6865 lines
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Entry
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- *600937 - POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11
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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">*600937</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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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600937">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<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 class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000187486;t=ENST00000339994" 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=3767" 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=600937" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000187486;t=ENST00000339994" 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_000525,NM_001166290,NM_001377296,NM_001377297" 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_000525" 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=600937" 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=09022&isoform_id=09022_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/KCNJ11" 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/1088445,26252173,62023267,62388888,85662656,119588844,189067467,194376970,238516967,238516970,261399884,269979217,559767904,559767906,559767908,1214987471,1214987793,1219731503,1788951001,1788951010,2245149903" 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/Q14654" 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=3767" 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=ENSG00000187486;t=ENST00000339994" 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=KCNJ11" 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=KCNJ11" 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+3767" 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/KCNJ11" 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:3767" 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/3767" 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=ENST00000339994.5&hgg_start=17385248&hgg_end=17389346&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/genes/HGNC:6257" 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=600937[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=600937[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/KCNJ11/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000187486" 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=KCNJ11" 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=KCNJ11" 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=KCNJ11" 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=KCNJ11&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/PA217" 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:6257" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0039081.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:107501" 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/KCNJ11#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:107501" 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/3767/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3767" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00002149;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00002149 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00002150;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00002150 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-060308-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:3767" 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=KCNJ11&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> 609581006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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600937
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
POTASSIUM CHANNEL, INWARDLY RECTIFYING, BIR SUBUNIT<br />
|
|
BETA-CELL INWARD RECTIFIER SUBUNIT; BIR<br />
|
|
INWARDLY RECTIFYING POTASSIUM CHANNEL Kir6.2
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KCNJ11" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KCNJ11</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/11/208?start=-3&limit=10&highlight=208">11p15.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:17385248-17389346&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'})">11:17,385,248-17,389,346</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=610582,618856,601820,616329" 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/11/208?start=-3&limit=10&highlight=208">
|
|
11p15.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Diabetes mellitus, transient neonatal 3
|
|
|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/610582"> 610582 </a>
|
|
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<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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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Diabetes, permanent neonatal 2, with or without neurologic features
|
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|
|
</span>
|
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</td>
|
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<td>
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<p>ATP-sensitive K+ (KATP) channels couple cell metabolism to membrane excitability in various cell types, including pancreatic beta cells, neurons, endocrine cells, and muscle cells. The archetypal KATP channel is an octameric complex of KCNJ11 subunits and either SUR1 (ABCC8; <a href="/entry/600509">600509</a>) subunits in pancreatic beta cells and many neurons or SUR2 (ABCC9; <a href="/entry/601439">601439</a>) subunits in muscle. Four KCNJ11 subunits form the channel pore, and each is associated with a SUR subunit that contributes to regulation of channel gating (summary by <a href="#10" class="mim-tip-reference" title="Girard, C. A., Wunderlich, F. T., Shimomura, K., Collins, S., Kaizik, S., Proks, P., Abdulkader, F., Clark, A., Ball, V., Zubcevic, L., Bentley, L., Clark, R., Church, C., Hugill, A., Galvanovskis, J., Cox, R., Rorsman, P., Bruning, J. C., Ashcroft, F. M. <strong>Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes.</strong> J. Clin. Invest. 119: 80-90, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19065048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19065048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19065048[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/JCI35772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19065048">Girard et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19065048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#22" class="mim-tip-reference" title="Inagaki, N., Gonoi, T., Clement, J. P., Namba, N., Inazawa, J., Gonzalez, G., Aguilar-Bryan, L., Seino, S., Bryan, J. <strong>Reconstitution of I(KATP): an inward rectifier subunit plus the sulfonylurea receptor.</strong> Science 270: 1166-1170, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502040</a>] [<a href="https://doi.org/10.1126/science.270.5239.1166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7502040">Inagaki et al. (1995)</a> cloned a member of the inwardly rectifying potassium channel family, which they called BIR, for 'beta-cell inward rectifier,' or Kir6.2, in the nomenclature of <a href="#4" class="mim-tip-reference" title="Chandy, K. G., Gutman, G. A. <strong>Nomenclature for mammalian potassium channel genes.</strong> Trends Pharm. Sci. 14: 434, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8122319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8122319</a>] [<a href="https://doi.org/10.1016/0165-6147(93)90181-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8122319">Chandy and Gutman (1993)</a>. The channel was expressed in large amounts in rat pancreatic islets and glucose-responsive insulin-secreting cell lines. The sequence showed a single open reading frame encoding a 390-amino acid protein with 2 putative transmembrane segments. The mouse homolog also had a single open reading frame encoding a 390-amino acid protein with 96% amino acid identity with human BIR. