8 representative loci was compared between 62 individuals exposed late in gestation and 62 of their unexposed sibs, methylation was different for GNASAS in both men and women, and LEP methylation was different in men only. <a href="#88" class="mim-tip-reference" title="Tobi, E. W., Lumey, L. H., Talens, R. P., Kremer, D., Putter, H., Stein, A. D., Slagboom, P. E., Heijmans, B. T. <strong>DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific.</strong> Hum. Molec. Genet. 18: 4046-4053, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19656776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19656776</a>] [<a href="https://doi.org/10.1093/hmg/ddp353" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19656776">Tobi et al. (2009)</a> concluded that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure, and that these changes may depend on the sex of the exposed individual and the gestational timing of the exposure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19656776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#49" 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 (INSR; <a href="/entry/147670">147670</a>) 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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In a patient with hyperproinsulinemia (<a href="/entry/616214">616214</a>), originally reported by <a href="#87" class="mim-tip-reference" title="Tager, H., Given, B., Baldwin, D., Mako, M., Markese, J., Rubenstein, A., Olefsky, J., Kobayashi, M., Kolterman, O., Poucher, R. <strong>A structurally abnormal insulin causing human diabetes.</strong> Nature 281: 122-125, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/381941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">381941</a>] [<a href="https://doi.org/10.1038/281122a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="381941">Tager et al. (1979)</a>, <a href="#79" class="mim-tip-reference" title="Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., Tager, H. <strong>Three mutant insulins in man.</strong> Nature 302: 540-543, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6339950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6339950</a>] [<a href="https://doi.org/10.1038/302540a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6339950">Shoelson et al. (1983)</a> identified a heterozygous change of leucine to phenylalanine at position 25 of the insulin B chain (<a href="#0001">176730.0001</a>). In another patient with hyperproinsulinemia, they identified a heterozygous change of leucine to phenylalanine at position 24 of the insulin B chain (<a href="#0002">176730.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=381941+6339950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 affected members of a family segregating hyperproinsulinemia, originally reported by <a href="#24" class="mim-tip-reference" title="Gruppuso, P. A., Gorden, P., Kahn, C. R., Cornblath, M., Zeller, W. P., Schwartz, R. <strong>Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin.</strong> New Eng. J. Med. 311: 629-634, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6382002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6382002</a>] [<a href="https://doi.org/10.1056/NEJM198409063111003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6382002">Gruppuso et al. (1984)</a>, <a href="#9" class="mim-tip-reference" title="Chan, S. J., Seino, S., Gruppuso, P. A., Schwartz, R., Steiner, D. F. <strong>A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.</strong> Proc. Nat. Acad. Sci. 84: 2194-2197, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3470784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3470784</a>] [<a href="https://doi.org/10.1073/pnas.84.8.2194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3470784">Chan et al. (1987)</a> identified a heterozygous C-to-G transversion in the INS gene, predicting a change of histidine to aspartic acid at position 10 of the insulin B chain (<a href="#0003">176730.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6382002+3470784" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 hyperproinsulinemia, previously reported by <a href="#79" class="mim-tip-reference" title="Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., Tager, H. <strong>Three mutant insulins in man.</strong> Nature 302: 540-543, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6339950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6339950</a>] [<a href="https://doi.org/10.1038/302540a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6339950">Shoelson et al. (1983)</a>, <a href="#54" class="mim-tip-reference" title="Nanjo, K., Sanke, T., Miyano, M., Okai, K., Sowa, R., Kondo, M., Nishimura, S., Iwo, K., Miyamura, K., Given, B. D., Chan, S. J., Tager, H. S., Steiner, D. F., Rubenstein, A. H. <strong>Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama): clinical and functional characteristics of (leu-A3) insulin.</strong> J. Clin. Invest. 77: 514-519, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3511099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3511099</a>] [<a href="https://doi.org/10.1172/JCI112331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3511099">Nanjo et al. (1986)</a> identified heterozygosity for a G-to-T transversion in the INS gene, predicting a val3-to-leu substitution in the insulin A chain (<a href="#0005">176730.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6339950+3511099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Permanent Neonatal Diabetes Mellitus 4</em></strong></p><p>
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In affected members of a 3-generation family in which permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>) segregated in an autosomal dominant fashion, who were negative for mutations in the KCNJ11 (<a href="/entry/600937">600937</a>) and ABCC8 (<a href="/entry/600509">600509</a>) genes, <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for a missense mutation in the INS gene (<a href="#0008">176730.0008</a>). The authors then sequenced the INS gene in 83 probands with PNDM without a known genetic cause and identified 9 additional heterozygous missense mutations in the INS gene in 15 families (see, e.g., <a href="#0009">176730.0009</a>-<a href="#0013">176730.0013</a>), including a patient with the same mutation (C96Y; <a href="#0011">176730.0011</a>) found in the Akita mouse. The mutations were in critical regions of the preproinsulin molecule and were predicted to prevent normal folding and progression of proinsulin in the insulin secretory pathway. The authors suggested that the abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta-cell death by apoptosis, as has been described in both the Akita and Munich mouse models. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> screened the INS gene in a series of 1,044 patients with permanent diabetes diagnosed during infancy, childhood, and adulthood and also in 49 patients with hyperinsulinism. The authors identified heterozygous INS mutations in 33 (23%) of 141 probands diagnosed at less than 6 months of age, in 2 (2%) of 86 probands diagnosed between 6 and 12 months of age, and in none of 58 probands diagnosed between 12 and 24 months of age. Twelve of the mutation-positive PNDM probands had been previously reported by <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al., 2007</a>. Only 1 (0.3%) of 296 probands with maturity-onset diabetes of the young (see MODY10, <a href="/entry/613370">613370</a>) had a mutation in the INS gene (R6C; <a href="#0014">176730.0014</a>); and 1 (0.2%) of 463 young type 2 diabetics (see <a href="/entry/125853">125853</a>) had a possible mutation identified. No mutations were found in the patients with hyperinsulinism. Three mutations, A24D (<a href="#0012">176730.0012</a>), F48C (<a href="#0013">176730.0013</a>), and R89C (<a href="#0010">176730.0010</a>), accounted for 46% of PNDM cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17855560+18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 9 probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (<a href="/entry/600937">600937</a>), <a href="#12" class="mim-tip-reference" title="Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., and 8 others. <strong>Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.</strong> J. Clin. Invest. 118: 2148-2156, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451997[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/JCI33777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18451997">Colombo et al. (2008)</a> identified heterozygosity for 7 different mutations in the INS gene (see, e.g., <a href="#0010">176730.0010</a>) that were not found in 200 Italian patients with normal glucose tolerance. Expression of the mutant proinsulins in HEK293 cells revealed defects in insulin protein folding and secretion; there was also increased expression of HSPA5 (<a href="/entry/138120">138120</a>) protein and XBP1 (<a href="/entry/194355">194355</a>) mRNA splicing, 2 markers of endoplasmic reticulum stress, and increased apoptosis. Transfected INS-1E insulinoma cells had diminished viability compared with those expressing wildtype proinsulin. The authors noted that all mutations found in patients with PNDM or infancy-onset diabetes were different from those previously associated with familial hyperinsulinemia or hyperproinsulinemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18451997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Polak, M., Dechaume, A., Cave, H., Nimri, R., Crosnier, H., Sulmont, V., de Kerdanet, M., Scharfmann, R., Lebenthal, Y., Froguel, P., Vaxillaire, M. <strong>Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group.</strong> Diabetes 57: 1115-1119, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18171712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18171712</a>] [<a href="https://doi.org/10.2337/db07-1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18171712">Polak et al. (2008)</a> analyzed the INS gene in 39 patients with PNDM who were negative for mutations in the GCK, KCNJ11, and ABCC8 genes, and identified heterozygosity for 3 different missense mutations in 4 probands (see <a href="#0010">176730.0010</a>-<a href="#0012">176730.0012</a>). The authors also sequenced the INS gene in 11 patients with transient neonatal diabetes (see <a href="/entry/601410">601410</a>) in whom chromosome 6 anomalies had been excluded, but found no mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18171712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 male infant with PNDM, born to first-cousin Southeast Asian parents, who was negative for mutation in 36 known monogenic diabetes-associated genes, <a href="#6" class="mim-tip-reference" title="Carmody, D., Park, S.-Y., Ye, H., Perrone, M. E., Alkorta-Aranburu, G., Highland, H. M., Hanis, C. L., Philipson, L. H., Bell, G. I., Greeley, S. A. W. <strong>Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.</strong> J. Med. Genet. 52: 612-616, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26101329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26101329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26101329[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/10.1136/jmedgenet-2015-103220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26101329">Carmody et al. (2015)</a> identified homozygosity for a deep intronic INS variant (<a href="#0017">176730.0017</a>). Noting that 20 to 30% of neonatal monogenic diabetes cases have no known etiology, the authors suggested that mutations within deep noncoding regions might be the cause. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26101329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Maturity-Onset Diabetes of the Young/Type 1 Diabetes Mellitus</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> found that 1 of 296 probands with maturity-onset diabetes of the young (see MODY10, <a href="/entry/613370">613370</a>) had a mutation in the INS gene (R6C; <a href="#0014">176730.0014</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#52" class="mim-tip-reference" title="Molven, A., Ringdal, M., Nordbo, A. M., Raeder, H., Stoy, J., Lipkind, G. M., Steiner, D. F., Philipson, L. H., Bergmann, I., Aarskog, D., Undlien, D. E., Joner, G., Sovik, O., Norwegian Childhood Diabetes Study Group, Bell, G. I., Njolstad, P. R. <strong>Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes.</strong> Diabetes 57: 1131-1135, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18192540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18192540</a>] [<a href="https://doi.org/10.2337/db07-1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18192540">Molven et al. (2008)</a> screened the INS gene in 62 probands with MODY and 30 probands with suspected MODY from the Norwegian MODY Registry, and 223 patients from the Norwegian Childhood Diabetes Registry who were autoantibody negative or had a family history of diabetes, and identified heterozygosity for 2 different missense mutations, R46Q (<a href="#0015">176730.0015</a>) in a 3-generation family with MODY (MODY10; <a href="/entry/613370">613370</a>) and R55C (<a href="#0016">176730.0016</a>) in a mother and daughter with type 1 diabetes (T1D2; <a href="/entry/125852">125852</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18192540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>INS VNTR</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Bell, G. I., Pictet, R. L., Rutter, W. J., Cordell, B., Tischer, E., Goodman, H. M. <strong>Sequence of the human insulin gene.</strong> Nature 284: 26-32, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6243748/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6243748</a>] [<a href="https://doi.org/10.1038/284026a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6243748">Bell et al. (1980)</a> sequenced the human insulin gene and found evidence for allelic variation in the 5-prime untranslated region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6243748" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#68" class="mim-tip-reference" title="Rotwein, P., Chyn, R., Chirgwin, J., Cordell, B., Goodman, H. M., Permutt, M. A. <strong>Polymorphism in the 5-prime-flanking region of the human insulin gene and its possible relation to type 2 diabetes.</strong> Science 213: 1117-1120, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6267694/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6267694</a>] [<a href="https://doi.org/10.1126/science.6267694" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6267694">Rotwein et al. (1981)</a>, as well as other groups, have found a polymorphism, in the form of an insertion of 1.5 to 3.4 kb pairs, in the 5-prime flanking region of the insulin gene. These insertions occur within 1.3 kb pairs of the transcription initiation site. In contrast, no insertions were found in the region 3-prime to the coding sequence. The frequency of insertions was 66% in those with type II diabetes (<a href="/entry/125853">125853</a>) and 29% in all others including nondiabetics and type I diabetics (P less than 0.001). Other studies suggested that DNA sequences several hundred bases 5-prime to the mRNA transcription initiation site may modulate RNA polymerase binding and initiation of transcription. <a href="#69" class="mim-tip-reference" title="Rotwein, P., Yokoyama, S., Didier, D. K., Chirgwin, J. M. <strong>Genetic analysis of the hypervariable region flanking the human insulin gene.</strong> Am. J. Hum. Genet. 39: 291-299, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2876625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2876625</a>]" pmid="2876625">Rotwein et al. (1986)</a> analyzed the nature of the hypervariable region 5-prime to the insulin gene. The association of certain 'alleles' in this region with noninsulin-dependent diabetes mellitus has been both claimed and refuted, and an association with atherosclerosis and with hypertriglyceridemia has also been reported. In different ethnic groups, <a href="#99" class="mim-tip-reference" title="Williams, L. G., Jowett, N. I., Vella, M. A., Humphries, S., Galton, D. J. <strong>Allelic variation adjacent to the human insulin and apolipoprotein C-II genes in different ethnic groups.</strong> Hum. Genet. 71: 227-230, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2998971/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2998971</a>] [<a href="https://doi.org/10.1007/BF00284580" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2998971">Williams et al. (1985)</a> found marked variability in insulin gene-related DNA polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2876625+2998971+6267694" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 structure of the 5-prime insulin minisatellite (<a href="/entry/147510">147510</a>) alleles is based on 11 variant repeats of a 14-bp consensus motif (ACAGGGGTGTGGGG). Among Caucasians, these minisatellite alleles have been typed as class I (small, with 28-44 repeats, frequency approximately 70%), class II (intermediate, rare), and class III (large, with 138-159 repeats, frequency approximately 30%). The obvious bimodal size distribution in Caucasians suggests a lower mutation rate and possibly different mutational processes compared with highly unstable minisatellites at other loci. <a href="#81" class="mim-tip-reference" title="Stead, J. D. H., Jeffreys, A. J. <strong>Allele diversity and germline mutation at the insulin minisatellite.</strong> Hum. Molec. Genet. 9: 713-723, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10749978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10749978</a>] [<a href="https://doi.org/10.1093/hmg/9.5.713" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10749978">Stead and Jeffreys (2000)</a> used minisatellite variant repeat mapping by PCR (MVR-PCR) to study mutation at the insulin minisatellite both indirectly from allele diversity surveys and directly by recovering de novo mutants from sperm DNA. From 438 individuals, structural analysis of variant repeat distributions in 876 alleles identified 189 different alleles, almost all of which could be assigned to 1 of 3 very distinct lineages. Within lineages, gain or loss of a few repeat units probably arose by mitotic replication slippage at a frequency of perhaps 10(-3) per gamete. Sperm DNA analysis from 3 Caucasian donors revealed a second class of mutation occurring at a frequency of approximately 2 x 10(-5) that involved highly complex intra- and interallelic rearrangements very similar to those seen at unstable minisatellites in other loci. The authors suggested that these complex rearrangements, not seen in somatic DNA, may be meiotic in origin. The authors concluded that the insulin minisatellite appears to have evolved by 2 distinct processes: one involving slippage-like events in mitosis and the second resulting in complex recombinational turnover of allele structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10749978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#42" class="mim-tip-reference" title="Lebo, R. V., Chakravarti, A., Buetow, K. H., Cheung, M.-C., Cann, H., Cordell, B., Goodman, H. <strong>Recombination within and between the human insulin and beta-globin gene loci.</strong> Proc. Nat. Acad. Sci. 80: 4808-4812, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6348773/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6348773</a>] [<a href="https://doi.org/10.1073/pnas.80.15.4808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6348773">Lebo et al. (1983)</a> found a large number of DNA polymorphisms in the region of the insulin gene on 11p. Population genetic analysis indicated that to generate this large number of polymorphisms recombination occurred 33 times more frequently than expected. Specific properties of the unique 14- to 16-basepair sequences 5-prime to the insulin gene probably promote increased unequal recombination. A recombination rate of 14% was found between the insulin and beta-globin genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6348773" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#47" class="mim-tip-reference" title="Mandrup-Poulsen, T., Owerbach, D., Mortensen, S. A., Johansen, K., Meinertz, H., Sorensen, H., Nerup, J. <strong>DNA sequences flanking the insulin gene on chromosome 11 confer risk of atherosclerosis.</strong> Lancet 323: 250-252, 1984. Note: Originally Volume I.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6142996/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6142996</a>] [<a href="https://doi.org/10.1016/s0140-6736(84)90126-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6142996">Mandrup-Poulsen et al. (1984)</a> found that the allelic frequency of DNA restriction fragments of a large-size class (U alleles) in the polymorphic region flanking the 5-prime end of the insulin gene is 2.5 times higher in patients with extensive atherosclerosis than in subjects in whom atherosclerosis could not be demonstrated by coronary arteriography and careful clinical examination. The mechanism of the increased risk conferred by the U allele is unknown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6142996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the course of screening the insulin promoter from 40 American subjects with noninsulin-dependent diabetes mellitus (NIDDM), <a href="#57" class="mim-tip-reference" title="Olansky, L., Welling, C., Giddings, S., Adler, S., Bourey, R., Dowse, G., Serjeantson, S., Zimmet, P., Permutt, M. A. <strong>A variant insulin promoter in non-insulin-dependent diabetes mellitus.</strong> J. Clin. Invest. 89: 1596-1602, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569197</a>] [<a href="https://doi.org/10.1172/JCI115754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569197">Olansky et al. (1992)</a> found an apparently larger allele in 2. In both, the larger allele had an 8-bp repeat, TGGTCTAA, from positions -322 to -315 of the insulin promoter. <a href="#57" class="mim-tip-reference" title="Olansky, L., Welling, C., Giddings, S., Adler, S., Bourey, R., Dowse, G., Serjeantson, S., Zimmet, P., Permutt, M. A. <strong>A variant insulin promoter in non-insulin-dependent diabetes mellitus.</strong> J. Clin. Invest. 89: 1596-1602, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1569197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1569197</a>] [<a href="https://doi.org/10.1172/JCI115754" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1569197">Olansky et al. (1992)</a> found that the 8-bp repeat was present in 5 of 100 American black NIDDM subjects and in 1 nondiabetic American black subject. Among Mauritius Creoles, also of African ancestry, they found the 8-bp repeat in 3 of 41 NIDDM subjects and in none of 41 nondiabetic subjects. Analysis of glucose metabolism in 3 presumed normal sibs of an NIDDM patient with an 8-bp repeat showed that 1 sib had overt diabetes and 2 sibs were glucose intolerant, but there was no consistent segregation of the insulin promoter variant with the diabetes phenotype. The variant promoter was not present in 35 Caucasian NIDDM patients or in 40 Pima Indians. Reduced activity of the variant form of the promoter was demonstrated by expression studies in cultured cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1569197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 which genetic factors predispose obese patients to pancreatic beta-cell dysfunction, and possibly to type II diabetes (<a href="/entry/125853">125853</a>), <a href="#41" class="mim-tip-reference" title="Le Stunff, C., Fallin, D., Schork, N. J., Bougneres, P. <strong>The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity.</strong> Nature Genet. 26: 444-446, 2000. Note: Erratum: Nature Genet. 28: 97 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11101842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11101842</a>] [<a href="https://doi.org/10.1038/82579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11101842">Le Stunff et al. (2000)</a> studied single-nucleotide polymorphisms in the region of the INS gene in 615 obese children. They found that in the early phase of obesity, alleles of the INS VNTR locus were associated with different effects of body fatness on insulin secretion. Young obese patients homozygous for class I VNTR alleles secreted more insulin than those with other genotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11101842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 -23Hph1 SNP in the INS gene as a surrogate marker for the INS VNTR, <a href="#41" class="mim-tip-reference" title="Le Stunff, C., Fallin, D., Schork, N. J., Bougneres, P. <strong>The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity.</strong> Nature Genet. 26: 444-446, 2000. Note: Erratum: Nature Genet. 28: 97 only, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11101842/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11101842</a>] [<a href="https://doi.org/10.1038/82579" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11101842">Le Stunff et al. (2000)</a> showed that the -23A/A genotype correlated with impaired insulin secretion in response to body weight gain in subjects of European descent. <a href="#58" class="mim-tip-reference" title="Osawa, H., Onuma, H., Murakami, A., Ochi, M., Nishimiya, T., Kato, K., Shimizu, I., Fujii, Y., Ohashi, J., Makino, H. <strong>Systematic search for single nucleotide polymorphisms in the insulin gene: evidence for a high frequency of -23T-A in Japanese subjects.