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8122319+7502040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#22" class="mim-tip-reference" title="Inagaki, N., Gonoi, T., Clement, J. P., Namba, N., Inazawa, J., Gonzalez, G., Aguilar-Bryan, L., Seino, S., Bryan, J. <strong>Reconstitution of I(KATP): an inward rectifier subunit plus the sulfonylurea receptor.</strong> Science 270: 1166-1170, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502040</a>] [<a href="https://doi.org/10.1126/science.270.5239.1166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7502040">Inagaki et al. (1995)</a> determined that KCNJ11, the gene encoding human BIR, is intronless in the protein-coding region. Several other genes encoding inward rectifiers lack introns. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7502040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 fluorescence in situ hybridization, <a href="#22" class="mim-tip-reference" title="Inagaki, N., Gonoi, T., Clement, J. P., Namba, N., Inazawa, J., Gonzalez, G., Aguilar-Bryan, L., Seino, S., Bryan, J. <strong>Reconstitution of I(KATP): an inward rectifier subunit plus the sulfonylurea receptor.</strong> Science 270: 1166-1170, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502040</a>] [<a href="https://doi.org/10.1126/science.270.5239.1166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7502040">Inagaki et al. (1995)</a> mapped the BIR gene to 11p15.1. The sequence obtained from 1 lambda clone at the 3-prime end of the SUR gene (ABCC8; <a href="/entry/600509">600509</a>) matched a part of the gene encoding BIR; with a sense primer near the 3-prime end of the SUR gene and an antisense primer near the 5-prime end of the BIR gene they PCR-amplified an approximately 4.5-kb fragment. Thus, the authors determined that the 2 genes are clustered at 11p15.1, with the BIR gene immediately 3-prime of the SUR gene. The SUR gene had previously been mapped to 11p15.1 by fluorescence in situ hybridization (<a href="#41" class="mim-tip-reference" title="Thomas, P. M., Cote, G. J., Hallman, D. M., Mathew, P. M. <strong>Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy.</strong> Am. J. Hum. Genet. 56: 416-421, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7847376/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7847376</a>]" pmid="7847376">Thomas et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7502040+7847376" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In pancreatic beta cells, ATP-potassium channels are crucial for the regulation of glucose-induced insulin secretion and are the target for the sulfonylureas, oral hypoglycemic agents widely used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM; <a href="/entry/125853">125853</a>), and for diazoxide, a potassium channel opener. The sulfonylurea receptor (SUR) is a member of the ATP-binding cassette superfamily with multiple transmembrane-spanning domains and 2 potential nucleotide-binding folds. <a href="#22" class="mim-tip-reference" title="Inagaki, N., Gonoi, T., Clement, J. P., Namba, N., Inazawa, J., Gonzalez, G., Aguilar-Bryan, L., Seino, S., Bryan, J. <strong>Reconstitution of I(KATP): an inward rectifier subunit plus the sulfonylurea receptor.</strong> Science 270: 1166-1170, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7502040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7502040</a>] [<a href="https://doi.org/10.1126/science.270.5239.1166" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7502040">Inagaki et al. (1995)</a> demonstrated that coexpression of BIR with SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to ATP and was inhibited by sulfonylureas and activated by diazoxide. The data indicated to the authors that these pancreatic beta-cell potassium channels are a complex composed of at least 2 subunits: BIR and SUR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7502040" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Inagaki, N., Gonoi, T., Clement, J. P., IV, Wang, C.-Z., Aguilar-Bryan, L., Bryan, J., Seino, S. <strong>A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K(+) channels.</strong> Neuron 16: 1011-1017, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8630239/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8630239</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80124-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8630239">Inagaki et al. (1996)</a> cloned rat SUR2 (<a href="/entry/601439">601439</a>) and found that coexpression of SUR2 and BIR in COS-1 cells reconstituted the properties of K(ATP) channels described in cardiac and skeletal muscle. However, they found that the SUR2/BIR channel is less sensitive than the SUR/BIR channel both to ATP and to the sulfonylurea glibenclamide, and is activated by the cardiac K(ATP) channel openers cromakalim and pinacidil but not by diazoxide. The affinity of SUR2 for sulfonylureas is 500 times lower than that of SUR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8630239" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#42" class="mim-tip-reference" title="Thomas, P., Ye, Y., Lightner, E. <strong>Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy.</strong> Hum. Molec. Genet. 5: 1809-1812, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8923010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8923010</a>] [<a href="https://doi.org/10.1093/hmg/5.11.1809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8923010">Thomas et al. (1996)</a> screened genomic DNA from members of 15 families with hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>) for mutations in the KCNJ11 gene. In a male infant with profound hypoglycemia, born of consanguineous Iranian parents, <a href="#42" class="mim-tip-reference" title="Thomas, P., Ye, Y., Lightner, E. <strong>Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy.</strong> Hum. Molec. Genet. 5: 1809-1812, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8923010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8923010</a>] [<a href="https://doi.org/10.1093/hmg/5.11.1809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8923010">Thomas et al. (1996)</a> identified homozygosity for a 649T-C mutation (<a href="#0001">600937.0001</a>). His parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8923010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 SSCP and nucleotide sequence analysis, <a href="#31" class="mim-tip-reference" title="Nestorowicz, A., Inagaki, N., Gonoi, T., Schoor, K. P., Wilson, B. A., Glaser, B., Landau, H., Stanley, C. A., Thornton, P. S., Seino, S., Permutt, M. A. <strong>A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.</strong> Diabetes 46: 1743-1748, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9356020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9356020</a>] [<a href="https://doi.org/10.2337/diab.46.11.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9356020">Nestorowicz et al. (1997)</a> screened 78 patients with hyperinsulinism for mutations in the KCNJ11 gene and identified homozygosity for a nonsense mutation (<a href="#0009">600937.0009</a>) in 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9356020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="de Lonlay, P., Fournet, J.-C., Rahier, J., Gross-Morand, M.-S., Poggi-Travert, F., Foussier, V., Bonnefont, J.-P., Brusset, M.-C., Brunelle, F., Robert, J.-J., Nihoul-Fekete, C., Saudubray, J.-M., Junien, C. <strong>Somatic deletion of the imprinted 11p15 region in sporadic persistent hyperinsulinemic hypoglycemia of infancy is specific of focal adenomatous hyperplasia and endorses partial pancreatectomy.</strong> J. Clin. Invest. 100: 802-807, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9259578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9259578</a>] [<a href="https://doi.org/10.1172/JCI119594" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9259578">De Lonlay et al. (1997)</a> showed that in cases of the focal form, but not those of the diffuse form, of hyperinsulinemic hypoglycemia there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event was consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, they provided the first molecular explanation for the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia. It is possible that in these cases of somatic loss of maternal 11p15.1, there is reduction to homozygosity for a recessive ABCC8 or KCNJ11 mutation on the paternal allele, since both ABCC8 and KCNJ11 are located in the 11p15.1 region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9259578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#43" class="mim-tip-reference" title="Tornovsky, S., Crane, A., Cosgrove, K. E., Hussain, K., Lavie, J., Heyman, M., Nesher, Y., Kuchinski, N., Ben-Shushan, E., Shatz, O., Nahari, E., Potikha, T., and 11 others. <strong>Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.</strong> J. Clin. Endocr. Metab. 89: 6224-6234, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579781</a>] [<a href="https://doi.org/10.1210/jc.2004-1233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579781">Tornovsky et al. (2004)</a> screened 15 patients with neonatal hyperinsulinemic hypoglycemia for mutations in the ABCC8 and KCNJ11 genes and identified 12 mutations in 11 patients. Homozygosity for a mutation in the promoter (<a href="#0010">600937.0010</a>) and in exon 1 (<a href="#0011">600937.0011</a>) of the KCNJ11 gene were identified in an Israeli Bedouin and an Arab patient, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Henwood, M. J., Kelly, A., MacMullen, C., Bhatia, P., Ganguly, A., Thornton, P. S., Stanley, C. A. <strong>Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.</strong> J. Clin. Endocr. Metab. 90: 789-794, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15562009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15562009</a>] [<a href="https://doi.org/10.1210/jc.2004-1604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15562009">Henwood et al. (2005)</a> measured acute insulin responses (AIRs) to calcium, leucine, glucose, and tolbutamide in 22 infants with recessive ABCC8 or KCNJ11 mutations (see, e.g., <a href="#0019">600937.0019</a>), 8 of whom had diffuse hyperinsulinism and 14 of whom had focal hyperinsulinism. Of the 24 total mutations, 7 showed evidence of residual K(ATP) channel function: 2 of the patients with partial defects were homozygous and 4 heterozygous for amino acid substitutions or insertions, and 1 was a compound heterozygote for 2 premature stop codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15562009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#26" class="mim-tip-reference" title="Lin, Y.-W., Bushman, J. D., Yan, F.-F., Haidar, S., MacMullen, C., Ganguly, A., Stanley, C. A., Shyng, S.-L. <strong>Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism.</strong> J. Biol. Chem. 283: 9146-9156, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250167</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250167[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M708798200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250167">Lin et al. (2008)</a> investigated the mechanisms by which hyperinsulinism-associated mutations of arg301 (R301) in KCNJ11 (e.g., R301H; <a href="#0019">600937.0019</a>) lead to channel dysfunction. They found that R301 mutations in rat Kcnj11 resulted in reduced channel expression at the cell surface in transfected cells and caused rapid, spontaneous current decay, or inactivation. Mutagenesis studies indicated that R301 is near the Kcnj11 subunit-subunit interface and likely stabilizes channel activity. To evaluate the effects of channel inactivation on beta cell function, <a href="#26" class="mim-tip-reference" title="Lin, Y.-W., Bushman, J. D., Yan, F.-F., Haidar, S., MacMullen, C., Ganguly, A., Stanley, C. A., Shyng, S.-L. <strong>Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism.</strong> J. Biol. Chem. 283: 9146-9156, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250167</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250167[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M708798200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250167">Lin et al. (2008)</a> expressed an alternative R301 mutation, R301A, which induces channel inactivation without affecting channel surface expression, in a rat insulinoma cell line. Expression of Kcnj11 with R301A resulted in more depolarized membrane potential and elevated insulin secretion at basal glucose concentration compared with cells expressing wildtype channels. <a href="#26" class="mim-tip-reference" title="Lin, Y.-W., Bushman, J. D., Yan, F.-F., Haidar, S., MacMullen, C., Ganguly, A., Stanley, C. A., Shyng, S.-L. <strong>Destabilization of ATP-sensitive potassium channel activity by novel KCNJ11 mutations identified in congenital hyperinsulinism.</strong> J. Biol. Chem. 283: 9146-9156, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250167</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18250167[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M708798200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250167">Lin et al. (2008)</a> concluded that mutations at R301 may cause channel inactivation by disrupting subunit-subunit interactions, and that this gating defect is sufficient to cause loss of channel function and hyperinsulinism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250167" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Pinney, S. E., MacMullen, C., Becker, S., Lin, Y.-W., Hanna, C., Thornton, P., Ganguly, A., Shyng, S.-L., Stanley, C. A. <strong>Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant K(ATP) channel mutations.</strong> J. Clin. Invest. 118: 2877-2886, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596924</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596924[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/JCI35414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596924">Pinney et al. (2008)</a> identified 14 different dominantly inherited K(ATP) channel mutations in 16 unrelated families, 13 with mutations in the ABCC8 gene (see, e.g., <a href="/entry/600509#0011">600509.0011</a>) and 3 with mutations in the KCNJ11 gene (see, e.g., <a href="#0020">600937.0020</a>). Unlike recessive mutations, dominantly inherited K(ATP) mutant subunits trafficked normally to the plasma membrane when expressed in simian kidney cells; dominant mutations also resulted in different channel-gating defects, with dominant ABCC8 mutations diminishing channel responses to magnesium adenosine diphosphate or diazoxide and dominant KCNJ11 mutations impairing channel opening even in the absence of nucleotides. <a href="#32" class="mim-tip-reference" title="Pinney, S. E., MacMullen, C., Becker, S., Lin, Y.-W., Hanna, C., Thornton, P., Ganguly, A., Shyng, S.-L., Stanley, C. A. <strong>Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant K(ATP) channel mutations.</strong> J. Clin. Invest. 118: 2877-2886, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596924</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596924[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/JCI35414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596924">Pinney et al. (2008)</a> concluded that there are distinctive features of dominant K(ATP) hyperinsulinism compared to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Taneja, T. K., Mankouri, J., Karnik, R., Kannan, S., Smith, A. J., Munsey, T., Christesen, H. B. T., Beech, D. J., Sivaprasadarao, A. <strong>Sar1-GTPase-dependent ER exit of K(ATP) channels revealed by a mutation causing congenital hyperinsulinism.</strong> Hum. Molec. Genet. 