</strong> Biochem. Biophys. Res. Commun. 286: 451-455, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11511079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11511079</a>] [<a href="https://doi.org/10.1006/bbrc.2001.5414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11511079">Osawa et al. (2001)</a> found a high frequency of the -23T-A change in Japanese. The allele frequency was 97.4% in Japanese subjects, whereas in Europeans it was about 30%. The A/A genotype was found in 94 of 99 Japanese subjects and <a href="#58" class="mim-tip-reference" title="Osawa, H., Onuma, H., Murakami, A., Ochi, M., Nishimiya, T., Kato, K., Shimizu, I., Fujii, Y., Ohashi, J., Makino, H. <strong>Systematic search for single nucleotide polymorphisms in the insulin gene: evidence for a high frequency of -23T-A in Japanese subjects.</strong> Biochem. Biophys. Res. Commun. 286: 451-455, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11511079/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11511079</a>] [<a href="https://doi.org/10.1006/bbrc.2001.5414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11511079">Osawa et al. (2001)</a> suggested that the high frequency could account for the fact that Japanese typically secrete lower levels of insulin than do Europeans. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11511079+11101842" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#40" class="mim-tip-reference" title="Le Stunff, C., Fallin, D., Bougneres, P. <strong>Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity.</strong> Nature Genet. 29: 96-99, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528401</a>] [<a href="https://doi.org/10.1038/ng707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528401">Le Stunff et al. (2001)</a> studied the parental transmission of alleles at the insulin locus to offspring with early-onset obesity in children of central European and north African descent. A VNTR polymorphism upstream of the insulin gene is associated with variations in the expression of INS and the nearby gene encoding insulin-like growth factor-2 (IGF2; <a href="/entry/147470">147470</a>). The class I allele of this VNTR contains 26 to 63 repeats, while the class III allele contains 141 to 209 repeats. <a href="#40" class="mim-tip-reference" title="Le Stunff, C., Fallin, D., Bougneres, P. <strong>Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity.</strong> Nature Genet. 29: 96-99, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528401</a>] [<a href="https://doi.org/10.1038/ng707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528401">Le Stunff et al. (2001)</a> found an excess of paternal transmission of class I VNTR alleles to obese children: children who inherited a class I allele from their father (but not those inheriting it from their mother) had a relative risk of early onset obesity of 1.8. Due to the frequency of class I alleles in this population, this risk concerns 65 to 70% of all infants. <a href="#40" class="mim-tip-reference" title="Le Stunff, C., Fallin, D., Bougneres, P. <strong>Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity.</strong> Nature Genet. 29: 96-99, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528401</a>] [<a href="https://doi.org/10.1038/ng707" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528401">Le Stunff et al. (2001)</a> concluded that increased in utero expression of paternal INS or IGF2 due to the class I INS VNTR allele may predispose offspring to postnatal fat deposition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Chromosomes carrying the protective long INS VNTR alleles (class III) produce higher levels of thymic INS mRNA than those with the predisposing, short class I alleles. However, complete silencing of thymic INS transcripts from the class III chromosome was found in a small proportion of heterozygous human thymus samples (<a href="#92" class="mim-tip-reference" title="Vafiadis, P., Bennett, S. T., Todd, J. A., Nadeau, J., Grabs, R., Goodyer, C. G., Wickramasinghe, S., Colle, E., Polychronakos, C. <strong>Insulin expression in the human thymus is modulated by INS VNTR alleles at the IDDM2 locus.</strong> Nature Genet. 15: 289-292, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054944</a>] [<a href="https://doi.org/10.1038/ng0397-289" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054944">Vafiadis et al., 1997</a>; <a href="#61" class="mim-tip-reference" title="Pugliese, A., Zeller, M., Fernandez, A., Jr., Zalcberg, L. J., Bartlett, R. J., Ricordi, C., Pietropaolo, M., Eisenbarth, G. S., Bennett, S. T., Patel, D. D. <strong>The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes.</strong> Nature Genet. 15: 293-297, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9054945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9054945</a>] [<a href="https://doi.org/10.1038/ng0397-293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9054945">Pugliese et al., 1997</a>). <a href="#93" class="mim-tip-reference" title="Vafiadis, P., Ounissi-Benkalha, H., Palumbo, M., Grabs, R., Rousseau, M., Goodyer, C. G., Polychronakos, C. <strong>Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes.</strong> J. Clin. Endocr. Metab. 86: 3705-3710, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502799</a>] [<a href="https://doi.org/10.1210/jcem.86.8.7733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502799">Vafiadis et al. (2001)</a> hypothesized that the specific class III alleles found on these chromosomes silence rather than enhance thymic insulin expression. To test the prediction that these alleles are predisposing, they developed a DNA fingerprinting method for detecting 2 putative 'silencing' alleles found in 2 thymus samples (S1, S2). In a set of 287 diabetic children and their parents they found 13 alleles matching the fingerprint of the S1 or S2 alleles. Of 18 possible transmissions, 12 of the S1-S2 alleles were transmitted to the diabetic offspring, a frequency of 0.67, significantly higher than the 0.38 seen in the remaining 142 class III alleles (P = 0.025). <a href="#93" class="mim-tip-reference" title="Vafiadis, P., Ounissi-Benkalha, H., Palumbo, M., Grabs, R., Rousseau, M., Goodyer, C. G., Polychronakos, C. <strong>Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes.</strong> J. Clin. Endocr. Metab. 86: 3705-3710, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502799</a>] [<a href="https://doi.org/10.1210/jcem.86.8.7733" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502799">Vafiadis et al. (2001)</a> concluded that this result confirmed their prediction and represented an additional level of correlation between thymic insulin and diabetes susceptibility. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11502799+9054945+9054944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Low birth weight associations with hyperinsulinemia and other adulthood disease risk factors have been described in several cohorts, including girls who present with precocious pubarche (pubic hair at less than 8 years). <a href="#33" class="mim-tip-reference" title="Ibanez, L., Ong, K., Potau, N., Marcos, M. V., de Zegher, F., Dunger, D. <strong>Insulin gene variable number of tandem repeat genotype and the low birth weight, precocious pubarche, and hyperinsulinism sequence.</strong> J. Clin. Endocr. Metab. 86: 5788-5793, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739440/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739440</a>] [<a href="https://doi.org/10.1210/jcem.86.12.8093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739440">Ibanez et al. (2001)</a> hypothesized that these associations might be influenced by the INS gene VNTR, a common polymorphism related to INS transcription levels. DNA was genotyped for INS VNTR allele class (I or III) in precocious pubarche girls and in 140 age- and body mass index-matched control girls. INS VNTR genotype distribution was similar in precocious pubarche and control girls. However, among precocious pubarche girls, INS VNTR genotype was related to the severity of phenotype; I/I and I/III genotypes had lower birth weights (P less than 0.01), higher mean serum insulin (MSI; P less than 0.005), and lower insulin sensitivity (P less than 0.005) than III/III girls. In precocious pubarche girls, birth weight was also inversely related to MSI, total cholesterol, and low density lipoprotein cholesterol. Using logistic regression, additive adverse effects of I/* genotype and low birth weight were seen on MSI and total cholesterol levels. The authors concluded that in girls who presented with precocious pubarche, hyperinsulinemia and dyslipidemia were related to both low birth weight and INS VNTR class I alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739440" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Rodriguez, S., Gaunt, T. R., O'Dell, S. D., Chen, X., Gu, D., Hawe, E., Miller, G. J., Humphries, S. E., Day, I. N. M. <strong>Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits.</strong> Hum. Molec. Genet. 13: 715-725, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14749349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14749349</a>] [<a href="https://doi.org/10.1093/hmg/ddh070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14749349">Rodriguez et al. (2004)</a> haplotyped 2,743 adult males at the IGF2-INS-TH (<a href="/entry/191290">191290</a>) region and related haplotypes to body weight and composition, blood pressure, and plasma triglycerides. Haplotype *5 protected against obesity; haplotype *6 was associated with raised plasma triglyceride levels. Haplotype *4, defined by the IGF2 ApaI(G), INS class III VNTR, and TH01 9.3 alleles, was associated with significantly higher fat mass and percentage fat, and with significantly higher diastolic blood pressure. Haplotype *8 showed similar magnitude of effects as *4. Haplotypes *4, *6, and *8 were the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displayed unique features in all 3 genes. The authors proposed that the long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, may predispose to the metabolic syndrome features of elevated blood pressure, fat mass, or triglyceride level, therefore appearing more frequently in type 2 diabetic (<a href="/entry/125853">125853</a>), polycystic ovary syndrome (see <a href="/entry/184700">184700</a>), and coronary heart disease cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14749349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 -23Hph1 A/T SNP, <a href="#48" class="mim-tip-reference" title="Meigs, J. B., Dupuis, J., Herbert, A. G., Liu, C., Wilson, P. W. F., Cupples, L. A. <strong>The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women.</strong> J. Clin. Endocr. Metab. 90: 1137-1143, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15562019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15562019</a>] [<a href="https://doi.org/10.1210/jc.2004-1212" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15562019">Meigs et al. (2005)</a> assessed variation in the INS VNTR minisatellite as a risk factor for 92 cases of incident type 2 diabetes in 883 unrelated Framingham Heart Study (FHS) subjects and in a separate sample of 698 members of 282 FHS nuclear families with 62 diabetes cases. In the unrelated sample, the -23Hph1 TT genotype frequency was 8.0% and was associated with a diabetes hazard ratio of 1.89 (95% CI, 1.01-3.52; P = 0.045) compared with the AA genotype using diabetes age of onset as the time failure variable in a proportional hazards model adjusted for age, offspring sex, body mass index, parental diabetes, and sex by parental diabetes interactions. In sex-stratified analyses, TT increased risk for diabetes in women, but not men. Using a family-based association test to assess transmission disequilibrium in the sample of related subjects, the age- and sex-adjusted z-score for diabetes associated with the T allele was 2.07 (P = 0.04), and a family-based association test using age of onset in a proportional hazards model was also statistically significant (P = 0.03), indicating that increased risk of diabetes was not attributable to population admixture. The authors concluded that these data support the hypothesis that the INS VNTR is a genetic risk factor for type 2 diabetes, with the TT genotype accounting for about 6.6% of cases in the FHS population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15562019" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 flow cytometry and RT-PCR, <a href="#55" class="mim-tip-reference" title="Narendran, P., Neale, A. M., Lee, B. H., Ngui, K., Steptoe, R. J., Morahan, G., Madsen, O., Dromey, J. A., Jensen, K. P., Harrison, L. C. <strong>Proinsulin is encoded by an RNA splice variant in human blood myeloid cells.</strong> Proc. Nat. Acad. Sci. 103: 16430-16435, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17053071[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.0607380103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053071">Narendran et al. (2006)</a> identified one of the self-antigens expressed by blood myeloid cells as a proinsulin splice variant. Expression of the immunoreactive proinsulin variant was decreased by small interfering RNA. Genotyping revealed that abundance of the proinsulin splice variant in blood cells corresponded with the length of the VNTRs 5-prime of the proinsulin gene. <a href="#55" class="mim-tip-reference" title="Narendran, P., Neale, A. M., Lee, B. H., Ngui, K., Steptoe, R. J., Morahan, G., Madsen, O., Dromey, J. A., Jensen, K. P., Harrison, L. C. <strong>Proinsulin is encoded by an RNA splice variant in human blood myeloid cells.</strong> Proc. Nat. Acad. Sci. 103: 16430-16435, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17053071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17053071</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17053071[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.0607380103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17053071">Narendran et al. (2006)</a> proposed that self-antigen expression by peripheral myeloid cells, by analogy with thymus, may be implicated in peripheral immune tolerance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17053071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Heude, B., Petry, C. J., Avon Longitudinal Study of Parents and Children (ALSPAC) study team, Pembrey, M., Dunger, D. B., Ong, K. K. <strong>The insulin gene variable number of tandem repeat: associations and interactions with childhood body fat mass and insulin secretion in normal children.</strong> J. Clin. Endocr. Metab. 91: 2770-2775, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16608900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16608900</a>] [<a href="https://doi.org/10.1210/jc.2005-2055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16608900">Heude et al. (2006)</a> reported INS VNTR associations with body composition and insulin secretion in children. Homozygous III/III children had higher BMI (P = 0.020), fat mass index (FMI) (P = 0.015), and truncal FMI (P = 0.022) at 9 years than class I bearers, but no difference in fat-free mass (P = 0.23). They clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population related to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. <a href="#30" class="mim-tip-reference" title="Heude, B., Petry, C. J., Avon Longitudinal Study of Parents and Children (ALSPAC) study team, Pembrey, M., Dunger, D. B., Ong, K. K. <strong>The insulin gene variable number of tandem repeat: associations and interactions with childhood body fat mass and insulin secretion in normal children.</strong> J. Clin. Endocr. Metab. 91: 2770-2775, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16608900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16608900</a>] [<a href="https://doi.org/10.1210/jc.2005-2055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16608900">Heude et al. (2006)</a> concluded that this genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16608900" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Santoro, N., Cirillo, G., Amato, A., Luongo, C., Raimondo, P., D'Aniello, A., Perrone, L., del Giudice, E. M. <strong>Insulin gene variable number of tandem repeats (INS VNTR) genotype and metabolic syndrome in childhood obesity.</strong> J. Clin. Endocr. Metab. 91: 4641-4644, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16868061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16868061</a>] [<a href="https://doi.org/10.1210/jc.2005-2705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16868061">Santoro et al. (2006)</a> screened for the INS VNTR in 320 obese children. The prevalence of metabolic syndrome reached 39%. No differences in INS VNTR genotype distribution were observed between obese subjects and 200 lean, age- and sex-matched children (P = 0.7). Among obese subjects, the prevalence of the metabolic syndrome was significantly higher in subjects with the I/I genotype (P = 0.006); the risk for developing the metabolic syndrome was significantly higher in subjects carrying the I/I genotype (odds ratio, 2.5; 95% confidence interval, 1.5-3.9). Obese subjects homozygous for the class I allele showed higher insulin levels and insulinogenic index but lower whole-body insulin sensitivity. <a href="#72" class="mim-tip-reference" title="Santoro, N., Cirillo, G., Amato, A., Luongo, C., Raimondo, P., D'Aniello, A., Perrone, L., del Giudice, E. M. <strong>Insulin gene variable number of tandem repeats (INS VNTR) genotype and metabolic syndrome in childhood obesity.</strong> J. Clin. Endocr. Metab. 91: 4641-4644, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16868061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16868061</a>] [<a href="https://doi.org/10.1210/jc.2005-2705" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16868061">Santoro et al. (2006)</a> concluded that the I variant of the insulin promoter, when expressed in homozygotes, can predispose obese children to develop the metabolic syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16868061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Awata, T., Kawasaki, E., Ikegami, H., Kobayashi, T., Maruyama, T., Nakanishi, K., Shimada, A., Iizuka, H., Kurihara, S., Osaki, M., Uga, M., Kawabata, Y., Tanaka, S., Kanazawa, Y., Katayama, S. <strong>Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes.</strong> J. Clin. Endocr. Metab. 92: 1791-1795, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17341563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17341563</a>] [<a href="https://doi.org/10.1210/jc.2006-2242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17341563">Awata et al. (2007)</a> studied the association between INS/IDDM2 and type 1 diabetes in Japanese. In total, 661 patients with type 1 diabetes and 706 control subjects were studied. The INS variable number of tandem repeat (VNTR) class I/class III status was estimated by genotyping the -23 HphI SNP. The frequency of the class I allele was 99.3% in patients and 96.7% in controls (p less than 10(-5)), and the class I/III or III/III genotype was found in 1.4% of patients and in 6.4% of controls (OR = 0.20, p less than 10(-5)). The class I subdivision revealed IC to increase significantly in patients with type 1 diabetes (P = 0.002), whereas ID did not; the distribution of IC and ID was significantly different between patients and controls (P = 0.014). <a href="#2" class="mim-tip-reference" title="Awata, T., Kawasaki, E., Ikegami, H., Kobayashi, T., Maruyama, T., Nakanishi, K., Shimada, A., Iizuka, H., Kurihara, S., Osaki, M., Uga, M., Kawabata, Y., Tanaka, S., Kanazawa, Y., Katayama, S. <strong>Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes.</strong> J. Clin. Endocr. Metab. 92: 1791-1795, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17341563/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17341563</a>] [<a href="https://doi.org/10.1210/jc.2006-2242" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17341563">Awata et al. (2007)</a> concluded that the IDDM2 region is also a susceptibility locus in the Japanese population. Furthermore, IC may be more susceptible to type I diabetes than ID, which could be evidence that the INS VNTR itself confers susceptibility to type 1 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17341563" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Other Variation</em></strong></p><p>
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<a href="#91" class="mim-tip-reference" title="Ullrich, A., Dull, T. J., Gray, A. <strong>Genetic variation in the human insulin gene.</strong> Science 209: 612-615, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6248962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6248962</a>] [<a href="https://doi.org/10.1126/science.6248962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6248962">Ullrich et al. (1980)</a> studied 4 recombinant lambda phages containing nucleotide sequences complementary to a cloned human preproinsulin DNA probe. Restriction analyses in conjunction with Southern blots showed 2 types of sequences which are presumably allelic. The sequences studied contained the entire preproinsulin messenger RNA region, 2 intervening sequences, 260 nucleotides upstream from the mRNA capping site, and 35 nucleotides beyond the polyadenylate attachment site. The 2 allelic genes were referred to as alpha and beta. Complete sequencing by the Maxam-Gilbert method showed differences at 4 positions: nucleotide 216 in IVS1, nucleotide 1045 in IVS2, and nucleotides 1367 and 1380 in the 3-prime untranslated region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6248962" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#75" class="mim-tip-reference" title="Seino, S., Funakoshi, A., Fu, Z. Z., Vinik, A. <strong>Identification of insulin variants in patients with hyperinsulinemia by reversed-phase high-performance liquid chromatography.</strong> Diabetes 34: 1-7, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3880547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3880547</a>] [<a href="https://doi.org/10.2337/diab.34.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3880547">Seino et al. (1985)</a> found 2 more examples of variant insulin. By HPLC, in neither case was any normal insulin found in the plasma. This is consistent with repression of the normal allele and may account for diabetes in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3880547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Reviews</em></strong></p><p>