18: 2400-2413, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19357197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19357197</a>] [<a href="https://doi.org/10.1093/hmg/ddp179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19357197">Taneja et al. (2009)</a> reported that the Kir6.2 channel contains a diacidic ER exit signal DXE at codons 280 to 282, which promotes concentration of the channel into COPII-enriched ER exit sites prior to ER export via a process that requires Sar1-GTPase (<a href="/entry/607690">607690</a>). They identified an E282K mutation (<a href="#0022">600937.0022</a>) in a Swedish patient with HHF2 with focal adenomatous hyperplasia. The E282K mutation abrogated the ER exit signal and prevented ER export and surface expression of the channel. When coexpressed, the E282K-mutant subunit was able to associate with the wildtype Kir6.2 and form functional channels, and unlike most mutations did not cause protein misfolding. Since in focal congenital hyperinsulinism, the maternal chromosome containing the K(ATP) channel genes is lost, beta-cells of the patient lacked wildtype Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal chromosome. The resultant absence of functional KATP channels leads to insulin hypersecretion. <a href="#40" class="mim-tip-reference" title="Taneja, T. K., Mankouri, J., Karnik, R., Kannan, S., Smith, A. J., Munsey, T., Christesen, H. B. T., Beech, D. J., Sivaprasadarao, A. <strong>Sar1-GTPase-dependent ER exit of K(ATP) channels revealed by a mutation causing congenital hyperinsulinism.</strong> Hum. Molec. Genet. 18: 2400-2413, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19357197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19357197</a>] [<a href="https://doi.org/10.1093/hmg/ddp179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19357197">Taneja et al. (2009)</a> concluded that surface expression of K(ATP) channels is critically dependent on the Sar1-GTPase-dependent ER exit mechanism, and abrogation of the diacidic ER exit signal leads to congenital hyperinsulinism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19357197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bellanne-Chantelot, C., Saint-Martin, C., Ribeiro, M.-J., Vaury, C., Verkarre, V., Arnoux, J.-B., Valayannopoulos, V., Gobrecht, S., Sempoux, C., Rahier, J., Fournet, J.-C., Jaubert, F., Aigrain, Y., Nihoul-Fekete, C., de Lonlay, P. <strong>ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.</strong> J. Med. Genet. 47: 752-759, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20685672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20685672</a>] [<a href="https://doi.org/10.1136/jmg.2009.075416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20685672">Bellanne-Chantelot et al. (2010)</a> analyzed the ABCC8 and KCNJ11 genes in 109 diazoxide-unresponsive patients with congenital hyperinsulinism and identified mutations in 89 (82%) of the probands. A total of 118 mutations were found, including 106 (90%) in ABCC8 and 12 (10%) in KCNJ11; 94 of the 118 were different mutations, and 41 had previously been reported. The 37 patients diagnosed with focal disease all had heterozygous mutations, whereas 30 (47%) of 64 patients known or suspected to have diffuse disease had homozygous or compound heterozygous mutations, 22 (34%) had a heterozygous mutation, and 12 (19%) had no mutation in the ABCC8 or KCNJ11 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20685672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Diabetes Mellitus Type 2 Susceptibility</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Hani, E. H., Boutin, P., Durand, E., Inoue, H., Permutt, M. A., Velho, G., Froguel, P. <strong>Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians.</strong> Diabetologia 41: 1511-1515, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9867219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9867219</a>] [<a href="https://doi.org/10.1007/s001250051098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9867219">Hani et al. (1998)</a> identified an association between an E23K variant in the KCNJ11 gene (<a href="#0014">600937.0014</a>) and type 2 diabetes mellitus (T2D; <a href="/entry/125853">125853</a>) in French families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9867219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hansen, S. K., Nielsen, E.-M. D., Ek, J., Andersen, G., Glumer, C., Carstensen, B., Mouritzen, P., Drivsholm, T., Borch-Johnsen, K., Jorgensen, T., Hansen, T., Pedersen, O. <strong>Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes.</strong> J. Clin. Endocr. Metab. 90: 3629-3637, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15797964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15797964</a>] [<a href="https://doi.org/10.1210/jc.2004-1942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15797964">Hansen et al. (2005)</a> studied the effects of the E23K polymorphism and a PPARG P12A polymorphism (<a href="/entry/601487#0002">601487.0002</a>) on the risk of type 2 diabetes and found that the polymorphisms may act in an additive manner to increase the risk of type 2 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15797964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 2</em></strong></p><p>
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Because ATP-sensitive potassium channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> hypothesized that activating mutations in the KCNJ11 gene might cause neonatal diabetes. They studied 29 patients with permanent neonatal diabetes (PNDM2; <a href="/entry/618856">618856</a>) characterized by ketoacidosis or marked hyperglycemia who were treated with insulin. The patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; 3 of them also had epilepsy and mild dysmorphic features (DEND). <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> sequenced the KCNJ11 gene in all 29 patients and identified 6 novel, heterozygous missense mutations in 10. In 4 of the 10 families, the mutation was an arg201-to-his (R201H) substitution (<a href="#0002">600937.0002</a>). In 2 patients, the diabetes was familial. In 8 patients, the diabetes arose from a spontaneous mutation (see, e.g., V59M; <a href="#0003">600937.0003</a>). When the most common mutation, R201H, was coexpressed with SUR in Xenopus oocytes, the ability of ATP to block mutant ATP-sensitive potassium channels was greatly reduced. Thus, whereas inactivating mutations of KCNJ11 lead to uncontrolled insulin secretion and congenital hyperinsulinism, activating mutations cause neonatal diabetes. <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> concluded that heterozygous activating mutations of the KCNJ11 gene are a common cause (approximately 34%) of permanent neonatal diabetes. In a high proportion (80%) of subjects studied in their series, the mutation occurred de novo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Gloyn, A. L., Reimann, F., Girard, C., Edghill, E. L., Proks, P., Pearson, E. R., Temple, I. K., Mackay, D. J. G., Shield, J. P. H., Freedenberg, D., Noyes, K., Ellard, S., Ashcroft, F. M., Gribble, F. M., Hattersley, A. T. <strong>Relapsing diabetes can result from moderately activating mutations in KCNJ11.</strong> Hum. Molec. Genet. 14: 925-934, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15718250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15718250</a>] [<a href="https://doi.org/10.1093/hmg/ddi086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15718250">Gloyn et al. (2005)</a> identified 3 novel heterozygous mutations (see, e.g., <a href="#0017">600937.0017</a>-<a href="#0018">600937.0018</a>) in 3 of 11 probands with clinically defined TNDM who did not have chromosome 6q24 abnormalities. The mutations cosegregated with diabetes in 2 families and were not found in 100 controls. All 3 probands had insulin-treated diabetes diagnosed in the first 4 months of life and went into remission by 7 to 17 months of age. In transformed Xenopus oocytes, all 3 heterozygous mutations resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations. <a href="#14" class="mim-tip-reference" title="Gloyn, A. L., Reimann, F., Girard, C., Edghill, E. L., Proks, P., Pearson, E. R., Temple, I. K., Mackay, D. J. G., Shield, J. P. H., Freedenberg, D., Noyes, K., Ellard, S., Ashcroft, F. M., Gribble, F. M., Hattersley, A. T. <strong>Relapsing diabetes can result from moderately activating mutations in KCNJ11.</strong> Hum. Molec. Genet. 14: 925-934, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15718250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15718250</a>] [<a href="https://doi.org/10.1093/hmg/ddi086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15718250">Gloyn et al. (2005)</a> concluded that mutations in KCNJ11 can cause both remitting and permanent diabetes, suggesting that a fixed ion channel abnormality may result in a fluctuating glycemic phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15718250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Proks, P., Girard, C., Ashcroft, F. M. <strong>Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP.</strong> Hum. Molec. Genet. 14: 2717-2726, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087682</a>] [<a href="https://doi.org/10.1093/hmg/ddi305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087682">Proks et al. (2005)</a> studied the MgATP sensitivity of neonatal diabetes-causing KCNJ11-mutant K(ATP) channels expressed in Xenopus oocytes. In contrast to wildtype channels, Mg(2+) dramatically reduced the ATP sensitivity of heterozygous R201C (<a href="#0004">600937.0004</a>), R201H, V59M, and V59G (<a href="#0005">600937.0005</a>) channels. This effect was predominantly mediated via the nucleotide-binding domains of SUR1 (ABCC8; <a href="/entry/600509">600509</a>) and resulted from an enhanced stimulatory action of MgATP. <a href="#34" class="mim-tip-reference" title="Proks, P., Girard, C., Ashcroft, F. M. <strong>Functional effects of KCNJ11 mutations causing neonatal diabetes: enhanced activation by MgATP.</strong> Hum. Molec. Genet. 14: 2717-2726, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087682</a>] [<a href="https://doi.org/10.1093/hmg/ddi305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087682">Proks et al. (2005)</a> concluded that KCNJ11 mutations increase the current magnitude of heterozygous K(ATP) channels by increasing MgATP activation and by decreasing ATP inhibition. The fraction of unblocked K(ATP) current at physiologic MgATP concentrations correlated with the severity of the clinical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Transient Neonatal Diabetes Mellitus 3</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Yorifuji, T., Nagashima, K., Kurokawa, K., Kawai, M., Oishi, M., Akazawa, Y., Hosokawa, M., Yamada, Y., Inagaki, N., Nakahata, T. <strong>The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.</strong> J. Clin. Endocr. Metab. 90: 3174-3178, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15784703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15784703</a>] [<a href="https://doi.org/10.1210/jc.2005-0096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15784703">Yorifuji et al. (2005)</a> found a missense mutation in the KCNJ11 gene (<a href="#0012">600937.0012</a>) in a 4-generation family with dominantly inherited diabetes mellitus observed in 3 generations. The onset and severity of the diabetes were variable: transient neonatal diabetes (TNDM3; <a href="/entry/610582">610582</a>), childhood-onset diabetes, gestational diabetes, or maturity-onset diabetes of the young. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15784703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 20-year-old woman who had transient neonatal diabetes mellitus that recurred at age 7 years, <a href="#6" class="mim-tip-reference" title="Colombo, C., Delvecchio, M., Zecchino, C., Faienza, M. F., Cavallo, L., Barbetti, F., Early Onset Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. <strong>Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation. (Letter)</strong> Diabetologia 48: 2439-2441, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16205880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16205880</a>] [<a href="https://doi.org/10.1007/s00125-005-1958-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16205880">Colombo et al. (2005)</a> identified heterozygosity for a de novo R201H mutation in the KCNJ11 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16205880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 13</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Yorifuji, T., Nagashima, K., Kurokawa, K., Kawai, M., Oishi, M., Akazawa, Y., Hosokawa, M., Yamada, Y., Inagaki, N., Nakahata, T. <strong>The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.</strong> J. Clin. Endocr. Metab. 90: 3174-3178, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15784703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15784703</a>] [<a href="https://doi.org/10.1210/jc.2005-0096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15784703">Yorifuji et al. (2005)</a> and <a href="#2" class="mim-tip-reference" title="Bonnefond, A., Philippe, J., Durand, E., Dechaume, A., Huyvaert, M., Montagne, L., Marre, M., Balkau, B., Fajardy, I., Vambergue, A., Vatin, V., Delplanque, J., Le Guilcher, D., De Graeve, F., Lecoeur, C., Sand, O., Vaxillaire, M., Froguel, P. <strong>Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene.</strong> PLoS One 7: e37423, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22701567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22701567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22701567[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/10.1371/journal.pone.0037423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22701567">Bonnefond et al. (2012)</a> reported families in which affected members had autosomal dominant early-onset diabetes that was responsive to sulfonylureas. The disease usually manifested before age 25 years and occurred in nonobese individuals, suggesting a diagnosis of maturity-onset diabetes of the young (MODY13; <a href="/entry/616329">616329</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15784703+22701567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Association with Impaired Exercise Stress Response</em></strong></p><p>
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<a href="#35" class="mim-tip-reference" title="Reyes, S., Park, S., Johnson, B. D., Terzic, A., Olson, T. M. <strong>K(ATP) channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response.</strong> Hum. Genet. 126: 779-789, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19685080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19685080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19685080[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/10.1007/s00439-009-0731-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19685080">Reyes et al. (2009)</a> found that the E23K polymorphism (<a href="#0014">600937.0014</a>) was overrepresented in individuals with dilated cardiomyopathy (see <a href="/entry/115200">115200</a>) and congestive heart failure (CHF) compared to controls, and that the KK genotype was associated with abnormal cardiopulmonary exercise stress testing. <a href="#35" class="mim-tip-reference" title="Reyes, S., Park, S., Johnson, B. D., Terzic, A., Olson, T. M. <strong>K(ATP) channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response.</strong> Hum. Genet. 