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<a href="#76" class="mim-tip-reference" title="Selden, R. F., Skoskiewicz, M. J., Russell, P. S., Goodman, H. M. <strong>Regulation of insulin-gene expression: implications for gene therapy.</strong> New Eng. J. Med. 317: 1067-1076, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3309655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3309655</a>] [<a href="https://doi.org/10.1056/NEJM198710223171706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3309655">Selden et al. (1987)</a> reviewed the regulation of expression of the insulin gene and its relevance to gene therapy of type I diabetes. <a href="#94" class="mim-tip-reference" title="Vinik, A., Bell, G. <strong>Mutant insulin syndromes.</strong> Horm. Metab. Res. 20: 1-10, 1988. Note: Erratum: Horm. Metab. Res. 20: 191 only, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3286444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3286444</a>] [<a href="https://doi.org/10.1055/s-2007-1010736" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3286444">Vinik and Bell (1988)</a> reviewed mutant insulin syndromes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3309655+3286444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By in situ hybridization, <a href="#51" class="mim-tip-reference" title="Michalova, K., Bucchini, D., Ripoche, M.-A., Pictet, R., Jami, J. <strong>Chromosome localization of the human insulin gene in transgenic mouse lines.</strong> Hum. Genet. 80: 247-252, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3056832/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3056832</a>]" pmid="3056832">Michalova et al. (1988)</a> demonstrated that the insulin gene was inserted in a different chromosome in each of 3 transgenic mouse lines--chromosomes 7, 13, and 18. In each case the insert appeared to be unique, although several copies of the human DNA fragment were arranged in head-to-tail arrays in each line. The insert was transmitted to progeny as a single genetic locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3056832" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Most of the monogenic diabetic syndromes in rodent models, such as ob, db, agouti, tubby, and fat mice, have accompanying obesity. The responsible genes are involved in the regulation of body weight, and their alterations result in increased insulin resistance in peripheral tissues, except in 'fat' mice. <a href="#101" class="mim-tip-reference" title="Yoshioka, M., Kayo, T., Ikeda, T., Koizumi, A. <strong>A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice.</strong> Diabetes 46: 887-894, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9133560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9133560</a>] [<a href="https://doi.org/10.2337/diab.46.5.887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9133560">Yoshioka et al. (1997)</a> established a monogenic model that they called the Akita mouse. This model does not have associated obesity or insulitis, but is accompanied by a notable pancreatic beta-cell dysfunction. Diabetes in this mouse resembles that of human MODY in terms of early onset, an autosomal dominant mode of inheritance, and primary dysfunction of the beta cells. The mouse locus was named Mody and was shown to be located on the distal end of chromosome 7 by linkage analysis (<a href="#37" class="mim-tip-reference" title="Kayo, T., Koizumi, A. <strong>Mapping of murine diabetogenic gene Mody on chromosome 7 at D7Mit258 and its involvement in pancreatic islet and beta cell development during the perinatal period.</strong> J. Clin. Invest. 101: 2112-2118, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9593767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9593767</a>] [<a href="https://doi.org/10.1172/JCI1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9593767">Kayo and Koizumi, 1998</a>). <a href="#96" class="mim-tip-reference" title="Wang, J., Takeuchi, T., Tanaka, S., Kubo, S.-K., Kayo, T., Lu, D., Takata, K., Koizumi, A., Izumi, T. <strong>A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse.</strong> J. Clin. Invest. 103: 27-37, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9884331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9884331</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9884331[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/JCI4431" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9884331">Wang et al. (1999)</a> demonstrated that the Mody mouse has a missense mutation of the insulin-2 gene (Ins2), which lies in the same area as the Mody locus identified by genetic analysis on mouse chromosome 7 (the Ins1 gene is located on mouse chromosome 6). The mutation changed codon 96 from TGC (cys) to TAC (tyr). The mutation disrupts a disulfide bond between the A and B chains and was presumed to induce a drastic conformational change in the molecule. Although there was no gross defect in the transcription from the wildtype insulin-2 allele or the 2 alleles of insulin-1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, suggesting that the number of wildtype proinsulin molecules was also decreased. Electron microscopy showed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proinsulin was processed to insulin, but high molecular weight forms of proinsulin existed with concomitant overexpression of BiP/Grp78 (<a href="/entry/138120">138120</a>), a molecular chaperone in the endoplasmic reticulum. Mutant cys96-to-tyr proinsulin expressed in Chinese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findings indicated that mutant proinsulin was trapped and accumulated in the endoplasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation. The phenotype of this mouse mutation is different from that of any human insulin mutation; insulin Chicago (<a href="#0001">176730.0001</a>), however, was found in a family thought to have MODY. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9593767+9133560+9884331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Cheung, A. T., Dayanandan, B., Lewis, J. T., Korbutt, G. S., Rajotte, R. V., Bryer-Ash, M., Boylan, M. O., Wolfe, M. M., Kieffer, T. J. <strong>Glucose-dependent insulin release from genetically engineered K cells.</strong> Science 290: 1959-1962, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110661</a>] [<a href="https://doi.org/10.1126/science.290.5498.1959" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11110661">Cheung et al. (2000)</a> found that gut K cells could be induced to produce human insulin by providing the cells with the human insulin gene linked to the 5-prime regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP; <a href="/entry/137240">137240</a>). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., Guenette, S. <strong>Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.</strong> Proc. Nat. Acad. Sci. 100: 4162-4167, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12634421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12634421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12634421[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.0230450100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12634421">Farris et al. (2003)</a> generated mice deficient in insulin-degrading enzyme (IDE; <a href="/entry/146680">146680</a>) by targeted disruption. Ide deficiency resulted in a greater than 50% decrease in amyloid-beta degradation in both membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The Ide-null mice showed increased cerebral accumulation of endogenous amyloid-beta, a hallmark of Alzheimer disease (<a href="/entry/104300">104300</a>), and had hyperinsulinemia and glucose intolerance, hallmarks of type II diabetes. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which had recently been found to be degraded by IDE in vitro. <a href="#19" class="mim-tip-reference" title="Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E. A., Frosch, M. P., Eckman, C. B., Tanzi, R. E., Selkoe, D. J., Guenette, S. <strong>Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.</strong> Proc. Nat. Acad. Sci. 100: 4162-4167, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12634421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12634421</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12634421[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.0230450100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12634421">Farris et al. (2003)</a> concluded that, together with emerging genetic evidence, their in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of Alzheimer disease and type II diabetes and provide a mechanism for the recognized association among hyperinsulinemia, diabetes, and Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12634421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#90" 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 (<a href="/entry/147670">147670</a>) and Igf1r (<a href="/entry/147370">147370</a>) 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="#90" 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>
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<p><a href="#65" class="mim-tip-reference" title="Robinson, G. L. W. G., Cordle, S. R., Henderson, E., Weil, P. A., Teitelman, G., Stein, R. <strong>Isolation and characterization of a novel transcription factor that binds to and activates insulin control element-mediated expression.</strong> Molec. Cell. Biol. 14: 6704-6714, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7935390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7935390</a>] [<a href="https://doi.org/10.1128/mcb.14.10.6704-6714.1994" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7935390">Robinson et al. (1994)</a> reported the identification of an insulin control element-binding transcription factor, or insulin activator factor (INSAF), by screening a human pancreatic insulinoma cDNA library with a concatamerized insulin control element (ICE)-binding site oligonucleotide. They concluded that INSAF acts as positive regulator of ICE-mediated activity. However, by sequence analysis, <a href="#74" class="mim-tip-reference" title="Scott, A. F. <strong>Personal Communication.</strong> Baltimore, Md. 6/21/2004."None>Scott (2004)</a> determined that the INSAF sequence does not represent a protein-coding gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7935390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs148685531 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs148685531;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/rs148685531?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=rs148685531" 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=rs148685531" 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="#87" class="mim-tip-reference" title="Tager, H., Given, B., Baldwin, D., Mako, M., Markese, J., Rubenstein, A., Olefsky, J., Kobayashi, M., Kolterman, O., Poucher, R. <strong>A structurally abnormal insulin causing human diabetes.</strong> Nature 281: 122-125, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/381941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">381941</a>] [<a href="https://doi.org/10.1038/281122a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="381941">Tager et al. (1979)</a> studied insulin isolated from the pancreas of a diabetic patient and concluded that one of the allelic genes had undergone a mutation resulting in substitution of leucine for phenylalanine at position 23 or 24 in the insulin B chain. Occurring in the invariant portion of the molecule, the mutation resulted in reduced biologic activity (<a href="#23" class="mim-tip-reference" title="Given, B. D., Mako, M. E., Tager, H. S., Baldwin, D., Markese, J., Rubenstein, A. H., Olefsky, J., Kobayashi, M., Kolterman, O., Poucher, R. <strong>Diabetes due to secretion of an abnormal insulin.</strong> New Eng. J. Med. 302: 129-135, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7350438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7350438</a>] [<a href="https://doi.org/10.1056/NEJM198001173020301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7350438">Given et al., 1980</a>). <a href="#38" class="mim-tip-reference" title="Kwok, S. C. M., Chan, S. J., Rubenstein, A. H., Poucher, R., Steiner, D. F. <strong>Loss of a restriction endonuclease cleavage site in the gene of a structurally abnormal human insulin.</strong> Biochem. Biophys. Res. Commun. 98: 844-849, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6261753/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6261753</a>] [<a href="https://doi.org/10.1016/0006-291x(81)91188-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6261753">Kwok et al. (1981)</a> isolated genomic DNA from the leukocytes of a diabetic patient with the mutant insulin identified by <a href="#23" class="mim-tip-reference" title="Given, B. D., Mako, M. E., Tager, H. S., Baldwin, D., Markese, J., Rubenstein, A. H., Olefsky, J., Kobayashi, M., Kolterman, O., Poucher, R. <strong>Diabetes due to secretion of an abnormal insulin.</strong> New Eng. J. Med. 302: 129-135, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7350438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7350438</a>] [<a href="https://doi.org/10.1056/NEJM198001173020301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7350438">Given et al. (1980)</a>. After digestion with restriction endonuclease MboII, electrophoresis, and hybridization with cloned human cDNA probes, one MboII cleavage site had been lost, which is consistent with the postulated replacement of phenylalanine by leucine at position 24 of the insulin gene. <a href="#79" class="mim-tip-reference" title="Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., Tager, H. <strong>Three mutant insulins in man.</strong> Nature 302: 540-543, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6339950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6339950</a>] [<a href="https://doi.org/10.1038/302540a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6339950">Shoelson et al. (1983)</a> demonstrated that the substitution in the mutant insulin identified by <a href="#87" class="mim-tip-reference" title="Tager, H., Given, B., Baldwin, D., Mako, M., Markese, J., Rubenstein, A., Olefsky, J., Kobayashi, M., Kolterman, O., Poucher, R. <strong>A structurally abnormal insulin causing human diabetes.</strong> Nature 281: 122-125, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/381941/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">381941</a>] [<a href="https://doi.org/10.1038/281122a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="381941">Tager et al. (1979)</a> and <a href="#23" class="mim-tip-reference" title="Given, B. D., Mako, M. E., Tager, H. S., Baldwin, D., Markese, J., Rubenstein, A. H., Olefsky, J., Kobayashi, M., Kolterman, O., Poucher, R. <strong>Diabetes due to secretion of an abnormal insulin.</strong> New Eng. J. Med. 302: 129-135, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7350438/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7350438</a>] [<a href="https://doi.org/10.1056/NEJM198001173020301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7350438">Given et al. (1980)</a> is leucine for phenylalanine at B25. They designated the variant 'insulin Chicago.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=381941+7350438+6339950+6261753" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0002 HYPERPROINSULINEMIA</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">rs80356668 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356668;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=rs80356668" 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=rs80356668" 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=RCV000014307" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014307" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014307</a>
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<p>In a patient with serum insulin consisting predominantly of an abnormal form that elutes before normal insulin as well as a small amount of normal insulin (<a href="/entry/616214">616214</a>), <a href="#79" class="mim-tip-reference" title="Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., Tager, H. <strong>Three mutant insulins in man.</strong> Nature 302: 540-543, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6339950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6339950</a>] [<a href="https://doi.org/10.1038/302540a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6339950">Shoelson et al. (1983)</a> concluded that the insulin variant had a substitution of serine for phenylalanine at position 24 of the B chain. The authors designated the variant 'insulin Los Angeles.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6339950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mild diabetes, marked fasting hyperinsulinemia, and a reduced fasting C-peptide:insulin molar ratio, Haneda et al. (<a href="#25" class="mim-tip-reference" title="Haneda, M., Chan, S. J., Kwok, S. C. M., Rubenstein, A. H., Steiner, D. F. <strong>Studies on mutant human insulin genes: identification and sequence analysis of a gene encoding (ser-B24) insulin.</strong> Proc. Nat. Acad. Sci. 80: 6366-6370, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6312455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6312455</a>] [<a href="https://doi.org/10.1073/pnas.80.20.6366" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6312455">1983</a>, <a href="#27" class="mim-tip-reference" title="Haneda, M., Polonsky, K. S., Bergenstal, R. M., Jaspan, J. B., Shoelson, S. E., Blix, P. M., Chan, S. J., Kwok, S. C. M., Wishner, W. B., Zeidler, A., Olefsky, J. M., Freidenberg, G., Tager, H. S., Steiner, D. F., Rubenstein, A. H. <strong>Familial hyperinsulinemia due to a structurally abnormal insulin: definition of an emerging new clinical syndrome.</strong> New Eng. J. Med. 310: 1288-1294, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6371526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6371526</a>] [<a href="https://doi.org/10.1056/NEJM198405173102004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6371526">1984</a>) found that one insulin gene had a point mutation at position 24 of the B chain resulting in substitution of serine for phenylalanine. The patient had abnormal circulating insulin molecules that could be distinguished from each other and from normal insulin. The patient responded normally to exogenous insulin. Five additional family members of both sexes in 3 generations were affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6371526+6312455" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hua, Q. X., Shoelson, S. E., Inouye, K., Weiss, M. A. <strong>Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 90: 582-586, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8421693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8421693</a>] [<a href="https://doi.org/10.1073/pnas.90.2.582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8421693">Hua et al. (1993)</a> pointed out that among vertebrate insulins phe(B24) is invariant, and in crystal structures the aromatic ring appears to anchor the putative receptor-binding surface through long-range packing interactions in the hydrophobic core. In 1 analog, namely, gly(B24)-insulin, partial unfolding of the B chain has been observed with paradoxical retention of near-native bioactivity. <a href="#31" class="mim-tip-reference" title="Hua, Q. X., Shoelson, S. E., Inouye, K., Weiss, M. A. <strong>Paradoxical structure and function in a mutant human insulin associated with diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 90: 582-586, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8421693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8421693</a>] [<a href="https://doi.org/10.1073/pnas.90.2.582" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8421693">Hua et al. (1993)</a> demonstrated that, contrariwise, in ser(B24)-insulin, near-native structure is restored despite significant loss of function. To their knowledge, this was the first structural study of a diabetes-associated mutant insulin and the findings supported the hypothesis that insulin undergoes a change in conformation on receptor binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8421693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0003 HYPERPROINSULINEMIA</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> rs121918101 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918101;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/rs121918101?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=rs121918101" 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=rs121918101" 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=RCV000014308" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014308" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014308</a>
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<p><a href="#24" class="mim-tip-reference" title="Gruppuso, P. A., Gorden, P., Kahn, C. R., Cornblath, M., Zeller, W. P., Schwartz, R. <strong>Familial hyperproinsulinemia due to a proposed defect in conversion of proinsulin to insulin.</strong> New Eng. J. Med. 311: 629-634, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6382002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6382002</a>] [<a href="https://doi.org/10.1056/NEJM198409063111003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6382002">Gruppuso et al. (1984)</a> identified a hyperproinsulinemia kindred in which the proband, a 14-year-old girl with a history of transient hyperglycemia at age 2 years, was studied for symptoms of hypoglycemia. Elevated proinsulin was found in her and 2 sibs, the father and the paternal grandfather, whereas 4 other close relatives were normal. The variant was designated 'proinsulin Providence.' Based on a linkage study using several RFLPs, <a href="#18" class="mim-tip-reference" title="Elbein, S. C., Gruppuso, P., Schwartz, R., Skolnick, M., Permutt, M. A. <strong>Hyperproinsulinemia in a family with a proposed defect in conversion is linked to the insulin gene.</strong> Diabetes 34: 821-824, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2991050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2991050</a>] [<a href="https://doi.org/10.2337/diab.34.8.821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2991050">Elbein et al. (1985)</a> reported that the defect in this family mapped at or near the insulin gene. <a href="#9" class="mim-tip-reference" title="Chan, S. J., Seino, S., Gruppuso, P. A., Schwartz, R., Steiner, D. F. <strong>A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.</strong> Proc. Nat. Acad. Sci. 84: 2194-2197, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3470784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3470784</a>] [<a href="https://doi.org/10.1073/pnas.84.8.2194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3470784">Chan et al. (1987)</a> cloned and sequenced both alleles of the insulin gene from 2 affected members of this family. They demonstrated a point mutation in the B chain coding region of the insulin gene. There was a single nucleotide substitution in the codon for residue 10: CAC was changed to GAC. The nucleotide change predicted substitution of aspartic acid for histidine. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6382002+3470784+2991050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#73" class="mim-tip-reference" title="Schwartz, G. P., Burke, G. T., Katsoyannis, P. G. <strong>A superactive insulin: [B10-aspartic acid]insulin(human).</strong> Proc. Nat. Acad. Sci. 84: 6408-6411, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3306677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3306677</a>] [<a href="https://doi.org/10.1073/pnas.84.18.6408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3306677">Schwartz et al. (1987)</a> synthesized an insulin analog with substitution of aspartic acid for histidine at position 10 of the B chain, the same alteration as that identified by <a href="#9" class="mim-tip-reference" title="Chan, S. J., Seino, S., Gruppuso, P. A., Schwartz, R., Steiner, D. F. <strong>A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.</strong> Proc. Nat. Acad. Sci. 84: 2194-2197, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3470784/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3470784</a>] [<a href="https://doi.org/10.1073/pnas.84.8.2194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3470784">Chan et al. (1987)</a> in a naturally-occurring mutation. <a href="#73" class="mim-tip-reference" title="Schwartz, G. P., Burke, G. T., Katsoyannis, P. G. <strong>A superactive insulin: [B10-aspartic acid]insulin(human).</strong> Proc. Nat. Acad. Sci. 84: 6408-6411, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3306677/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3306677</a>] [<a href="https://doi.org/10.1073/pnas.84.18.6408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3306677">Schwartz et al. (1987)</a> found that the insulin analog was superactive, probably as a result of stronger interaction with the insulin receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3470784+3306677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Carroll, R. J., Hammer, R. E., Chan, S. J., Swift, H. H., Rubenstein, A. H., Steiner, D. F. <strong>A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway.</strong> Proc. Nat. Acad. Sci. 85: 8943-8947, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3057496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3057496</a>] [<a href="https://doi.org/10.1073/pnas.85.23.8943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3057496">Carroll et al. (1988)</a> created a model of the familial hyperproinsulinemia resulting from the B10 his-to-asp mutation by introducing the gene into transgenic mice. A high level of mutant prohormone was expressed in their islets of Langerhans. Hyperproinsulinemia in the mice, and by implication in the patients, appeared to be the result of the continuous secretion of unprocessed mutant proenzyme from the islets via an alternative unregulated pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3057496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs28933985 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933985;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/rs28933985?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=rs28933985" 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=rs28933985" 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=RCV000014310 OR RCV001091846 OR RCV003407328 OR RCV005042049" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014310, RCV001091846, RCV003407328, RCV005042049" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014310...</a>
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<p>Studying leukocyte DNA, <a href="#77" class="mim-tip-reference" title="Shibasaki, Y., Kawakami, T., Kanazawa, Y., Akanuma, Y., Takaku, F. <strong>Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia.</strong> J. Clin. Invest. 76: 378-380, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4019786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4019786</a>] [<a href="https://doi.org/10.1172/JCI111973" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4019786">Shibasaki et al. (1985)</a> found a point mutation, substitution of adenine for guanine, in the insulin gene of a Japanese family with hyperproinsulinemia. This transition implies substitution of histidine for arginine at amino acid position 65 (R65H). Furthermore, it implies that arginine-65 is essential to proinsulin-insulin conversion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4019786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Robbins et al. (<a href="#62" class="mim-tip-reference" title="Robbins, D. C., Blix, P. M., Rubenstein, A. H., Kanazawa, Y., Kosaka, K., Tager, H. S. <strong>A human proinsulin variant at arginine 65.</strong> Nature 291: 679-681, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7242673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7242673</a>] [<a href="https://doi.org/10.1038/291679a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7242673">1981</a>, <a href="#63" class="mim-tip-reference" title="Robbins, D. C., Shoelson, S. E., Rubenstein, A. H., Tager, H. S. <strong>Familial hyperproinsulinemia: two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.</strong> J. Clin. Invest. 73: 714-719, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6368587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6368587</a>] [<a href="https://doi.org/10.1172/JCI111264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6368587">1984</a>) had earlier described an arginine-65 variant of proinsulin associated with hyperproinsulinemia; the amino acid substitution was not identified at that time. <a href="#3" class="mim-tip-reference" title="Barbetti, F., Raben, N., Kadowaki, T., Cama, A., Accili, D., Gabbay, K. H., Merenich, J. A., Taylor, S. I., Roth, J. <strong>Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction.</strong> J. Clin. Endocr. Metab. 71: 164-169, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2196279/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2196279</a>] [<a href="https://doi.org/10.1210/jcem-71-1-164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2196279">Barbetti et al. (1990)</a> found the same mutation, CGT to CAT at codon 65, in 2 unrelated Caucasian families, one of which was the family reported by Robbins et al. (<a href="#62" class="mim-tip-reference" title="Robbins, D. C., Blix, P. M., Rubenstein, A. H., Kanazawa, Y., Kosaka, K., Tager, H. S. <strong>A human proinsulin variant at arginine 65.</strong> Nature 291: 679-681, 1981.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7242673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7242673</a>] [<a href="https://doi.org/10.1038/291679a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7242673">1981</a>, <a href="#63" class="mim-tip-reference" title="Robbins, D. C., Shoelson, S. E., Rubenstein, A. H., Tager, H. S. <strong>Familial hyperproinsulinemia: two cohorts secreting indistinguishable type II intermediates of proinsulin conversion.</strong> J. Clin. Invest. 73: 714-719, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6368587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6368587</a>] [<a href="https://doi.org/10.1172/JCI111264" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6368587">1984</a>). (In describing a novel insulin variant, Robbins et al. (1984) used the term 'cohort' as synonymous with 'kindred' or 'family'--a possible source of confusion in light of the well-established use of the term 'cohort' in epidemiology.) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6368587+2196279+7242673" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#66" class="mim-tip-reference" title="Roder, M. E., Vissing, H., Nauck, M. A. <strong>Hyperproinsulinemia in a three-generation Caucasian family due to mutant proinsulin (Arg(65)->His) not associated with impaired glucose tolerance: the contribution of mutant proinsulin to insulin bioactivity.</strong> J. Clin. Endocr. Metab. 81: 1634-1640, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8636380/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8636380</a>] [<a href="https://doi.org/10.1210/jcem.81.4.8636380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8636380">Roder et al. (1996)</a> reported a 3-generation Caucasian kindred with the R65H mutation. Using specific enzyme-linked immunosorbent assay methods, they quantified insulin, proinsulin, and the impact of this mutation on glucose tolerance. All affected subjects had normal oral glucose tolerance, assuming 9% activity for the mutant arg65-to-his proinsulin. The calculated insulin bioactivities of affected subjects were comparable to those of normals. Thus, in this kindred, heterozygosity for R65H proinsulin was not associated with impaired glucose tolerance. Previous reports of the association of this mutation with impaired glucose tolerance may be due to bias of ascertainment or differences in genetic background or environment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8636380" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2-generation European Caucasian family with hyperproinsulinemia associated with normal glucose tolerance and normal insulin sensitivity, <a href="#11" class="mim-tip-reference" title="Collinet, M., Berthelon, M., Benit, P., Laborde, K., Desbuquois, B., Munnich, A., Robert, J. J. <strong>Familial hyperproinsulinaemia due to a mutation substituting histidine for arginine at position 65 in proinsulin: identification of the mutation by restriction enzyme mapping.</strong> Europ. J. Pediat. 157: 456-460, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9667398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9667398</a>] [<a href="https://doi.org/10.1007/s004310050852" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9667398">Collinet et al. (1998)</a> demonstrated the R65H mutation by restriction enzyme mapping. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9667398" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 HYPERPROINSULINEMIA</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">rs121918102 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918102;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=rs121918102" 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=rs121918102" 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=RCV000014311 OR RCV003460471" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014311, RCV003460471" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014311...</a>
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<p>In a patient previously reported by <a href="#79" class="mim-tip-reference" title="Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., Tager, H. <strong>Three mutant insulins in man.</strong> Nature 302: 540-543, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6339950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6339950</a>] [<a href="https://doi.org/10.1038/302540a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6339950">Shoelson et al. (1983)</a> to have an abnormal insulin, designated 'insulin Wakayama,' <a href="#54" class="mim-tip-reference" title="Nanjo, K., Sanke, T., Miyano, M., Okai, K., Sowa, R., Kondo, M., Nishimura, S., Iwo, K., Miyamura, K., Given, B. D., Chan, S. J., Tager, H. S., Steiner, D. F., Rubenstein, A. H. <strong>Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama): clinical and functional characteristics of (leu-A3) insulin.</strong> J. Clin. Invest. 77: 514-519, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3511099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3511099</a>] [<a href="https://doi.org/10.1172/JCI112331" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3511099">Nanjo et al. (1986)</a> identified heterozygosity for a GTG-to-TTG transversion in the INS gene, predicting a val3-to-leu substitution in the insulin A chain. The patient had noninsulin-dependent diabetes with fasting hyperinsulinemia, elevated insulin:C-peptide molar ratio, normal insulin counterregulatory hormone levels, and adequate response to exogenous insulin. The serum contained no insulin-binding antibodies and red cell insulin receptor binding was normal. Insulin purified from the patient's serum showed reduced binding and ability to stimulate glucose uptake and oxidation in vitro. High-performance liquid chromatography (HPLC) showed 2 insulins; 7.3% of insulin immunoreactivity coeluted with normal insulin whereas 92.7% eluted as a single peak with increased hydrophobicity. Four of 5 relatives in 3 generations also had hyperinsulinemia and those tested had the abnormal insulin. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6339950+3511099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#71" class="mim-tip-reference" title="Sakura, H., Iwamoto, Y., Sakamoto, Y., Kuzuya, T., Hirata, H. <strong>Structurally abnormal insulin in a diabetic patient: characterization of the mutant insulin A3 (val-to-leu) isolated from the pancreas.</strong> J. Clin. Invest. 78: 1666-1672, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3537011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3537011</a>] [<a href="https://doi.org/10.1172/JCI112760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3537011">Sakura et al. (1986)</a> found another example of insulin Wakayama. The proband was a diabetic woman who, because of gallstones, underwent cholecystectomy. During the procedure, with the informed consent of the patient, a piece of pancreas was obtained from the pancreatic tail and venous blood samples were taken from the portal vein. Despite her diabetes, the patient had hyperinsulinemia with demonstration of an abnormal as well as a normal insulin in the circulation. Whereas in the pancreas the ratio of the 2 insulins was about equal, in the peripheral blood the abnormal insulin predominated over the normal insulin in a ratio of 7:1. The abnormal insulin had about 5% of the normal binding activity and about 8% of the normal biological activity. Analysis of amino acid sequences suggested the presence of leucine for valine at the third position of the A chain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3537011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs28933985 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933985;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/rs28933985?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=rs28933985" 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=rs28933985" 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=RCV000014313" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014313" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014313</a>
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<p>In a 65-year-old nonobese Japanese man with diabetes mellitus, fasting hyperinsulinemia, and a reduced fasting C-peptide/insulin molar ratio of 2.5-3.0, <a href="#100" class="mim-tip-reference" title="Yano, H., Kitano, N., Morimoto, M., Polonsky, K. S., Imura, H., Seino, Y. <strong>A novel point mutation in the human insulin gene giving rise to hyperproinsulinemia (proinsulin Kyoto).</strong> J. Clin. Invest. 89: 1902-1907, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1601997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1601997</a>] [<a href="https://doi.org/10.1172/JCI115795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1601997">Yano et al. (1992)</a> found a G-to-T transversion in the INS gene, which gave rise to a new HindIII recognition site and resulted in the amino acid replacement of leucine for arginine at position 65 (R65L). This result and that of the R65H mutation (<a href="#0004">176730.0004</a>) indicate that replacement of arg65 prevents recognition of the dibasic protease. Fasting hyperinsulinemia was found in the proband's son and daughter who also had the mutation. The variant was designated 'proinsulin Kyoto.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1601997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs28933985 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28933985;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/rs28933985?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=rs28933985" 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=rs28933985" 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=RCV000014315" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014315" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014315</a>
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<p><a href="#97" class="mim-tip-reference" title="Warren-Perry, M. G., Manley, S. E., Ostrega, D., Polonsky, K., Mussett, S., Brown, P., Turner, R. C. <strong>A novel point mutation in the insulin gene giving rise to hyperproinsulinemia.</strong> J. Clin. Endocr. Metab. 82: 1629-1631, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9141561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9141561</a>] [<a href="https://doi.org/10.1210/jcem.82.5.3914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9141561">Warren-Perry et al. (1997)</a> found a 58-year-old, obese, Caucasian male type 2 diabetic in the UK Prospective Diabetes Study to have raised fasting total proinsulin and normal specific plasma insulin levels. The INS gene contained a point mutation, 1552G-C, which results in an arg65-to-pro (R65P) substitution. This mutation prevented cleavage of the C-peptide A-chain dibasic cleavage site (lys-arg) by the processing protease in the pancreatic cells. The plasma proinsulin and insulin levels were in accord with expression of both the wildtype and the mutant alleles. The authors determined that the 1552G-C mutation was not linked with diabetes, because it was present in a 37-year-old nondiabetic daughter and not in a 35-year-old daughter who had had gestational diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9141561" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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, PERMANENT NEONATAL, 4</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">rs80356664 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356664;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=rs80356664" 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=rs80356664" 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=RCV000020212 OR RCV000030072 OR RCV000117279 OR RCV001089451 OR RCV001775542" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020212, RCV000030072, RCV000117279, RCV001089451, RCV001775542" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020212...</a>
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<p>In 4 affected members of a 3-generation family and an unrelated proband with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for a gly32-to-ser (G32S) substitution in the INS gene (residue B8 of the insulin molecule), predicted to induce a major conformational change that would disrupt folding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356666 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356666;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=rs80356666" 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=rs80356666" 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=RCV000020204 OR RCV000030069 OR RCV001089452 OR RCV003445080" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020204, RCV000030069, RCV001089452, RCV003445080" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020204...</a>
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<p>In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for a cys43-to-gly (C43G) substitution in the INS gene at the highly conserved residue B19 of the insulin molecule, predicted to disrupt the normal disulfide bond at B19-A20 and potentially hinder subsequent folding steps. Both probands were diagnosed before 1 year of age, but the carrier father of 1 of the probands was diagnosed with mild type 2 diabetes (<a href="/entry/125853">125853</a>) at 30 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356669 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356669;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=rs80356669" 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=rs80356669" 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=RCV000020207 OR RCV001089453 OR RCV002051790 OR RCV002513137 OR RCV004730851" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020207, RCV001089453, RCV002051790, RCV002513137, RCV004730851" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020207...</a>
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<p>In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for an arg89-to-cys (R89C) substitution in the INS gene at the A-chain/C-peptide cleavage site, thus adding an additional unpaired cysteine residue at a solvent-exposed position in the molecule that is invariant among proinsulin sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 unrelated mothers and sons and 2 other unrelated probands with PNDM, <a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> identified heterozygosity for the R89C mutation in the INS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 5 affected individuals from 2 families with PNDM, <a href="#60" class="mim-tip-reference" title="Polak, M., Dechaume, A., Cave, H., Nimri, R., Crosnier, H., Sulmont, V., de Kerdanet, M., Scharfmann, R., Lebenthal, Y., Froguel, P., Vaxillaire, M. <strong>Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group.</strong> Diabetes 57: 1115-1119, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18171712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18171712</a>] [<a href="https://doi.org/10.2337/db07-1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18171712">Polak et al. (2008)</a> identified heterozygosity for R89C in the INS gene. The authors noted that one family ('family H') had diabetes that appeared to be nonautoimmune early-onset type 1 rather than bona fide neonatal diabetes, with diagnosis at 4 years of age in the mother and at 4.25 and 2.3 years of age in her son and daughter, respectively. Insulin requirements were relatively low for the patients in family H, and C-peptide levels were detectable, consistent with partially preserved beta-cell secretory function. In contrast, the mother in the other family ('family B') had poor metabolic control over the years and developed severe retinopathy, neuropathy, and macroangiopathy; at age 35 years, she underwent amputation of both feet. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18171712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 3 unrelated probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (<a href="/entry/600937">600937</a>), <a href="#12" class="mim-tip-reference" title="Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., and 8 others. <strong>Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.</strong> J. Clin. Invest. 118: 2148-2156, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18451997/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18451997</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18451997[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/JCI33777" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18451997">Colombo et al. (2008)</a> identified heterozygosity for an arg-to-cys substitution in the INS gene, which they designated R65C, located in the dibasic doublet between the C-peptide and the A-chain. Expression of the mutant proinsulin in HEK293 cells demonstrated defects in insulin protein folding and secretion. The mother of 1 patient and the father of another, who were also heterozygous for the mutation, had developed diabetes at 1 year and 4 years of age, respectively. C-peptide was initially detected in all 3 probands and was unexpectedly high in 1 of them; C-peptide declined to undetectable levels by the end of the study, supporting the hypothesis that postnatal failure to maintain beta-cell mass due to proteotoxic proinsulin misfolding is a primary cause of PNDM in patients with INS mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18451997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356671 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356671;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=rs80356671" 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=rs80356671" 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=RCV000014319 OR RCV000517445 OR RCV001089454 OR RCV002051784" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014319, RCV000517445, RCV001089454, RCV002051784" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014319...</a>
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<p>In a proband with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for a cys96-to-tyr (C96Y) substitution in the INS gene (residue A7 of the insulin molecule), predicted to disrupt the normal disulfide bond at A7-B7 and potentially hinder subsequent folding steps. This mutation is identical to that found in the Akita mouse. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mother and daughter and an unrelated proband with PNDM4, <a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> identified heterozygosity for the C96Y mutation in the INS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4-year-old boy who presented with polyuria and polydipsia at 4.8 months of age, <a href="#60" class="mim-tip-reference" title="Polak, M., Dechaume, A., Cave, H., Nimri, R., Crosnier, H., Sulmont, V., de Kerdanet, M., Scharfmann, R., Lebenthal, Y., Froguel, P., Vaxillaire, M. <strong>Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group.</strong> Diabetes 57: 1115-1119, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18171712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18171712</a>] [<a href="https://doi.org/10.2337/db07-1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18171712">Polak et al. (2008)</a> identified a de novo C96Y mutation in the INS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18171712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356663 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356663;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=rs80356663" 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=rs80356663" 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=RCV000014320 OR RCV001089455 OR RCV001818156" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014320, RCV001089455, RCV001818156" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014320...</a>
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<p>In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for an ala24-to-asp (A24D) substitution in the INS gene, at the last residue of the signal peptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 father and 2 sons and 2 unrelated probands with PNDM, <a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> identified heterozygosity for the A24D mutation in the INS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 22-month-old girl who presented with ketoacidosis at 3 weeks of age, <a href="#60" class="mim-tip-reference" title="Polak, M., Dechaume, A., Cave, H., Nimri, R., Crosnier, H., Sulmont, V., de Kerdanet, M., Scharfmann, R., Lebenthal, Y., Froguel, P., Vaxillaire, M. <strong>Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group.</strong> Diabetes 57: 1115-1119, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18171712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18171712</a>] [<a href="https://doi.org/10.2337/db07-1358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18171712">Polak et al. (2008)</a> identified heterozygosity for a de novo A24D mutation in the INS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18171712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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=RCV000014321 OR RCV001089456 OR RCV002051785" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014321, RCV001089456, RCV002051785" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014321...</a>