126: 779-789, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19685080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19685080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19685080[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/10.1007/s00439-009-0731-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19685080">Reyes et al. (2009)</a> suggested that E23K might represent a biomarker for impaired stress performance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19685080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>To determine why some mutations in the KCNJ11 gene cause PNDM in isolation whereas others cause PNDM associated with marked developmental delay, muscle weakness, and epilepsy, <a href="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> expressed wildtype or mutant Kir6.2/sulfonylurea receptor-1 channels in Xenopus oocytes. All of the mutations investigated (R201C, Q52R, and V59G) increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but in the simulated heterozygous state, the mutation causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). These findings suggested that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extra pancreatic cell function. <a href="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> also found that mutations causing PNDM alone impaired ATP sensitivity directly (at the binding site), whereas those associated with severe disease acted indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflected the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. The results showed that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating and suggesting that the efficacy of sulfonylurea therapy in PNDM may vary with genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15583126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> screened the KCNJ11 gene in 18 Italian patients with what they termed 'permanent diabetes mellitus of infancy' (PDMI), including 12 patients with onset within 3 months after birth and 6 with onset between 3 months to 1 year of age. Five different heterozygous mutations were identified in 8 patients with diabetes diagnosed between day 3 and day 182. Two of these mutations were novel. Four of the 8 patients also had motor and/or developmental delay. <a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> concluded that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutations in the genes encoding the 2 essential subunits of the channel, KCNJ11 and ABCC8, can result in either hypoglycemia or hyperglycemia. <a href="#15" class="mim-tip-reference" title="Gloyn, A. L., Siddiqui, J., Ellard, S. <strong>Mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism.</strong> Hum. Mutat. 27: 220-231, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16416420/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16416420</a>] [<a href="https://doi.org/10.1002/humu.20292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16416420">Gloyn et al. (2006)</a> reviewed the loss-of-function mutations in KCNJ11 and ABCC8, which can cause oversecretion of insulin and result in hyperinsulinemia of infancy. They reviewed the management of patients in whom mutations in these genes are found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16416420" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>From a study of 49 patients with activating Kir6.2 mutations, <a href="#39" class="mim-tip-reference" title="Slingerland, A. S., Hattersley, A. T. <strong>Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes.</strong> J. Clin. Endocr. Metab. 91: 2782-2788, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16636122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16636122</a>] [<a href="https://doi.org/10.1210/jc.2006-0201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16636122">Slingerland and Hattersley (2006)</a> concluded that these mutations cause a severe reduction in fetal insulin secretion and hence fetal growth but that this is independent of mutation severity. Postnatal catch-up required insulin treatment but was complete, except in those with epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16636122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#30" class="mim-tip-reference" title="Miki, T., Tashiro, F., Iwanaga, T., Nagashima, K., Yoshitomi, H., Aihara, H., Nitta, Y., Gonoi, T., Inagaki, N., Miyazaki, J., Seino, S. <strong>Abnormalities of pancreatic islets by targeted expression of a dominant-negative K(ATP) channel.</strong> Proc. Nat. Acad. Sci. 94: 11969-11973, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342346[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.94.22.11969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9342346">Miki et al. (1997)</a> generated transgenic mice expressing a dominant-negative mutation within the conserved gly-tyr-gly motif of the putative K(+)-permeable domain of Kcnj11. The gene was inserted downstream of the human insulin promoter region for selective expression in pancreatic beta cells. Transgenic mice developed hypoglycemia with hyperinsulinemia as neonates and hyperglycemia with hypoinsulinemia and decreased beta cell numbers as adults. Kcnj11 function was impaired in the beta cells of transgenic mice with hyperglycemia, and both resting membrane potential and basal calcium concentrations were significantly elevated in transgenic mice. <a href="#30" class="mim-tip-reference" title="Miki, T., Tashiro, F., Iwanaga, T., Nagashima, K., Yoshitomi, H., Aihara, H., Nitta, Y., Gonoi, T., Inagaki, N., Miyazaki, J., Seino, S. <strong>Abnormalities of pancreatic islets by targeted expression of a dominant-negative K(ATP) channel.</strong> Proc. Nat. Acad. Sci. 94: 11969-11973, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9342346/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9342346</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9342346[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.94.22.11969" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9342346">Miki et al. (1997)</a> also observed a high frequency of apoptotic beta cells prior to the development of hyperglycemia, suggesting a role for Kcnj11 in cell survival as well as in regulating insulin secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9342346" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Koster, J. C., Marshall, B. A., Ensor, N., Corbett, J. A., Nichols, C. G. <strong>Targeted overactivity of beta cell KATP channels induces profound neonatal diabetes.</strong> Cell 100: 645-654, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10761930/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10761930</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80701-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10761930">Koster et al. (2000)</a> generated transgenic mice expressing pancreatic beta-cell K(ATP) channels with reduced ATP sensitivity. They used transgenes with truncation of the N-terminal 30 amino acids of the Kir6.2 subunit, and a double mutant with the 30-amino acid truncation and a lys185-to-gln mutation. These transgenes were fused at the C terminus with the green fluorescent protein to allow for detection under ultraviolet illumination. Transgenic animals developed severe hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days, and typically died within 5 days. Nevertheless, islet morphology, insulin localization, and alpha- and beta-cell distributions were normal (before day 3), pointing to reduced insulin secretion as causal. The data indicated that normal K(ATP) channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10761930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice with a conditional deletion of Hnf4a (<a href="/entry/600281">600281</a>) in pancreatic beta cells, <a href="#16" class="mim-tip-reference" title="Gupta, R. K., Vatamaniuk, M. Z., Lee, C. S., Flaschen, R. C., Fulmer, J. T., Matschinsky, F. M., Duncan, S. A., Kaestner, K. H. <strong>The MODY1 gene HNF-4-alpha regulates selected genes involved in insulin secretion.</strong> J. Clin. Invest. 115: 1006-1015, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15761495[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/JCI22365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761495">Gupta et al. (2005)</a> observed hyperinsulinemia in fasted and fed animals but also impaired glucose tolerance. Islet perfusion and calcium-imaging studies showed abnormal beta cell responses to stimulation by glucose and sulfonylureas, explainable in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. Cotransfection assays revealed that the Kir6.2 gene is a transcriptional target of HNF4A. <a href="#16" class="mim-tip-reference" title="Gupta, R. K., Vatamaniuk, M. Z., Lee, C. S., Flaschen, R. C., Fulmer, J. T., Matschinsky, F. M., Duncan, S. A., Kaestner, K. H. <strong>The MODY1 gene HNF-4-alpha regulates selected genes involved in insulin secretion.</strong> J. Clin. Invest. 