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<p>In 3 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#85" class="mim-tip-reference" title="Stoy, J., Edghill, E. L., Flanagan, S. E., Ye, H., Paz, V. P., Pluzhnikov, A., Below, J. E., Hayes, M. G., Cox, N. J., Lipkind, G. M., Lipton, R. B., Greeley, S. A. W., Patch, A.-M., Ellard, S., Steiner, D. F., Hattersley, A. T., Philipson, L. H., Bell, G. I. <strong>Insulin gene mutations as a cause of permanent neonatal diabetes.</strong> Proc. Nat. Acad. Sci. 104: 15040-15044, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17855560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17855560</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17855560[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.0707291104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17855560">Stoy et al. (2007)</a> identified heterozygosity for a phe48-to-cys (F48C) substitution in the INS gene, at residue B24 of the insulin molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17855560" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mother and daughter and an unrelated proband with PNDM, <a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> identified heterozygosity for the F48C mutation in the INS gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs121908278 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908278;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/rs121908278?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=rs121908278" 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=rs121908278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 affected members of a 3-generation family from the United Kingdom with diabetes fulfilling the criteria for maturity-onset diabetes of the young (MODY10; <a href="/entry/613370">613370</a>), <a href="#17" class="mim-tip-reference" title="Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S. <strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong> Diabetes 57: 1034-1042, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18162506/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18162506</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18162506[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/10.2337/db07-1405" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18162506">Edghill et al. (2008)</a> identified heterozygosity for a 16C-T transition in the INS gene, resulting in an arg6-to-cys (R6C) substitution at a conserved residue in the signal peptide of the preproinsulin molecule. The mutation was not found in 222 UK Caucasian controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18162506" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 10</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">rs121908260 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908260;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=rs121908260" 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=rs121908260" 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=RCV000014323 OR RCV001851851 OR RCV003445068" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014323, RCV001851851, RCV003445068" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014323...</a>
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<p>In affected members of a 3-generation Norwegian family fulfilling conventional criteria for maturity-onset diabetes of the young (MODY10; <a href="/entry/613370">613370</a>), <a href="#52" class="mim-tip-reference" title="Molven, A., Ringdal, M., Nordbo, A. M., Raeder, H., Stoy, J., Lipkind, G. M., Steiner, D. F., Philipson, L. H., Bergmann, I., Aarskog, D., Undlien, D. E., Joner, G., Sovik, O., Norwegian Childhood Diabetes Study Group, Bell, G. I., Njolstad, P. R. <strong>Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes.</strong> Diabetes 57: 1131-1135, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18192540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18192540</a>] [<a href="https://doi.org/10.2337/db07-1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18192540">Molven et al. (2008)</a> identified heterozygosity for a 137G-A transition in the INS gene, resulting in an arg46-to-gln (R46Q) substitution in the preproinsulin molecule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18192540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 TYPE 1 DIABETES MELLITUS 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908261 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908261;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/rs121908261?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=rs121908261" 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=rs121908261" 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=RCV000014324 OR RCV001558886 OR RCV003445069 OR RCV003987320 OR RCV004752705" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014324, RCV001558886, RCV003445069, RCV003987320, RCV004752705" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014324...</a>
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<p>In a Norwegian mother and daughter with type 1 diabetes mellitus (T1D2; <a href="/entry/125852">125852</a>), <a href="#52" class="mim-tip-reference" title="Molven, A., Ringdal, M., Nordbo, A. M., Raeder, H., Stoy, J., Lipkind, G. M., Steiner, D. F., Philipson, L. H., Bergmann, I., Aarskog, D., Undlien, D. E., Joner, G., Sovik, O., Norwegian Childhood Diabetes Study Group, Bell, G. I., Njolstad, P. R. <strong>Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes.</strong> Diabetes 57: 1131-1135, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18192540/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18192540</a>] [<a href="https://doi.org/10.2337/db07-1467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18192540">Molven et al. (2008)</a> identified heterozygosity for a 163C-T transition in the INS gene, resulting in an arg55-to-cys (R55C) substitution in the preproinsulin molecule. The daughter presented with frank diabetes at 10 years of age, with a markedly elevated blood glucose and ketoacidosis, and was insulin-dependent from the time of diagnosis. Her mother, 40 years old at the time of the report, was diagnosed with type 1 diabetes at 13 years of age and was treated with insulin. Both mother and daughter had autoantibodies against insulin, but GAD (glutamate decarboxylase; see <a href="/entry/605363">605363</a>) and IA-2 were negative, and both had residual beta-cell function. The maternal grandparents did not carry the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18192540" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0017 DIABETES MELLITUS, PERMANENT NEONATAL, 4</strong>
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INS, IVS2, G-A, +241
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886041083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886041083;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=rs886041083" 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=rs886041083" 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=RCV000258877" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000258877" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000258877</a>
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<p>In a Southeast Asian male infant with permanent neonatal diabetes mellitus (PNDM4; <a href="/entry/618858">618858</a>), <a href="#6" class="mim-tip-reference" title="Carmody, D., Park, S.-Y., Ye, H., Perrone, M. E., Alkorta-Aranburu, G., Highland, H. M., Hanis, C. L., Philipson, L. H., Bell, G. I., Greeley, S. A. W. <strong>Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.</strong> J. Med. Genet. 52: 612-616, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26101329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26101329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26101329[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/10.1136/jmedgenet-2015-103220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26101329">Carmody et al. (2015)</a> identified homozygosity for a c.187+241G-A transition in intron 2 of the INS gene, creating a 5-prime donor splice site. The mutation was present in heterozygosity in his first-cousin parents and 1 brother, none of whom had diabetes, although his mother had required insulin to treat gestational diabetes in all 3 of her pregnancies. In addition, the proband's maternal grandmother, who was heterozygous for the mutation, developed insulin-requiring diabetes mellitus at age 45, and a maternal aunt and uncle, for whom DNA was not available, were diagnosed with insulin-requiring diabetes mellitus at 28 and 36 years of age, respectively. The nondiabetic paternal grandmother also carried the mutation. No insulin RT-PCR product was detected from the proband's lymphoblastoid cell line or blood. Analysis of transfected INS-1 cells revealed 2 novel transcripts and no wildtype transcript. Sequencing revealed 1 transcript to be the predicted alternatively spliced transcript; the other transcript, without a stop codon, resulted from insertion of a 79-nucleotide pseudoexon following exon 2 through use of a native potential 3-prime acceptor site. Expression analysis following cycloheximide treatment of the transfected INS-1 cells showed an approximately 7-fold relative increase in the second transcript, whereas the first was not detected. <a href="#6" class="mim-tip-reference" title="Carmody, D., Park, S.-Y., Ye, H., Perrone, M. E., Alkorta-Aranburu, G., Highland, H. M., Hanis, C. L., Philipson, L. H., Bell, G. I., Greeley, S. A. W. <strong>Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.</strong> J. Med. Genet. 52: 612-616, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26101329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26101329</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26101329[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/10.1136/jmedgenet-2015-103220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26101329">Carmody et al. (2015)</a> suggested that the first transcript undergoes rapid nonsense-mediated decay, and the second undergoes non-stop-mediated decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26101329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#Bell1979" class="mim-tip-reference" title="Bell, G. I., Swain, W. F., Pictet, R., Cordell, B., Goodman, H. M., Rutter, W. J. <strong>Nucleotide sequence of cDNA clone encoding human preproinsulin.</strong> Nature 282: 525-527, 1979.">Bell et al. (1979)</a>; <a href="#Dayhoff1972" class="mim-tip-reference" title="Dayhoff, M. O. <strong>Atlas of Protein Sequence and Structure. Proinsulin. Vol. 5.</strong> Washington: National Biomedical Research Foundation (pub.) 1972. P. D208.">Dayhoff (1972)</a>; <a href="#Gabbay1979" class="mim-tip-reference" title="Gabbay, K. H., Bergenstal, R. M., Wolff, J., Mako, M. E., Rubenstein, A. H. <strong>Familial hyperproinsulinemia: partial characterization of circulating proinsulin-like material.</strong> Proc. Nat. Acad. Sci. 76: 2881-2885, 1979.">Gabbay et al. (1979)</a>; <a href="#Gabbay1976" class="mim-tip-reference" title="Gabbay, K. H., DeLuca, K., Fisher, J. N., Jr., Mako, M. E., Rubenstein, A. H. <strong>Familial hyperproinsulinemia: an autosomal dominant defect.</strong> New Eng. J. Med. 294: 911-915, 1976.">Gabbay et
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al. (1976)</a>; <a href="#Haneda1986" class="mim-tip-reference" title="Haneda, M., Kobayashi, M., Maegawa, H., Shigeta, Y. <strong>Low frequency of the large insertion in the human insulin gene in Japanese.</strong> Diabetes 35: 115-118, 1986.">Haneda et al. (1986)</a>; <a href="#Jaquet2000" class="mim-tip-reference" title="Jaquet, D., Gaboriau, A., Czernichow, P., Levy-Marchal, C. <strong>Insulin resistance early in adulthood in subjects born with intrauterine growth retardation.</strong> J. Clin. Endocr. Metab. 85: 1401-1406, 2000.">Jaquet et al. (2000)</a>; <a href="#Kanazawa1978" class="mim-tip-reference" title="Kanazawa, Y., Hayashi, M., Ikeuchi, M., Hiramatsu, K., Kosaka, K. <strong>Familial proinsulinemia: a possible cause of abnormal glucose tolerance. (Abstract)</strong> Europ. J. Clin. Invest. 8: 327, 1978.">Kanazawa et
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al. (1978)</a>; <a href="#Kwok1983" class="mim-tip-reference" title="Kwok, S. C. M., Steiner, D. F., Rubenstein, A. H., Tager, H. S. <strong>Identification of a point mutation in the human insulin gene giving rise to a structurally abnormal insulin (insulin Chicago).</strong> Diabetes 32: 872-875, 1983.">Kwok et al. (1983)</a>; <a href="#Owerbach1980" class="mim-tip-reference" title="Owerbach, D., Bell, G. I., Rutter, W. J., Shows, T. B. <strong>The insulin gene is located on chromosome 11 in human.</strong> Nature 286: 82-84, 1980.">Owerbach et al. (1980)</a>; <a href="#Robbins1984" class="mim-tip-reference" title="Robbins, D. C., Tager, H. S., Rubenstein, A. H. <strong>Biologic and clinical importance of proinsulin.</strong> New Eng. J. Med. 310: 1165-1175, 1984.">Robbins et
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al. (1984)</a>; <a href="#Rubenstein1983" class="mim-tip-reference" title="Rubenstein, A. H. <strong>Personal Communication.</strong> Chicago, Ill. 6/17/1983.">Rubenstein (1983)</a>; <a href="#Shoelson1983" class="mim-tip-reference" title="Shoelson, S., Haneda, M., Blix, P., Nanjo, A., Sanke, T., Inouye, K., Steiner, D., Rubenstein, A., Tager, H. <strong>Three mutant insulins in man.</strong> Nature 302: 540-543, 1983.">Shoelson et al. (1983)</a>; <a href="#Steiner1985" class="mim-tip-reference" title="Steiner, D. F., Chan, S. J., Welsh, J. M., Kwok, S. C. M. <strong>Structure and evolution of the insulin gene.</strong> Annu. Rev. Genet. 19: 463-484, 1985.">Steiner et al.
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(1985)</a>; <a href="#Steiner1976" class="mim-tip-reference" title="Steiner, D. F. <strong>Errors in insulin biosynthesis. (Editorial)</strong> New Eng. J. Med. 294: 952-953, 1976.">Steiner (1976)</a>; <a href="#Sures1980" class="mim-tip-reference" title="Sures, I., Goeddel, D. V., Gray, A., Ullrich, A. <strong>Nucleotide sequences of human preproinsulin complementation DNA.</strong> Science 208: 57-59, 1980.">Sures et al. (1980)</a>; <a href="#Vinik1986" class="mim-tip-reference" title="Vinik, A. I., Seino, S., Funakoshi, A., Schwartz, J., Matsumoto, M., Schteingart, D. E., Fu, Z.-Z., Tsai, S.-T. <strong>Familial hyperinsulinemia associated with secretion of an abnormal insulin, and coexistence of insulin resistance in the propositus.</strong> J. Clin. Endocr. Metab. 62: 645-652, 1986.">Vinik et al. (1986)</a>
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Abney, M., Ober, C., McPeek, M. S.
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<strong>Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites.</strong>
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Am. J. Hum. Genet. 70: 920-934, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11880950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11880950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11880950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11880950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/339705" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.34.8.821" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0230450100" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/db06-1698" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.76.6.2881" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM197604222941701" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198001173020301" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198409063111003" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.80.20.6366" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.35.1.115" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1056/NEJM198405173102004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.78.7.4458" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.90.2.582" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.12.8093" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI1842" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.2337/diab.32.9.872" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem.86.8.7733" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jcem-62-4-645" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/313101a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/BF00284580" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI115795" target="_blank">Full Text</a>]
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Yoshioka, M., Kayo, T., Ikeda, T., Koizumi, A.
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<strong>A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice.</strong>
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[<a href="https://doi.org/10.2337/diab.46.5.887" target="_blank">Full Text</a>]
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Marla J. F. O'Neill - updated : 11/14/2016
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Ada Hamosh - updated : 5/16/2013<br>George E. Tiller - updated : 10/27/2010<br>Patricia A. Hartz - updated : 10/27/2010<br>Marla J. F. O'Neill - updated : 4/19/2010<br>Carol A. Bocchini - updated : 2/16/2009<br>Patricia A. Hartz - updated : 12/10/2008<br>John A. Phillips, III - updated : 3/24/2008<br>John A. Phillips, III - updated : 10/2/2007<br>John A. Phillips, III - updated : 7/18/2007<br>Paul J. Converse - updated : 1/22/2007<br>George E. Tiller - updated : 10/9/2006<br>John A. Phillips, III - updated : 8/22/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Alan F. Scott - updated : 6/21/2004<br>Cassandra L. Kniffin - updated : 3/30/2004<br>Ada Hamosh - updated : 7/24/2003<br>John A. Phillips, III - updated : 6/27/2002<br>Victor A. McKusick - updated : 4/12/2002<br>John A. Phillips, III - updated : 3/6/2002<br>John A. Phillips, III - updated : 2/18/2002<br>Victor A. McKusick - updated : 9/25/2001<br>Ada Hamosh - updated : 8/27/2001<br>Ada Hamosh - updated : 12/15/2000<br>Victor A. McKusick - updated : 11/27/2000<br>John A. Phillips, III - updated : 11/16/2000<br>George E. Tiller - updated : 4/25/2000<br>Victor A. McKusick - updated : 3/3/1999<br>Victor A. McKusick - updated : 8/26/1998<br>John A. Phillips, III - updated : 5/29/1997<br>John A. Phillips, III - updated : 4/16/1996
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Victor A. McKusick : 6/23/1986
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carol : 07/28/2023<br>alopez : 07/27/2023<br>alopez : 12/01/2020<br>carol : 09/05/2020<br>carol : 09/03/2020<br>alopez : 04/30/2020<br>alopez : 11/14/2016<br>carol : 10/14/2016<br>carol : 02/05/2015<br>alopez : 5/16/2013<br>terry : 5/27/2011<br>carol : 10/29/2010<br>wwang : 10/27/2010<br>wwang : 10/27/2010<br>alopez : 4/21/2010<br>alopez : 4/20/2010<br>alopez : 4/20/2010<br>terry : 4/19/2010<br>carol : 2/16/2009<br>terry : 2/9/2009<br>mgross : 12/10/2008<br>carol : 7/21/2008<br>carol : 7/18/2008<br>carol : 3/24/2008<br>alopez : 10/2/2007<br>alopez : 7/18/2007<br>mgross : 1/22/2007<br>alopez : 10/9/2006<br>alopez : 10/9/2006<br>alopez : 8/22/2006<br>mgross : 8/9/2006<br>wwang : 5/4/2006<br>wwang : 4/27/2006<br>terry : 3/16/2005<br>carol : 6/21/2004<br>tkritzer : 3/31/2004<br>ckniffin : 3/30/2004<br>mgross : 3/17/2004<br>carol : 7/24/2003<br>carol : 7/24/2003<br>terry : 7/24/2003<br>alopez : 6/27/2002<br>terry : 6/26/2002<br>alopez : 5/10/2002<br>alopez : 4/15/2002<br>terry : 4/12/2002<br>alopez : 3/6/2002<br>alopez : 2/18/2002<br>carol : 1/4/2002<br>carol : 9/27/2001<br>terry : 9/25/2001<br>alopez : 8/30/2001<br>terry : 8/27/2001<br>alopez : 5/9/2001<br>mgross : 12/15/2000<br>mgross : 11/27/2000<br>mgross : 11/27/2000<br>terry : 11/16/2000<br>alopez : 4/25/2000<br>carol : 3/5/1999<br>terry : 3/3/1999<br>carol : 8/26/1998<br>terry : 8/26/1998<br>terry : 8/3/1998<br>terry : 5/29/1998<br>joanna : 5/6/1998<br>jenny : 6/5/1997<br>jenny : 5/29/1997<br>mark : 9/4/1996<br>joanna : 4/19/1996<br>joanna : 4/19/1996<br>joanna : 4/19/1996<br>joanna : 4/16/1996<br>davew : 8/5/1994<br>jason : 7/1/1994<br>terry : 5/5/1994<br>mimadm : 4/18/1994<br>warfield : 4/14/1994<br>carol : 3/10/1994
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 176730
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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INSULIN; INS
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</span>
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</h3>
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</div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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PROINSULIN
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</span>
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</h4>
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</div>
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<br />
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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INS-IGF2 SPLICED READ-THROUGH TRANSCRIPTS, INCLUDED
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</span>
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</div>
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<span class="h4 mim-font">
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INSIGF, INCLUDED
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: INS</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> 237613005, 609577006;
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</span>
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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: 11p15.5
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:2,159,779-2,161,209 </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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<br />
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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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</thead>
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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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11p15.5
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<span class="mim-font">
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Diabetes mellitus, insulin-dependent, 2
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</td>
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<td>
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<span class="mim-font">
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125852
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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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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Diabetes mellitus, permanent neonatal 4
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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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618858
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; 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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<tr>
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<td>
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<span class="mim-font">
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Hyperproinsulinemia
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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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616214
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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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Maturity-onset diabetes of the young, type 10
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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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613370
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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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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Insulin, synthesized by the beta cells of the islets of Langerhans, consists of 2 dissimilar polypeptide chains, A and B, which are linked by 2 disulfide bonds. However, unlike many other proteins, e.g., hemoglobin, made up of structurally distinct subunits, insulin is under the control of a single genetic locus; chains A and B are derived from a 1-chain precursor, proinsulin, which was discovered by Steiner and Oyer (1967). Proinsulin is converted to insulin by the enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the C (for 'connecting') peptide. </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>The human insulin gene contains 3 exons; exon 2 encodes the signal peptide, the B chain, and part of the C-peptide, while exon 3 encodes the remainder of the C-peptide and the A chain (Steiner and Oyer, 1967). </p><p>The rat, mouse, and at least 3 fish species have 2 insulin genes (Lomedico et al., 1979). The single human insulin gene corresponds to rat gene II; each has 2 introns at corresponding positions. Deltour et al. (1993) showed that in the mouse embryo the 2 proinsulin genes are regulated independently, at least in part. The existence of a single insulin gene in man is supported by the findings in patients with mutations. The greatest variation among species is in the C-peptide. Receptor binding parts have been highly conserved. Some of these sites are involved with insulin-like activity, some with growth-factor activity, and some with both. </p><p><strong><em>INS-IGF2 Spliced Read-Through Transcripts</em></strong></p><p>
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By EST database analysis and RT-PCR, Monk et al. (2006) identified 2 read-through transcripts, which they called the INSIGF long and short isoforms, that contain exons from both the INS gene and the downstream IGF2 gene (147470). The INSIGF short isoform contains INS exons 1 and 2 fused to IGF2 exons 2, 3, and 4. The deduced 200-amino acid INSIGF protein has an N terminus that includes the insulin leader sequence and B-chain peptide followed by a unique C terminus. The INSIGF long isoform has INS exons 1 and 2 fused to IGF2 exons 2, 3, 7, 8, and 9. This transcript is predicted to be bicistronic and contain reading frames for both INSIGF and IGF2. Sequence alignment between the human and mouse Insigf genomic regions suggested that mouse may expresses Insigf, but the expressed protein is predicted to differ substantially from human INSIGF in its C terminus. </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>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>Harper et al. (1981) and Harper and Saunders (1981) assigned the insulin gene to chromosome 11p15.5 by in situ hybridization. They used 10% dextran sulfate to enhance labeling. </p><p>Lebo et al. (1981) studied the linkage between 2 restriction polymorphisms, the HpaI polymorphism on the 3-prime side of the beta-globin gene (HBB; 141900) and the SacI polymorphism on the 5-prime side of the insulin gene. They found 4 recombinants in 34 meioses (12%), giving 90% confidence limits for the interval as 6-22 cM. Given that the HBB globin gene is on 11p12 and the insulin gene on 11p15, that chromosome 11 represents about 4.8% of the genetic length of the genome, and that the total genetic length is 3,000 cM, then one would expect an interval of 29-42 cM. Lebo et al. (1982) determined the regional location of the insulin gene by restriction endonuclease analysis of DNA isolated from metaphase chromosomes, sorted according to relative Hoechst fluorescence intensity by the fluorescence activated chromosome sorter. They showed that the 2 restriction fragments represent insulin gene polymorphism and not duplicate gene loci such as those found in 2 rodent and 2 fish species. </p><p>By deletion mapping, Huerre et al. (1984) assigned the insulin gene to 11p15.5-p15.1. By in situ hybridization of meiotic pachytene bivalents, Chaganti et al. (1985) arrived at the following localizations: PTH, 11p11.21; HBB, 11p11.22; HRAS, 11p14.1; INS, 11p14.1. Meyers et al. (1986) concluded that the Utah database (White et al., 1985) provides greater support for the conclusion that the HRAS1 locus (190020) is distal to the INS locus. The beta-hemoglobin cluster is about 10 cM centromeric from this pair of loci; INS and HRAS1 are separated by about 2 to 4 cM. Lichter et al. (1990) presented a method for high resolution fluorescence in situ hybridization. By hybridizing 3 or more cosmids simultaneously, gene order on the chromosome could be established unequivocally. The map coordinates established by in situ hybridization studies of chromosome 11 showed a 1-to-1 correspondence with those determined by Southern blot analysis of hybrid cell lines containing fragments of chromosome 11. </p><p>The rat insulin I and II genes are on chromosome 1 about 100,000 kb apart. In the mouse, they lie on different chromosomes, no. 6 and no. 7; the mouse Hbb gene is also on chromosome 7. The insulin gene duplication-transposition obviously preceded separation of rat and mouse in the evolutionary process. The preproinsulin gene I in rat and mouse has lost 1 of the 2 introns present in gene II, is flanked by a long (41-base) direct repeat, and has a remnant of a polydeoxyadenylate acid tract preceding the downstream direct repeat. These structural features suggested to Soares et al. (1985) that gene I is a functional transposon, i.e., was generated by an RNA-mediated duplication-transposition event involving a transcript of gene II that was initiated upstream from the normal capping site. Gene I has a single intron. Todd et al. (1985) found that in the rat, the parathyroid hormone and calcitonin genes are, like the insulin genes I and II, on chromosome 1. Jones et al. (1992) localized Ins2, one of the 2 insulin genes of the mouse, to a specific region of chromosome 7 within a human-mouse conserved linkage group. They also demonstrated that the obesity mutant tubby (tub) is a locus distinct from Ins2. The tub gene was found to lie 2.4 cM from the Hbb gene. Jones et al. (1992) suggested that the human homolog of 'tubby' resides in 11p15 and that the HBB locus in the human could be used as a linkage marker for studies of familial obesity in humans. Contradictory mapping results were obtained by Davies et al. (1994). Experiments using 3 different PCR primer pairs in 2 independent interspecific murine crosses conclusively localized the murine Ins1 gene to distal chromosome 19. They raised the question of chromosomal rearrangements having occurred in the cell lines used in the previous chromosomal assignments to mouse chromosome 6 through RFLP analysis of mouse/hamster somatic cell hybrids. They suggested that the use of polymorphisms detectable between murine strains or between various mouse species for genetic linkage analysis remains a more reliable method for determining the chromosomal location of genes. </p><p><strong><em>Fasting Insulin Level Quantitative Trait Loci</em></strong></p><p>
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With a genome screen for genetic control of fasting insulin level in the Hutterites, Abney et al. (2002) illustrated methods for linkage and association mapping of quantitative traits in a founder population with a large, known genealogy. They detected linkage to quantitative-trait loci (QTLs) through a multipoint homozygosity-mapping method. They proposed 2 association methods, one of which is multipoint and uses homozygosity by descent for a particular allele. Applied to fasting insulin level, the methods found significant linkage on chromosome 19 and suggestive evidence of QTLs on chromosomes 1 and 16. </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>Dandona et al. (2001) infused insulin intravenously into obese subjects to investigate the potential antiinflammatory effects of insulin. NF-kappa-B (NFKB; see 164011) in mononuclear cells fell at 2 hours and further at 4 hours, reverting toward the baseline at 6 hours. IKB (see 164008) increased significantly at 2 hours, increasing further at 4 hours and remaining elevated at 6 hours. Reactive oxygen species generation by mononuclear cells fell significantly at 2 hours and fell further at 4 hours. The authors concluded that insulin has a potent acute antiinflammatory effect, including a reduction in intranuclear NFKB, an increase in IKB, and decreases in the generation of reactive oxygen species. </p><p>In rats, Obici et al. (2002) found that infusion of insulin into the third cerebral ventricle, with access to the hypothalamus, suppressed glucose production independent of circulating levels of insulin or of other glucoregulatory hormones, whereas central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. The findings indicated that the hypothalamus is a site of insulin action in the regulation of glucose production. </p><p>Monk et al. (2006) found that the INSIGF read-through transcript were monoallelically/parentally expressed in adult and fetal eye and limb, but pancreas showed biallelic expression. </p><p>Frosig et al. (2007) studied insulin-related responses in 8 healthy men who performed 3 weeks of 1-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was about 60% higher in trained compared with untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies obtained before and after training as well as after 10 and 20 minutes of insulin stimulation showed increased protein content of AKT1 (164730)/AKT2 (164731), AS160 (TBC1D4; 612465), GLUT4 (SLC2A4; 138190), HK2 (601125), and LNPEP (151300) in response to training. Training improved insulin action on thigh blood flow, and in both basal and insulin-stimulated muscle tissue, activities of AKT1 and GYS1 (138570) and phosphorylation of AS160 increased with training. In contrast, training reduced IRS1 (147545)-associated PI3K (see 601232) activity in both basal and insulin-stimulated muscle tissue. Frosig et al. (2007) concluded that improved insulin-stimulated glucose uptake after endurance training results from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism. </p><p><strong><em>Gene-Environment Interaction</em></strong></p><p>
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Prenatal famine in humans has been associated with various consequences in later life, depending on the gestational timing of the insult and the sex of the exposed individual. Epigenetic mechanisms have been proposed to underlie these associations. Tobi et al. (2009) investigated the methylation of 15 loci implicated in growth and metabolic disease in individuals who were prenatally exposed to war-time famine in the Netherlands from 1944 to 1945. Methylation of INSIGF, the alternately spliced read-through transcript of INS and IGF2 (147470), was lower among 60 individuals who were periconceptionally exposed to the famine compared to 60 of their unexposed same-sex sibs, whereas methylation of IL10 (124092), LEP (164160), ABCA1 (600046), GNASAS (610540) and MEG3 (605636) was higher than control. A significant interaction with sex was observed for INSIGF, LEP, and GNASAS. When methylation of 8 representative loci was compared between 62 individuals exposed late in gestation and 62 of their unexposed sibs, methylation was different for GNASAS in both men and women, and LEP methylation was different in men only. Tobi et al. (2009) concluded that persistent changes in DNA methylation may be a common consequence of prenatal famine exposure, and that these changes may depend on the sex of the exposed individual and the gestational timing of the exposure. </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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Menting et al. (2013) presented a view of the interaction of insulin with its primary binding site on the insulin receptor (INSR; 147670) 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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<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><strong><em>Hyperproinsulinemia</em></strong></p><p>
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In a patient with hyperproinsulinemia (616214), originally reported by Tager et al. (1979), Shoelson et al. (1983) identified a heterozygous change of leucine to phenylalanine at position 25 of the insulin B chain (176730.0001). In another patient with hyperproinsulinemia, they identified a heterozygous change of leucine to phenylalanine at position 24 of the insulin B chain (176730.0002). </p><p>In affected members of a family segregating hyperproinsulinemia, originally reported by Gruppuso et al. (1984), Chan et al. (1987) identified a heterozygous C-to-G transversion in the INS gene, predicting a change of histidine to aspartic acid at position 10 of the insulin B chain (176730.0003). </p><p>In a patient with hyperproinsulinemia, previously reported by Shoelson et al. (1983), Nanjo et al. (1986) identified heterozygosity for a G-to-T transversion in the INS gene, predicting a val3-to-leu substitution in the insulin A chain (176730.0005). </p><p><strong><em>Permanent Neonatal Diabetes Mellitus 4</em></strong></p><p>
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In affected members of a 3-generation family in which permanent neonatal diabetes mellitus (PNDM4; 618858) segregated in an autosomal dominant fashion, who were negative for mutations in the KCNJ11 (600937) and ABCC8 (600509) genes, Stoy et al. (2007) identified heterozygosity for a missense mutation in the INS gene (176730.0008). The authors then sequenced the INS gene in 83 probands with PNDM without a known genetic cause and identified 9 additional heterozygous missense mutations in the INS gene in 15 families (see, e.g., 176730.0009-176730.0013), including a patient with the same mutation (C96Y; 176730.0011) found in the Akita mouse. The mutations were in critical regions of the preproinsulin molecule and were predicted to prevent normal folding and progression of proinsulin in the insulin secretory pathway. The authors suggested that the abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially beta-cell death by apoptosis, as has been described in both the Akita and Munich mouse models. </p><p>Edghill et al. (2008) screened the INS gene in a series of 1,044 patients with permanent diabetes diagnosed during infancy, childhood, and adulthood and also in 49 patients with hyperinsulinism. The authors identified heterozygous INS mutations in 33 (23%) of 141 probands diagnosed at less than 6 months of age, in 2 (2%) of 86 probands diagnosed between 6 and 12 months of age, and in none of 58 probands diagnosed between 12 and 24 months of age. Twelve of the mutation-positive PNDM probands had been previously reported by Stoy et al., 2007. Only 1 (0.3%) of 296 probands with maturity-onset diabetes of the young (see MODY10, 613370) had a mutation in the INS gene (R6C; 176730.0014); and 1 (0.2%) of 463 young type 2 diabetics (see 125853) had a possible mutation identified. No mutations were found in the patients with hyperinsulinism. Three mutations, A24D (176730.0012), F48C (176730.0013), and R89C (176730.0010), accounted for 46% of PNDM cases. </p><p>In 9 probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (600937), Colombo et al. (2008) identified heterozygosity for 7 different mutations in the INS gene (see, e.g., 176730.0010) that were not found in 200 Italian patients with normal glucose tolerance. Expression of the mutant proinsulins in HEK293 cells revealed defects in insulin protein folding and secretion; there was also increased expression of HSPA5 (138120) protein and XBP1 (194355) mRNA splicing, 2 markers of endoplasmic reticulum stress, and increased apoptosis. Transfected INS-1E insulinoma cells had diminished viability compared with those expressing wildtype proinsulin. The authors noted that all mutations found in patients with PNDM or infancy-onset diabetes were different from those previously associated with familial hyperinsulinemia or hyperproinsulinemia. </p><p>Polak et al. (2008) analyzed the INS gene in 39 patients with PNDM who were negative for mutations in the GCK, KCNJ11, and ABCC8 genes, and identified heterozygosity for 3 different missense mutations in 4 probands (see 176730.0010-176730.0012). The authors also sequenced the INS gene in 11 patients with transient neonatal diabetes (see 601410) in whom chromosome 6 anomalies had been excluded, but found no mutations. </p><p>In a male infant with PNDM, born to first-cousin Southeast Asian parents, who was negative for mutation in 36 known monogenic diabetes-associated genes, Carmody et al. (2015) identified homozygosity for a deep intronic INS variant (176730.0017). Noting that 20 to 30% of neonatal monogenic diabetes cases have no known etiology, the authors suggested that mutations within deep noncoding regions might be the cause. </p><p><strong><em>Maturity-Onset Diabetes of the Young/Type 1 Diabetes Mellitus</em></strong></p><p>
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Edghill et al. (2008) found that 1 of 296 probands with maturity-onset diabetes of the young (see MODY10, 613370) had a mutation in the INS gene (R6C; 176730.0014). </p><p>Molven et al. (2008) screened the INS gene in 62 probands with MODY and 30 probands with suspected MODY from the Norwegian MODY Registry, and 223 patients from the Norwegian Childhood Diabetes Registry who were autoantibody negative or had a family history of diabetes, and identified heterozygosity for 2 different missense mutations, R46Q (176730.0015) in a 3-generation family with MODY (MODY10; 613370) and R55C (176730.0016) in a mother and daughter with type 1 diabetes (T1D2; 125852). </p><p><strong><em>INS VNTR</em></strong></p><p>
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Bell et al. (1980) sequenced the human insulin gene and found evidence for allelic variation in the 5-prime untranslated region. </p><p>Rotwein et al. (1981), as well as other groups, have found a polymorphism, in the form of an insertion of 1.5 to 3.4 kb pairs, in the 5-prime flanking region of the insulin gene. These insertions occur within 1.3 kb pairs of the transcription initiation site. In contrast, no insertions were found in the region 3-prime to the coding sequence. The frequency of insertions was 66% in those with type II diabetes (125853) and 29% in all others including nondiabetics and type I diabetics (P less than 0.001). Other studies suggested that DNA sequences several hundred bases 5-prime to the mRNA transcription initiation site may modulate RNA polymerase binding and initiation of transcription. Rotwein et al. (1986) analyzed the nature of the hypervariable region 5-prime to the insulin gene. The association of certain 'alleles' in this region with noninsulin-dependent diabetes mellitus has been both claimed and refuted, and an association with atherosclerosis and with hypertriglyceridemia has also been reported. In different ethnic groups, Williams et al. (1985) found marked variability in insulin gene-related DNA polymorphisms. </p><p>The structure of the 5-prime insulin minisatellite (147510) alleles is based on 11 variant repeats of a 14-bp consensus motif (ACAGGGGTGTGGGG). Among Caucasians, these minisatellite alleles have been typed as class I (small, with 28-44 repeats, frequency approximately 70%), class II (intermediate, rare), and class III (large, with 138-159 repeats, frequency approximately 30%). The obvious bimodal size distribution in Caucasians suggests a lower mutation rate and possibly different mutational processes compared with highly unstable minisatellites at other loci. Stead and Jeffreys (2000) used minisatellite variant repeat mapping by PCR (MVR-PCR) to study mutation at the insulin minisatellite both indirectly from allele diversity surveys and directly by recovering de novo mutants from sperm DNA. From 438 individuals, structural analysis of variant repeat distributions in 876 alleles identified 189 different alleles, almost all of which could be assigned to 1 of 3 very distinct lineages. Within lineages, gain or loss of a few repeat units probably arose by mitotic replication slippage at a frequency of perhaps 10(-3) per gamete. Sperm DNA analysis from 3 Caucasian donors revealed a second class of mutation occurring at a frequency of approximately 2 x 10(-5) that involved highly complex intra- and interallelic rearrangements very similar to those seen at unstable minisatellites in other loci. The authors suggested that these complex rearrangements, not seen in somatic DNA, may be meiotic in origin. The authors concluded that the insulin minisatellite appears to have evolved by 2 distinct processes: one involving slippage-like events in mitosis and the second resulting in complex recombinational turnover of allele structure. </p><p>Lebo et al. (1983) found a large number of DNA polymorphisms in the region of the insulin gene on 11p. Population genetic analysis indicated that to generate this large number of polymorphisms recombination occurred 33 times more frequently than expected. Specific properties of the unique 14- to 16-basepair sequences 5-prime to the insulin gene probably promote increased unequal recombination. A recombination rate of 14% was found between the insulin and beta-globin genes. </p><p>Mandrup-Poulsen et al. (1984) found that the allelic frequency of DNA restriction fragments of a large-size class (U alleles) in the polymorphic region flanking the 5-prime end of the insulin gene is 2.5 times higher in patients with extensive atherosclerosis than in subjects in whom atherosclerosis could not be demonstrated by coronary arteriography and careful clinical examination. The mechanism of the increased risk conferred by the U allele is unknown. </p><p>In the course of screening the insulin promoter from 40 American subjects with noninsulin-dependent diabetes mellitus (NIDDM), Olansky et al. (1992) found an apparently larger allele in 2. In both, the larger allele had an 8-bp repeat, TGGTCTAA, from positions -322 to -315 of the insulin promoter. Olansky et al. (1992) found that the 8-bp repeat was present in 5 of 100 American black NIDDM subjects and in 1 nondiabetic American black subject. Among Mauritius Creoles, also of African ancestry, they found the 8-bp repeat in 3 of 41 NIDDM subjects and in none of 41 nondiabetic subjects. Analysis of glucose metabolism in 3 presumed normal sibs of an NIDDM patient with an 8-bp repeat showed that 1 sib had overt diabetes and 2 sibs were glucose intolerant, but there was no consistent segregation of the insulin promoter variant with the diabetes phenotype. The variant promoter was not present in 35 Caucasian NIDDM patients or in 40 Pima Indians. Reduced activity of the variant form of the promoter was demonstrated by expression studies in cultured cells. </p><p>To determine which genetic factors predispose obese patients to pancreatic beta-cell dysfunction, and possibly to type II diabetes (125853), Le Stunff et al. (2000) studied single-nucleotide polymorphisms in the region of the INS gene in 615 obese children. They found that in the early phase of obesity, alleles of the INS VNTR locus were associated with different effects of body fatness on insulin secretion. Young obese patients homozygous for class I VNTR alleles secreted more insulin than those with other genotypes. </p><p>Using the -23Hph1 SNP in the INS gene as a surrogate marker for the INS VNTR, Le Stunff et al. (2000) showed that the -23A/A genotype correlated with impaired insulin secretion in response to body weight gain in subjects of European descent. Osawa et al. (2001) found a high frequency of the -23T-A change in Japanese. The allele frequency was 97.4% in Japanese subjects, whereas in Europeans it was about 30%. The A/A genotype was found in 94 of 99 Japanese subjects and Osawa et al. (2001) suggested that the high frequency could account for the fact that Japanese typically secrete lower levels of insulin than do Europeans. </p><p>Le Stunff et al. (2001) studied the parental transmission of alleles at the insulin locus to offspring with early-onset obesity in children of central European and north African descent. A VNTR polymorphism upstream of the insulin gene is associated with variations in the expression of INS and the nearby gene encoding insulin-like growth factor-2 (IGF2; 147470). The class I allele of this VNTR contains 26 to 63 repeats, while the class III allele contains 141 to 209 repeats. Le Stunff et al. (2001) found an excess of paternal transmission of class I VNTR alleles to obese children: children who inherited a class I allele from their father (but not those inheriting it from their mother) had a relative risk of early onset obesity of 1.8. Due to the frequency of class I alleles in this population, this risk concerns 65 to 70% of all infants. Le Stunff et al. (2001) concluded that increased in utero expression of paternal INS or IGF2 due to the class I INS VNTR allele may predispose offspring to postnatal fat deposition. </p><p>Chromosomes carrying the protective long INS VNTR alleles (class III) produce higher levels of thymic INS mRNA than those with the predisposing, short class I alleles. However, complete silencing of thymic INS transcripts from the class III chromosome was found in a small proportion of heterozygous human thymus samples (Vafiadis et al., 1997; Pugliese et al., 1997). Vafiadis et al. (2001) hypothesized that the specific class III alleles found on these chromosomes silence rather than enhance thymic insulin expression. To test the prediction that these alleles are predisposing, they developed a DNA fingerprinting method for detecting 2 putative 'silencing' alleles found in 2 thymus samples (S1, S2). In a set of 287 diabetic children and their parents they found 13 alleles matching the fingerprint of the S1 or S2 alleles. Of 18 possible transmissions, 12 of the S1-S2 alleles were transmitted to the diabetic offspring, a frequency of 0.67, significantly higher than the 0.38 seen in the remaining 142 class III alleles (P = 0.025). Vafiadis et al. (2001) concluded that this result confirmed their prediction and represented an additional level of correlation between thymic insulin and diabetes susceptibility. </p><p>Low birth weight associations with hyperinsulinemia and other adulthood disease risk factors have been described in several cohorts, including girls who present with precocious pubarche (pubic hair at less than 8 years). Ibanez et al. (2001) hypothesized that these associations might be influenced by the INS gene VNTR, a common polymorphism related to INS transcription levels. DNA was genotyped for INS VNTR allele class (I or III) in precocious pubarche girls and in 140 age- and body mass index-matched control girls. INS VNTR genotype distribution was similar in precocious pubarche and control girls. However, among precocious pubarche girls, INS VNTR genotype was related to the severity of phenotype; I/I and I/III genotypes had lower birth weights (P less than 0.01), higher mean serum insulin (MSI; P less than 0.005), and lower insulin sensitivity (P less than 0.005) than III/III girls. In precocious pubarche girls, birth weight was also inversely related to MSI, total cholesterol, and low density lipoprotein cholesterol. Using logistic regression, additive adverse effects of I/* genotype and low birth weight were seen on MSI and total cholesterol levels. The authors concluded that in girls who presented with precocious pubarche, hyperinsulinemia and dyslipidemia were related to both low birth weight and INS VNTR class I alleles. </p><p>Rodriguez et al. (2004) haplotyped 2,743 adult males at the IGF2-INS-TH (191290) region and related haplotypes to body weight and composition, blood pressure, and plasma triglycerides. Haplotype *5 protected against obesity; haplotype *6 was associated with raised plasma triglyceride levels. Haplotype *4, defined by the IGF2 ApaI(G), INS class III VNTR, and TH01 9.3 alleles, was associated