115: 1006-1015, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15761495/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15761495</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15761495[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/JCI22365" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15761495">Gupta et al. (2005)</a> concluded that HNF4A is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15761495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>ATP-sensitive potassium channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in the control of seizures. <a href="#44" class="mim-tip-reference" title="Yamada, K., Ji, J. J., Yuan, H., Miki, T., Sata, S., Horimoto, N., Shimizu, T., Seino, S., Inagaki, N. <strong>Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure.</strong> Science 292: 1543-1546, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11375491/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11375491</a>] [<a href="https://doi.org/10.1126/science.1059829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11375491">Yamada et al. (2001)</a> studied mutant mice lacking the Kir6.2 subunit of ATP-sensitive potassium channels and found that they were susceptible to generalized seizures after brief hypoxia. In normal mice, the substantia nigra pars reticulata neuron activity was inactivated during hypoxia by the opening of the postsynaptic ATP-sensitive potassium channels, whereas in knockout mice, the activity of these neurons was enhanced. ATP-sensitive potassium channels exert a depressant effect on substantia nigra pars reticulata neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11375491" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Girard, C. A., Wunderlich, F. T., Shimomura, K., Collins, S., Kaizik, S., Proks, P., Abdulkader, F., Clark, A., Ball, V., Zubcevic, L., Bentley, L., Clark, R., Church, C., Hugill, A., Galvanovskis, J., Cox, R., Rorsman, P., Bruning, J. C., Ashcroft, F. M. <strong>Expression of an activating mutation in the gene encoding the K(ATP) channel subunit Kir6.2 in mouse pancreatic beta cells recapitulates neonatal diabetes.</strong> J. Clin. Invest. 119: 80-90, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19065048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19065048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19065048[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/JCI35772" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19065048">Girard et al. (2009)</a> created a mouse strain conditionally expressing the human Kir6.2 V59M mutation (<a href="#0003">600937.0003</a>) specifically in pancreatic beta cells. Kir6.2(V59M) mRNA was expressed at a level comparable to that of endogenous wildtype Kir6.2 mRNA. Mutant mice (beta-V59M mice) developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Isolated beta-V59M islets displayed a reduced percentage of beta cells, abnormal morphology, abnormal calcium oscillations, lower insulin content, and decreased expression of Kir6.2, Sur1, and insulin mRNA. Beta-V59M islets secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose than wildtype islets, which was due to reduced sensitivity of Kir6.2(V69M) channels to ATP or glucose. Current and secretion events downstream of channel closure remained intact. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19065048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 using mice carrying the human V59M mutation in Kir6.2 (<a href="#0003">600937.0003</a>) targeted to either muscle or nerve, <a href="#5" class="mim-tip-reference" title="Clark, R. H., McTaggart, J. S., Webster, R., Mannikko, R., Iberl, M., Sim, X. L., Rorsman, P., Glitsch, M., Beeson, D., Ashcroft, F. M. <strong>Muscle dysfunction caused by a K(ATP) channel mutation in neonatal diabetes is neuronal in origin.</strong> Science 329: 458-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20595581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20595581</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20595581[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/10.1126/science.1186146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20595581">Clark et al. (2010)</a> showed that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. <a href="#5" class="mim-tip-reference" title="Clark, R. H., McTaggart, J. S., Webster, R., Mannikko, R., Iberl, M., Sim, X. L., Rorsman, P., Glitsch, M., Beeson, D., Ashcroft, F. M. <strong>Muscle dysfunction caused by a K(ATP) channel mutation in neonatal diabetes is neuronal in origin.</strong> Science 329: 458-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20595581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20595581</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20595581[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/10.1126/science.1186146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20595581">Clark et al. (2010)</a> also identified locomotor hyperactivity as a feature of K(ATP) channel overactivity. <a href="#5" class="mim-tip-reference" title="Clark, R. H., McTaggart, J. S., Webster, R., Mannikko, R., Iberl, M., Sim, X. L., Rorsman, P., Glitsch, M., Beeson, D., Ashcroft, F. M. <strong>Muscle dysfunction caused by a K(ATP) channel mutation in neonatal diabetes is neuronal in origin.</strong> Science 329: 458-461, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20595581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20595581</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20595581[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/10.1126/science.1186146" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20595581">Clark et al. (2010)</a> concluded that their finding suggested that drugs targeted against neuronal, rather than muscle, K(ATP) channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20595581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a male infant with profound hypoglycemia (HHF2; <a href="/entry/601820">601820</a>), born of consanguineous Iranian parents, <a href="#42" class="mim-tip-reference" title="Thomas, P., Ye, Y., Lightner, E. <strong>Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy.</strong> Hum. Molec. Genet. 5: 1809-1812, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8923010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8923010</a>] [<a href="https://doi.org/10.1093/hmg/5.11.1809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8923010">Thomas et al. (1996)</a> identified homozygosity for a 649T-C mutation in the KCNJ11 gene, resulting in a leu147-to-pro (L147P) substitution predicted to cause disruption of the M2 alpha-helical transmembrane domain of the protein. His parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8923010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs80356624 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356624;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/rs80356624?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=rs80356624" 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=rs80356624" 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=RCV000009198 OR RCV000009200 OR RCV000146114 OR RCV000712160 OR RCV001089463 OR RCV002051777 OR RCV002227021" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009198, RCV000009200, RCV000146114, RCV000712160, RCV001089463, RCV002051777, RCV002227021" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009198...</a>
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<p><strong><em>Permanent Neonatal Diabetes Mellitus 2</em></strong></p><p>