with significantly higher fat mass and percentage fat, and with significantly higher diastolic blood pressure. Haplotype *8 showed similar magnitude of effects as *4. Haplotypes *4, *6, and *8 were the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displayed unique features in all 3 genes. The authors proposed that the long repeat insertion in the insulin gene promoter ('class III'), reported to result in low insulin production, may predispose to the metabolic syndrome features of elevated blood pressure, fat mass, or triglyceride level, therefore appearing more frequently in type 2 diabetic (125853), polycystic ovary syndrome (see 184700), and coronary heart disease cases. </p><p>Using the -23Hph1 A/T SNP, Meigs et al. (2005) assessed variation in the INS VNTR minisatellite as a risk factor for 92 cases of incident type 2 diabetes in 883 unrelated Framingham Heart Study (FHS) subjects and in a separate sample of 698 members of 282 FHS nuclear families with 62 diabetes cases. In the unrelated sample, the -23Hph1 TT genotype frequency was 8.0% and was associated with a diabetes hazard ratio of 1.89 (95% CI, 1.01-3.52; P = 0.045) compared with the AA genotype using diabetes age of onset as the time failure variable in a proportional hazards model adjusted for age, offspring sex, body mass index, parental diabetes, and sex by parental diabetes interactions. In sex-stratified analyses, TT increased risk for diabetes in women, but not men. Using a family-based association test to assess transmission disequilibrium in the sample of related subjects, the age- and sex-adjusted z-score for diabetes associated with the T allele was 2.07 (P = 0.04), and a family-based association test using age of onset in a proportional hazards model was also statistically significant (P = 0.03), indicating that increased risk of diabetes was not attributable to population admixture. The authors concluded that these data support the hypothesis that the INS VNTR is a genetic risk factor for type 2 diabetes, with the TT genotype accounting for about 6.6% of cases in the FHS population. </p><p>Using flow cytometry and RT-PCR, Narendran et al. (2006) identified one of the self-antigens expressed by blood myeloid cells as a proinsulin splice variant. Expression of the immunoreactive proinsulin variant was decreased by small interfering RNA. Genotyping revealed that abundance of the proinsulin splice variant in blood cells corresponded with the length of the VNTRs 5-prime of the proinsulin gene. Narendran et al. (2006) proposed that self-antigen expression by peripheral myeloid cells, by analogy with thymus, may be implicated in peripheral immune tolerance. </p><p>Heude et al. (2006) reported INS VNTR associations with body composition and insulin secretion in children. Homozygous III/III children had higher BMI (P = 0.020), fat mass index (FMI) (P = 0.015), and truncal FMI (P = 0.022) at 9 years than class I bearers, but no difference in fat-free mass (P = 0.23). They clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population related to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. Heude et al. (2006) concluded that this genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity. </p><p>Santoro et al. (2006) screened for the INS VNTR in 320 obese children. The prevalence of metabolic syndrome reached 39%. No differences in INS VNTR genotype distribution were observed between obese subjects and 200 lean, age- and sex-matched children (P = 0.7). Among obese subjects, the prevalence of the metabolic syndrome was significantly higher in subjects with the I/I genotype (P = 0.006); the risk for developing the metabolic syndrome was significantly higher in subjects carrying the I/I genotype (odds ratio, 2.5; 95% confidence interval, 1.5-3.9). Obese subjects homozygous for the class I allele showed higher insulin levels and insulinogenic index but lower whole-body insulin sensitivity. Santoro et al. (2006) concluded that the I variant of the insulin promoter, when expressed in homozygotes, can predispose obese children to develop the metabolic syndrome. </p><p>Awata et al. (2007) studied the association between INS/IDDM2 and type 1 diabetes in Japanese. In total, 661 patients with type 1 diabetes and 706 control subjects were studied. The INS variable number of tandem repeat (VNTR) class I/class III status was estimated by genotyping the -23 HphI SNP. The frequency of the class I allele was 99.3% in patients and 96.7% in controls (p less than 10(-5)), and the class I/III or III/III genotype was found in 1.4% of patients and in 6.4% of controls (OR = 0.20, p less than 10(-5)). The class I subdivision revealed IC to increase significantly in patients with type 1 diabetes (P = 0.002), whereas ID did not; the distribution of IC and ID was significantly different between patients and controls (P = 0.014). Awata et al. (2007) concluded that the IDDM2 region is also a susceptibility locus in the Japanese population. Furthermore, IC may be more susceptible to type I diabetes than ID, which could be evidence that the INS VNTR itself confers susceptibility to type 1 diabetes. </p><p><strong><em>Other Variation</em></strong></p><p>
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Ullrich et al. (1980) studied 4 recombinant lambda phages containing nucleotide sequences complementary to a cloned human preproinsulin DNA probe. Restriction analyses in conjunction with Southern blots showed 2 types of sequences which are presumably allelic. The sequences studied contained the entire preproinsulin messenger RNA region, 2 intervening sequences, 260 nucleotides upstream from the mRNA capping site, and 35 nucleotides beyond the polyadenylate attachment site. The 2 allelic genes were referred to as alpha and beta. Complete sequencing by the Maxam-Gilbert method showed differences at 4 positions: nucleotide 216 in IVS1, nucleotide 1045 in IVS2, and nucleotides 1367 and 1380 in the 3-prime untranslated region. </p><p>Seino et al. (1985) found 2 more examples of variant insulin. By HPLC, in neither case was any normal insulin found in the plasma. This is consistent with repression of the normal allele and may account for diabetes in these patients. </p><p><strong><em>Reviews</em></strong></p><p>
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Selden et al. (1987) reviewed the regulation of expression of the insulin gene and its relevance to gene therapy of type I diabetes. Vinik and Bell (1988) reviewed mutant insulin syndromes. </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>By in situ hybridization, Michalova et al. (1988) demonstrated that the insulin gene was inserted in a different chromosome in each of 3 transgenic mouse lines--chromosomes 7, 13, and 18. In each case the insert appeared to be unique, although several copies of the human DNA fragment were arranged in head-to-tail arrays in each line. The insert was transmitted to progeny as a single genetic locus. </p><p>Most of the monogenic diabetic syndromes in rodent models, such as ob, db, agouti, tubby, and fat mice, have accompanying obesity. The responsible genes are involved in the regulation of body weight, and their alterations result in increased insulin resistance in peripheral tissues, except in 'fat' mice. Yoshioka et al. (1997) established a monogenic model that they called the Akita mouse. This model does not have associated obesity or insulitis, but is accompanied by a notable pancreatic beta-cell dysfunction. Diabetes in this mouse resembles that of human MODY in terms of early onset, an autosomal dominant mode of inheritance, and primary dysfunction of the beta cells. The mouse locus was named Mody and was shown to be located on the distal end of chromosome 7 by linkage analysis (Kayo and Koizumi, 1998). Wang et al. (1999) demonstrated that the Mody mouse has a missense mutation of the insulin-2 gene (Ins2), which lies in the same area as the Mody locus identified by genetic analysis on mouse chromosome 7 (the Ins1 gene is located on mouse chromosome 6). The mutation changed codon 96 from TGC (cys) to TAC (tyr). The mutation disrupts a disulfide bond between the A and B chains and was presumed to induce a drastic conformational change in the molecule. Although there was no gross defect in the transcription from the wildtype insulin-2 allele or the 2 alleles of insulin-1, levels of proinsulin and insulin were profoundly diminished in the beta cells of Mody mice, suggesting that the number of wildtype proinsulin molecules was also decreased. Electron microscopy showed a dramatic reduction of secretory granules and a remarkably enlarged lumen of the endoplasmic reticulum. Little proinsulin was processed to insulin, but high molecular weight forms of proinsulin existed with concomitant overexpression of BiP/Grp78 (138120), a molecular chaperone in the endoplasmic reticulum. Mutant cys96-to-tyr proinsulin expressed in Chinese hamster ovary cells was inefficiently secreted, and its intracellular fraction formed complexes with BiP and was eventually degraded. These findings indicated that mutant proinsulin was trapped and accumulated in the endoplasmic reticulum, which could induce beta-cell dysfunction and account for the dominant phenotype of this mutation. The phenotype of this mouse mutation is different from that of any human insulin mutation; insulin Chicago (176730.0001), however, was found in a family thought to have MODY. </p><p>Cheung et al. (2000) found that gut K cells could be induced to produce human insulin by providing the cells with the human insulin gene linked to the 5-prime regulatory region of the gene encoding glucose-dependent insulinotropic polypeptide (GIP; 137240). Mice expressing this transgene produced human insulin specifically in gut K cells. This insulin protected the mice from developing diabetes and maintained glucose tolerance after destruction of the native insulin-producing beta cells. </p><p>Farris et al. (2003) generated mice deficient in insulin-degrading enzyme (IDE; 146680) by targeted disruption. Ide deficiency resulted in a greater than 50% decrease in amyloid-beta degradation in both membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The Ide-null mice showed increased cerebral accumulation of endogenous amyloid-beta, a hallmark of Alzheimer disease (104300), and had hyperinsulinemia and glucose intolerance, hallmarks of type II diabetes. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which had recently been found to be degraded by IDE in vitro. Farris et al. (2003) concluded that, together with emerging genetic evidence, their in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of Alzheimer disease and type II diabetes and provide a mechanism for the recognized association among hyperinsulinemia, diabetes, and Alzheimer disease. </p><p>Ueki et al. (2006) created mice lacking both Insr (147670) and Igf1r (147370) 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>
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<strong>History</strong>
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<p>Robinson et al. (1994) reported the identification of an insulin control element-binding transcription factor, or insulin activator factor (INSAF), by screening a human pancreatic insulinoma cDNA library with a concatamerized insulin control element (ICE)-binding site oligonucleotide. They concluded that INSAF acts as positive regulator of ICE-mediated activity. However, by sequence analysis, Scott (2004) determined that the INSAF sequence does not represent a protein-coding gene. </p>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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<strong>17 Selected Examples):</strong>
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<span class="mim-font">
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<strong>.0001 HYPERPROINSULINEMIA</strong>
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INS, PHE25LEU
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SNP: rs148685531,
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gnomAD: rs148685531,
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ClinVar: RCV000014306
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<p>Tager et al. (1979) studied insulin isolated from the pancreas of a diabetic patient and concluded that one of the allelic genes had undergone a mutation resulting in substitution of leucine for phenylalanine at position 23 or 24 in the insulin B chain. Occurring in the invariant portion of the molecule, the mutation resulted in reduced biologic activity (Given et al., 1980). Kwok et al. (1981) isolated genomic DNA from the leukocytes of a diabetic patient with the mutant insulin identified by Given et al. (1980). After digestion with restriction endonuclease MboII, electrophoresis, and hybridization with cloned human cDNA probes, one MboII cleavage site had been lost, which is consistent with the postulated replacement of phenylalanine by leucine at position 24 of the insulin gene. Shoelson et al. (1983) demonstrated that the substitution in the mutant insulin identified by Tager et al. (1979) and Given et al. (1980) is leucine for phenylalanine at B25. They designated the variant 'insulin Chicago.' </p>
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 HYPERPROINSULINEMIA</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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INS, PHE24SER
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<br />
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SNP: rs80356668,
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ClinVar: RCV000014307
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with serum insulin consisting predominantly of an abnormal form that elutes before normal insulin as well as a small amount of normal insulin (616214), Shoelson et al. (1983) concluded that the insulin variant had a substitution of serine for phenylalanine at position 24 of the B chain. The authors designated the variant 'insulin Los Angeles.' </p><p>In a patient with mild diabetes, marked fasting hyperinsulinemia, and a reduced fasting C-peptide:insulin molar ratio, Haneda et al. (1983, 1984) found that one insulin gene had a point mutation at position 24 of the B chain resulting in substitution of serine for phenylalanine. The patient had abnormal circulating insulin molecules that could be distinguished from each other and from normal insulin. The patient responded normally to exogenous insulin. Five additional family members of both sexes in 3 generations were affected. </p><p>Hua et al. (1993) pointed out that among vertebrate insulins phe(B24) is invariant, and in crystal structures the aromatic ring appears to anchor the putative receptor-binding surface through long-range packing interactions in the hydrophobic core. In 1 analog, namely, gly(B24)-insulin, partial unfolding of the B chain has been observed with paradoxical retention of near-native bioactivity. Hua et al. (1993) demonstrated that, contrariwise, in ser(B24)-insulin, near-native structure is restored despite significant loss of function. To their knowledge, this was the first structural study of a diabetes-associated mutant insulin and the findings supported the hypothesis that insulin undergoes a change in conformation on receptor binding. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 HYPERPROINSULINEMIA</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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INS, HIS10ASP
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<br />
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SNP: rs121918101,
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gnomAD: rs121918101,
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ClinVar: RCV000014308
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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>Gruppuso et al. (1984) identified a hyperproinsulinemia kindred in which the proband, a 14-year-old girl with a history of transient hyperglycemia at age 2 years, was studied for symptoms of hypoglycemia. Elevated proinsulin was found in her and 2 sibs, the father and the paternal grandfather, whereas 4 other close relatives were normal. The variant was designated 'proinsulin Providence.' Based on a linkage study using several RFLPs, Elbein et al. (1985) reported that the defect in this family mapped at or near the insulin gene. Chan et al. (1987) cloned and sequenced both alleles of the insulin gene from 2 affected members of this family. They demonstrated a point mutation in the B chain coding region of the insulin gene. There was a single nucleotide substitution in the codon for residue 10: CAC was changed to GAC. The nucleotide change predicted substitution of aspartic acid for histidine. </p><p>Schwartz et al. (1987) synthesized an insulin analog with substitution of aspartic acid for histidine at position 10 of the B chain, the same alteration as that identified by Chan et al. (1987) in a naturally-occurring mutation. Schwartz et al. (1987) found that the insulin analog was superactive, probably as a result of stronger interaction with the insulin receptor. </p><p>Carroll et al. (1988) created a model of the familial hyperproinsulinemia resulting from the B10 his-to-asp mutation by introducing the gene into transgenic mice. A high level of mutant prohormone was expressed in their islets of Langerhans. Hyperproinsulinemia in the mice, and by implication in the patients, appeared to be the result of the continuous secretion of unprocessed mutant proenzyme from the islets via an alternative unregulated pathway. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 HYPERPROINSULINEMIA</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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INS, ARG65HIS
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<br />
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SNP: rs28933985,
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gnomAD: rs28933985,
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ClinVar: RCV000014310, RCV001091846, RCV003407328, RCV005042049
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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>Studying leukocyte DNA, Shibasaki et al. (1985) found a point mutation, substitution of adenine for guanine, in the insulin gene of a Japanese family with hyperproinsulinemia. This transition implies substitution of histidine for arginine at amino acid position 65 (R65H). Furthermore, it implies that arginine-65 is essential to proinsulin-insulin conversion. </p><p>Robbins et al. (1981, 1984) had earlier described an arginine-65 variant of proinsulin associated with hyperproinsulinemia; the amino acid substitution was not identified at that time. Barbetti et al. (1990) found the same mutation, CGT to CAT at codon 65, in 2 unrelated Caucasian families, one of which was the family reported by Robbins et al. (1981, 1984). (In describing a novel insulin variant, Robbins et al. (1984) used the term 'cohort' as synonymous with 'kindred' or 'family'--a possible source of confusion in light of the well-established use of the term 'cohort' in epidemiology.) </p><p>Roder et al. (1996) reported a 3-generation Caucasian kindred with the R65H mutation. Using specific enzyme-linked immunosorbent assay methods, they quantified insulin, proinsulin, and the impact of this mutation on glucose tolerance. All affected subjects had normal oral glucose tolerance, assuming 9% activity for the mutant arg65-to-his proinsulin. The calculated insulin bioactivities of affected subjects were comparable to those of normals. Thus, in this kindred, heterozygosity for R65H proinsulin was not associated with impaired glucose tolerance. Previous reports of the association of this mutation with impaired glucose tolerance may be due to bias of ascertainment or differences in genetic background or environment. </p><p>In a 2-generation European Caucasian family with hyperproinsulinemia associated with normal glucose tolerance and normal insulin sensitivity, Collinet et al. (1998) demonstrated the R65H mutation by restriction enzyme mapping. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0005 HYPERPROINSULINEMIA</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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INS, VAL3LEU
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<br />
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SNP: rs121918102,
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ClinVar: RCV000014311, RCV003460471
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a patient previously reported by Shoelson et al. (1983) to have an abnormal insulin, designated 'insulin Wakayama,' Nanjo et al. (1986) identified heterozygosity for a GTG-to-TTG transversion in the INS gene, predicting a val3-to-leu substitution in the insulin A chain. The patient had noninsulin-dependent diabetes with fasting hyperinsulinemia, elevated insulin:C-peptide molar ratio, normal insulin counterregulatory hormone levels, and adequate response to exogenous insulin. The serum contained no insulin-binding antibodies and red cell insulin receptor binding was normal. Insulin purified from the patient's serum showed reduced binding and ability to stimulate glucose uptake and oxidation in vitro. High-performance liquid chromatography (HPLC) showed 2 insulins; 7.3% of insulin immunoreactivity coeluted with normal insulin whereas 92.7% eluted as a single peak with increased hydrophobicity. Four of 5 relatives in 3 generations also had hyperinsulinemia and those tested had the abnormal insulin. </p><p>Sakura et al. (1986) found another example of insulin Wakayama. The proband was a diabetic woman who, because of gallstones, underwent cholecystectomy. During the procedure, with the informed consent of the patient, a piece of pancreas was obtained from the pancreatic tail and venous blood samples were taken from the portal vein. Despite her diabetes, the patient had hyperinsulinemia with demonstration of an abnormal as well as a normal insulin in the circulation. Whereas in the pancreas the ratio of the 2 insulins was about equal, in the peripheral blood the abnormal insulin predominated over the normal insulin in a ratio of 7:1. The abnormal insulin had about 5% of the normal binding activity and about 8% of the normal biological activity. Analysis of amino acid sequences suggested the presence of leucine for valine at the third position of the A chain. </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 HYPERPROINSULINEMIA</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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INS, ARG65LEU
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<br />
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SNP: rs28933985,
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gnomAD: rs28933985,
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ClinVar: RCV000014313
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 65-year-old nonobese Japanese man with diabetes mellitus, fasting hyperinsulinemia, and a reduced fasting C-peptide/insulin molar ratio of 2.5-3.0, Yano et al. (1992) found a G-to-T transversion in the INS gene, which gave rise to a new HindIII recognition site and resulted in the amino acid replacement of leucine for arginine at position 65 (R65L). This result and that of the R65H mutation (176730.0004) indicate that replacement of arg65 prevents recognition of the dibasic protease. Fasting hyperinsulinemia was found in the proband's son and daughter who also had the mutation. The variant was designated 'proinsulin Kyoto.' </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0007 HYPERPROINSULINEMIA</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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INS, ARG65PRO
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<br />
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SNP: rs28933985,
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gnomAD: rs28933985,
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ClinVar: RCV000014315
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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>Warren-Perry et al. (1997) found a 58-year-old, obese, Caucasian male type 2 diabetic in the UK Prospective Diabetes Study to have raised fasting total proinsulin and normal specific plasma insulin levels. The INS gene contained a point mutation, 1552G-C, which results in an arg65-to-pro (R65P) substitution. This mutation prevented cleavage of the C-peptide A-chain dibasic cleavage site (lys-arg) by the processing protease in the pancreatic cells. The plasma proinsulin and insulin levels were in accord with expression of both the wildtype and the mutant alleles. The authors determined that the 1552G-C mutation was not linked with diabetes, because it was present in a 37-year-old nondiabetic daughter and not in a 35-year-old daughter who had had gestational diabetes. </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>.0008 DIABETES MELLITUS, PERMANENT NEONATAL, 4</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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INS, GLY32SER
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<br />
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|
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SNP: rs80356664,
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ClinVar: RCV000020212, RCV000030072, RCV000117279, RCV001089451, RCV001775542
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 affected members of a 3-generation family and an unrelated proband with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for a gly32-to-ser (G32S) substitution in the INS gene (residue B8 of the insulin molecule), predicted to induce a major conformational change that would disrupt folding. </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>.0009 DIABETES MELLITUS, PERMANENT NEONATAL, 4</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">
|
|
|
|
INS, CYS43GLY
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<br />
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SNP: rs80356666,
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|
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ClinVar: RCV000020204, RCV000030069, RCV001089452, RCV003445080
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for a cys43-to-gly (C43G) substitution in the INS gene at the highly conserved residue B19 of the insulin molecule, predicted to disrupt the normal disulfide bond at B19-A20 and potentially hinder subsequent folding steps. Both probands were diagnosed before 1 year of age, but the carrier father of 1 of the probands was diagnosed with mild type 2 diabetes (125853) at 30 years of age. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DIABETES MELLITUS, PERMANENT NEONATAL, 4</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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INS, ARG89CYS
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<br />
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SNP: rs80356669,
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ClinVar: RCV000020207, RCV001089453, RCV002051790, RCV002513137, RCV004730851
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for an arg89-to-cys (R89C) substitution in the INS gene at the A-chain/C-peptide cleavage site, thus adding an additional unpaired cysteine residue at a solvent-exposed position in the molecule that is invariant among proinsulin sequences. </p><p>In 2 unrelated mothers and sons and 2 other unrelated probands with PNDM, Edghill et al. (2008) identified heterozygosity for the R89C mutation in the INS gene. </p><p>In 5 affected individuals from 2 families with PNDM, Polak et al. (2008) identified heterozygosity for R89C in the INS gene. The authors noted that one family ('family H') had diabetes that appeared to be nonautoimmune early-onset type 1 rather than bona fide neonatal diabetes, with diagnosis at 4 years of age in the mother and at 4.25 and 2.3 years of age in her son and daughter, respectively. Insulin requirements were relatively low for the patients in family H, and C-peptide levels were detectable, consistent with partially preserved beta-cell secretory function. In contrast, the mother in the other family ('family B') had poor metabolic control over the years and developed severe retinopathy, neuropathy, and macroangiopathy; at age 35 years, she underwent amputation of both feet. </p><p>In 3 unrelated probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (600937), Colombo et al. (2008) identified heterozygosity for an arg-to-cys substitution in the INS gene, which they designated R65C, located in the dibasic doublet between the C-peptide and the A-chain. Expression of the mutant proinsulin in HEK293 cells demonstrated defects in insulin protein folding and secretion. The mother of 1 patient and the father of another, who were also heterozygous for the mutation, had developed diabetes at 1 year and 4 years of age, respectively. C-peptide was initially detected in all 3 probands and was unexpectedly high in 1 of them; C-peptide declined to undetectable levels by the end of the study, supporting the hypothesis that postnatal failure to maintain beta-cell mass due to proteotoxic proinsulin misfolding is a primary cause of PNDM in patients with INS mutations. </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>.0011 DIABETES MELLITUS, PERMANENT NEONATAL, 4</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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INS, CYS96TYR
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<br />
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SNP: rs80356671,
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ClinVar: RCV000014319, RCV000517445, RCV001089454, RCV002051784
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a proband with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for a cys96-to-tyr (C96Y) substitution in the INS gene (residue A7 of the insulin molecule), predicted to disrupt the normal disulfide bond at A7-B7 and potentially hinder subsequent folding steps. This mutation is identical to that found in the Akita mouse. </p><p>In a mother and daughter and an unrelated proband with PNDM4, Edghill et al. (2008) identified heterozygosity for the C96Y mutation in the INS gene. </p><p>In a 4-year-old boy who presented with polyuria and polydipsia at 4.8 months of age, Polak et al. (2008) identified a de novo C96Y mutation in the INS gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DIABETES MELLITUS, PERMANENT NEONATAL, 4</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
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INS, ALA24ASP
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<br />
|
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|
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SNP: rs80356663,
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|
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ClinVar: RCV000014320, RCV001089455, RCV001818156
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for an ala24-to-asp (A24D) substitution in the INS gene, at the last residue of the signal peptide. </p><p>In a father and 2 sons and 2 unrelated probands with PNDM, Edghill et al. (2008) identified heterozygosity for the A24D mutation in the INS gene. </p><p>In a 22-month-old girl who presented with ketoacidosis at 3 weeks of age, Polak et al. (2008) identified heterozygosity for a de novo A24D mutation in the INS gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0013 DIABETES MELLITUS, PERMANENT NEONATAL, 4</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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INS, PHE48CYS
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<br />
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SNP: rs80356668,
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ClinVar: RCV000014321, RCV001089456, RCV002051785
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 unrelated probands with permanent neonatal diabetes mellitus (PNDM4; 618858), Stoy et al. (2007) identified heterozygosity for a phe48-to-cys (F48C) substitution in the INS gene, at residue B24 of the insulin molecule. </p><p>In a mother and daughter and an unrelated proband with PNDM, Edghill et al. (2008) identified heterozygosity for the F48C mutation in the INS gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0014 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 10</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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INS, ARG6CYS
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<br />
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SNP: rs121908278,
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gnomAD: rs121908278,
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ClinVar: RCV000014322
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 affected members of a 3-generation family from the United Kingdom with diabetes fulfilling the criteria for maturity-onset diabetes of the young (MODY10; 613370), Edghill et al. (2008) identified heterozygosity for a 16C-T transition in the INS gene, resulting in an arg6-to-cys (R6C) substitution at a conserved residue in the signal peptide of the preproinsulin molecule. The mutation was not found in 222 UK Caucasian controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0015 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 10</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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INS, ARG46GLN
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<br />
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SNP: rs121908260,
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ClinVar: RCV000014323, RCV001851851, RCV003445068
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a 3-generation Norwegian family fulfilling conventional criteria for maturity-onset diabetes of the young (MODY10; 613370), Molven et al. (2008) identified heterozygosity for a 137G-A transition in the INS gene, resulting in an arg46-to-gln (R46Q) substitution in the preproinsulin molecule. </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>.0016 TYPE 1 DIABETES MELLITUS 2</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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INS, ARG55CYS
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<br />
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SNP: rs121908261,
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gnomAD: rs121908261,
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ClinVar: RCV000014324, RCV001558886, RCV003445069, RCV003987320, RCV004752705
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Norwegian mother and daughter with type 1 diabetes mellitus (T1D2; 125852), Molven et al. (2008) identified heterozygosity for a 163C-T transition in the INS gene, resulting in an arg55-to-cys (R55C) substitution in the preproinsulin molecule. The daughter presented with frank diabetes at 10 years of age, with a markedly elevated blood glucose and ketoacidosis, and was insulin-dependent from the time of diagnosis. Her mother, 40 years old at the time of the report, was diagnosed with type 1 diabetes at 13 years of age and was treated with insulin. Both mother and daughter had autoantibodies against insulin, but GAD (glutamate decarboxylase; see 605363) and IA-2 were negative, and both had residual beta-cell function. The maternal grandparents did not carry 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>
|
|
<span class="mim-font">
|
|
<strong>.0017 DIABETES MELLITUS, PERMANENT NEONATAL, 4</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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INS, IVS2, G-A, +241
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<br />
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SNP: rs886041083,
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ClinVar: RCV000258877
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In a Southeast Asian male infant with permanent neonatal diabetes mellitus (PNDM4; 618858), Carmody et al. (2015) identified homozygosity for a c.187+241G-A transition in intron 2 of the INS gene, creating a 5-prime donor splice site. The mutation was present in heterozygosity in his first-cousin parents and 1 brother, none of whom had diabetes, although his mother had required insulin to treat gestational diabetes in all 3 of her pregnancies. In addition, the proband's maternal grandmother, who was heterozygous for the mutation, developed insulin-requiring diabetes mellitus at age 45, and a maternal aunt and uncle, for whom DNA was not available, were diagnosed with insulin-requiring diabetes mellitus at 28 and 36 years of age, respectively. The nondiabetic paternal grandmother also carried the mutation. No insulin RT-PCR product was detected from the proband's lymphoblastoid cell line or blood. Analysis of transfected INS-1 cells revealed 2 novel transcripts and no wildtype transcript. Sequencing revealed 1 transcript to be the predicted alternatively spliced transcript; the other transcript, without a stop codon, resulted from insertion of a 79-nucleotide pseudoexon following exon 2 through use of a native potential 3-prime acceptor site. Expression analysis following cycloheximide treatment of the transfected INS-1 cells showed an approximately 7-fold relative increase in the second transcript, whereas the first was not detected. Carmody et al. (2015) suggested that the first transcript undergoes rapid nonsense-mediated decay, and the second undergoes non-stop-mediated decay. </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>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Bell et al. (1979); Dayhoff (1972); Gabbay et al. (1979); Gabbay et
|
|
al. (1976); Haneda et al. (1986); Jaquet et al. (2000); Kanazawa et
|
|
al. (1978); Kwok et al. (1983); Owerbach et al. (1980); Robbins et
|
|
al. (1984); Rubenstein (1983); Shoelson et al. (1983); Steiner et al.
|
|
(1985); Steiner (1976); Sures et al. (1980); Vinik et al. (1986)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Abney, M., Ober, C., McPeek, M. S.
|
|
<strong>Quantitative-trait homozygosity and association mapping and empirical genomewide significance in large, complex pedigrees: fasting serum-insulin level in the Hutterites.</strong>
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|
Am. J. Hum. Genet. 70: 920-934, 2002.
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[PubMed: 11880950]
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[Full Text: https://doi.org/10.1086/339705]
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Awata, T., Kawasaki, E., Ikegami, H., Kobayashi, T., Maruyama, T., Nakanishi, K., Shimada, A., Iizuka, H., Kurihara, S., Osaki, M., Uga, M., Kawabata, Y., Tanaka, S., Kanazawa, Y., Katayama, S.
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<strong>Insulin gene/IDDM2 locus in Japanese type 1 diabetes: contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes.</strong>
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<li>
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<p class="mim-text-font">
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Barbetti, F., Raben, N., Kadowaki, T., Cama, A., Accili, D., Gabbay, K. H., Merenich, J. A., Taylor, S. I., Roth, J.
|
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<strong>Two unrelated patients with familial hyperproinsulinemia due to a mutation substituting histidine for arginine at position 65 in the proinsulin molecule: identification of the mutation by direct sequencing of genomic deoxyribonucleic acid amplified by polymerase chain reaction.</strong>
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J. Clin. Endocr. Metab. 71: 164-169, 1990.
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[PubMed: 2196279]
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[Full Text: https://doi.org/10.1210/jcem-71-1-164]
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<li>
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<p class="mim-text-font">
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Bell, G. I., Pictet, R. L., Rutter, W. J., Cordell, B., Tischer, E., Goodman, H. M.
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<strong>Sequence of the human insulin gene.</strong>
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Nature 284: 26-32, 1980.
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[PubMed: 6243748]
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[Full Text: https://doi.org/10.1038/284026a0]
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<p class="mim-text-font">
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Bell, G. I., Swain, W. F., Pictet, R., Cordell, B., Goodman, H. M., Rutter, W. J.
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<strong>Nucleotide sequence of cDNA clone encoding human preproinsulin.</strong>
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Nature 282: 525-527, 1979.
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[PubMed: 503234]
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[Full Text: https://doi.org/10.1038/282525a0]
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Carmody, D., Park, S.-Y., Ye, H., Perrone, M. E., Alkorta-Aranburu, G., Highland, H. M., Hanis, C. L., Philipson, L. H., Bell, G. I., Greeley, S. A. W.
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<strong>Continued lessons from the INS gene: an intronic mutation causing diabetes through a novel mechanism.</strong>
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J. Med. Genet. 52: 612-616, 2015.
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[PubMed: 26101329]
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[Full Text: https://doi.org/10.1136/jmedgenet-2015-103220]
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Carroll, R. J., Hammer, R. E., Chan, S. J., Swift, H. H., Rubenstein, A. H., Steiner, D. F.
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<strong>A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway.</strong>
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Proc. Nat. Acad. Sci. 85: 8943-8947, 1988.
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[PubMed: 3057496]
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[Full Text: https://doi.org/10.1073/pnas.85.23.8943]
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Chaganti, R. S. K., Jhanwar, S. C., Antonarakis, S. E., Hayward, W. S.
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<strong>Germ-line chromosomal localization of genes in chromosome 11p linkage; parathyroid hormone, beta-globin, c-Ha-ras-1, and insulin.</strong>
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Somat. Cell Molec. Genet. 11: 197-202, 1985.
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[PubMed: 3885418]
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[Full Text: https://doi.org/10.1007/BF01534708]
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<p class="mim-text-font">
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Chan, S. J., Seino, S., Gruppuso, P. A., Schwartz, R., Steiner, D. F.
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<strong>A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.</strong>
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Proc. Nat. Acad. Sci. 84: 2194-2197, 1987.
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[PubMed: 3470784]
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[Full Text: https://doi.org/10.1073/pnas.84.8.2194]
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<p class="mim-text-font">
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Cheung, A. T., Dayanandan, B., Lewis, J. T., Korbutt, G. S., Rajotte, R. V., Bryer-Ash, M., Boylan, M. O., Wolfe, M. M., Kieffer, T. J.
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<strong>Glucose-dependent insulin release from genetically engineered K cells.</strong>
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Science 290: 1959-1962, 2000.
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[PubMed: 11110661]
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[Full Text: https://doi.org/10.1126/science.290.5498.1959]
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</p>
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<p class="mim-text-font">
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Collinet, M., Berthelon, M., Benit, P., Laborde, K., Desbuquois, B., Munnich, A., Robert, J. J.
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<strong>Familial hyperproinsulinaemia due to a mutation substituting histidine for arginine at position 65 in proinsulin: identification of the mutation by restriction enzyme mapping.</strong>
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Europ. J. Pediat. 157: 456-460, 1998.
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[PubMed: 9667398]
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[Full Text: https://doi.org/10.1007/s004310050852]
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</p>
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<li>
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<p class="mim-text-font">
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Colombo, C., Porzio, O., Liu, M., Massa, O., Vasta, M., Salardi, S., Beccaria, L., Monciotti, C., Toni, S., Pedersen, O., Hansen, T., Federici, L., and 8 others.
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<strong>Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.</strong>
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J. Clin. Invest. 118: 2148-2156, 2008.
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[PubMed: 18451997]
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[Full Text: https://doi.org/10.1172/JCI33777]
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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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Dandona, P., Aljada, A., Mohanty, P., Ghanim, H., Hamouda, W., Assian, E., Ahmad, S.
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<strong>Insulin inhibits intranuclear nuclear factor kappa-B and stimulates I-kappa-B in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect?</strong>
|
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J. Clin. Endocr. Metab. 86: 3257-3265, 2001.
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[PubMed: 11443198]
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[Full Text: https://doi.org/10.1210/jcem.86.7.7623]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Davies, P. O., Poirier, C., Deltour, L., Montagutelli, X.
|
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<strong>Genetic reassignment of the insulin-1 (Ins1) gene to distal mouse chromosome 19.</strong>
|
|
Genomics 21: 665-667, 1994.
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[PubMed: 7959751]
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[Full Text: https://doi.org/10.1006/geno.1994.1334]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Dayhoff, M. O.
|
|
<strong>Atlas of Protein Sequence and Structure. Proinsulin. Vol. 5.</strong>
|
|
Washington: National Biomedical Research Foundation (pub.) 1972. P. D208.
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|
|
</p>
|
|
</li>
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|
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<li>
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<p class="mim-text-font">
|
|
Deltour, L., Leduque, P., Blume, N., Madsen, O., Dubois, P., Jami, J., Bucchini, D.
|
|
<strong>Differential expression of the two nonallelic proinsulin genes in the developing mouse embryo.</strong>
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|
Proc. Nat. Acad. Sci. 90: 527-531, 1993.
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|
|
|
|
|
[PubMed: 8421685]
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|
|
[Full Text: https://doi.org/10.1073/pnas.90.2.527]
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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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Edghill, E. L., Flanagan, S. E., Patch, A.-M., Boustred, C., Parrish, A., Shields, B., Shepherd, M. H., Hussain, K., Kapoor, R. R., Malecki, M., MacDonald, M. J., Stoy, J., Steiner, D. F., Philipson, L. H., Bell, G. I., Neonatal Diabetes International Collaborative Group, Hattersley, A. T., Ellard, S.
|
|
<strong>Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.</strong>
|
|
Diabetes 57: 1034-1042, 2008.
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|
|
[PubMed: 18162506]
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[Full Text: https://doi.org/10.2337/db07-1405]
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</p>
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</li>
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<li>
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Marla J. F. O'Neill - updated : 11/14/2016<br>Ada Hamosh - updated : 5/16/2013<br>George E. Tiller - updated : 10/27/2010<br>Patricia A. Hartz - updated : 10/27/2010<br>Marla J. F. O'Neill - updated : 4/19/2010<br>Carol A. Bocchini - updated : 2/16/2009<br>Patricia A. Hartz - updated : 12/10/2008<br>John A. Phillips, III - updated : 3/24/2008<br>John A. Phillips, III - updated : 10/2/2007<br>John A. Phillips, III - updated : 7/18/2007<br>Paul J. Converse - updated : 1/22/2007<br>George E. Tiller - updated : 10/9/2006<br>John A. Phillips, III - updated : 8/22/2006<br>Victor A. McKusick - updated : 4/27/2006<br>Alan F. Scott - updated : 6/21/2004<br>Cassandra L. Kniffin - updated : 3/30/2004<br>Ada Hamosh - updated : 7/24/2003<br>John A. Phillips, III - updated : 6/27/2002<br>Victor A. McKusick - updated : 4/12/2002<br>John A. Phillips, III - updated : 3/6/2002<br>John A. Phillips, III - updated : 2/18/2002<br>Victor A. McKusick - updated : 9/25/2001<br>Ada Hamosh - updated : 8/27/2001<br>Ada Hamosh - updated : 12/15/2000<br>Victor A. McKusick - updated : 11/27/2000<br>John A. Phillips, III - updated : 11/16/2000<br>George E. Tiller - updated : 4/25/2000<br>Victor A. McKusick - updated : 3/3/1999<br>Victor A. McKusick - updated : 8/26/1998<br>John A. Phillips, III - updated : 5/29/1997<br>John A. Phillips, III - updated : 4/16/1996
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