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In 4 unrelated patients with permanent neonatal diabetes (PNDM2; <a href="/entry/618856">618856</a>), <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> identified a heterozygous arg201-to-his (R201H) mutation in the KCNJ11 gene. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (<a href="#36" class="mim-tip-reference" title="Ribalet, B., John, S. A., Weiss, J. N. <strong>Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.</strong> Biophys. J. 84: 266-276, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524280</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12524280[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0006-3495(03)74847-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12524280">Ribalet et al., 2003</a>). In 1 family reported by <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a>, 2 brothers and the father were affected. Diabetes in the brothers was diagnosed under the age of 3 or 4 weeks, and in the father at the age of 12 weeks. The father was age 46 years at the time of report. In another family, mother and son were affected. The diagnosis had been made at birth in the son and at age 6 weeks in the mother, who was 36 years old at the time of report. None of the patients with the R201H mutation had muscle weakness, neurologic abnormalities, or dysmorphic features. The arginine residue at position 201 of Kir6.2 lies close to the ATP-binding site and was previously implicated in ATP sensing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12524280+15115830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 functional expression studies in Xenopus oocytes, <a href="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> found that mutations at the arg201 residue (see also R201C; <a href="#0004">600937.0004</a>) caused a decrease in ATP sensitivity by altering the ATP-binding site. However, the decreased sensitivity found in cells with a mutation at arg201 was not as severe as that found in cells with a mutation at val59 (see V59M, <a href="#0003">600937.0003</a> and V59G, <a href="#0005">600937.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15583126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanne-Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., Robert, J. J. <strong>KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.</strong> Europ. J. Hum. Genet. 14: 824-830, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670688</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16670688">Gloyn et al. (2006)</a> reported 2 unrelated infants with PNDM and the R201H mutation. The male infant (family NECKER4) also had dysmorphic facial features and neurologic involvement, including seizures, developmental delay, and axial hypotonia. On the basis of clinical and neuroimaging findings, the neurological involvement was thought to represent acute cerebral edema, which is a known complication of severe ketoacidosis in young children. The facial dysmorphism was considered to be unlike the classical features reported in other cases of syndromic PNDM. In contrast, the other infant (family NECKER6) did not have neurologic involvement, and her mother, who also carried the mutation, had severe diabetes mellitus without neurologic involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16670688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Transient Neonatal Diabetes Mellitus 3</em></strong></p><p>
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In a 20-year-old woman with transient neonatal diabetes mellitus (TNDM3; <a href="/entry/610582">610582</a>) in whom diabetes remitted at age 29 months and recurred at age 7 years, <a href="#6" class="mim-tip-reference" title="Colombo, C., Delvecchio, M., Zecchino, C., Faienza, M. F., Cavallo, L., Barbetti, F., Early Onset Study Group of the Italian Society of Paediatric Endocrinology and Diabetology. <strong>Transient neonatal diabetes mellitus is associated with a recurrent (R201H) KCNJ11 (KIR6.2) mutation. (Letter)</strong> Diabetologia 48: 2439-2441, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16205880/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16205880</a>] [<a href="https://doi.org/10.1007/s00125-005-1958-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16205880">Colombo et al. (2005)</a> identified heterozygosity for a de novo 602G-A (R201H) mutation in the KCNJ11 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16205880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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">rs80356616 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356616;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=rs80356616" 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=rs80356616" 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=RCV000009201 OR RCV000030665 OR RCV000146104 OR RCV000724752 OR RCV002051778 OR RCV002227022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009201, RCV000030665, RCV000146104, RCV000724752, RCV002051778, RCV002227022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009201...</a>
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<p>In 2 unrelated males (ISPAD54 and ISPAD55) with permanent neonatal diabetes (PNDM2; <a href="/entry/618856">618856</a>), <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> found heterozygosity for a val59-to-met (V59M) mutation in the KCNJ11 gene. One of the patients (ISPAD55) had muscle weakness and delayed motor and mental development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> noted that 2 mutations in the same residue of Kir6.2, V59M and V59G (<a href="#0005">600937.0005</a>), are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (<a href="#0002">600937.0002</a>) and R201C (<a href="#0004">600937.0004</a>). They found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the 'slide helix,' a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15583126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> found the V59M mutation in 4 unrelated Italian patients with PNDM. Two of the patients had motor and mental developmental delay. One of the patients was diagnosed at over 6 months of age (182 days). <a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> suggested that the designation 'permanent diabetes mellitus of infancy' (PDMI) replace 'permanent neonatal diabetes mellitus.' <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanne-Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., Robert, J. J. <strong>KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.</strong> Europ. J. Hum. Genet. 14: 824-830, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670688</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16670688">Gloyn et al. (2006)</a> reported a patient (ANGERS1) with the V59M mutation who had PNDM and neurologic features, including mild motor developmental delay and axial hypotonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16670688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356625 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356625;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=rs80356625" 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=rs80356625" 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=RCV000009202 OR RCV000146113 OR RCV001089465 OR RCV001530196 OR RCV001851755 OR RCV002051779 OR RCV002227023 OR RCV002227024 OR RCV005051732" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009202, RCV000146113, RCV001089465, RCV001530196, RCV001851755, RCV002051779, RCV002227023, RCV002227024, RCV005051732" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009202...</a>
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<p>In a patient with permanent neonatal diabetes mellitus (PNDM2; <a href="/entry/618856">618856</a>), <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> identified a heterozygous arg201-to-cys (R201C) mutation in the Kir6.2 gene. The patient was diagnosed at 4 weeks of age and had no additional neurologic or dysmorphic features. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (<a href="#36" class="mim-tip-reference" title="Ribalet, B., John, S. A., Weiss, J. N. <strong>Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.</strong> Biophys. J. 84: 266-276, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12524280/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12524280</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12524280[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/S0006-3495(03)74847-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12524280">Ribalet et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12524280+15115830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> stated that the 2 mutations in residue arg201, R201H (<a href="#0002">600937.0002</a>) and R201C, which lie in the ATP-binding site of Kir6.2, cause milder PNDM disease without neurologic features; however, <a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> identified the R201C mutation in a patient with PNDM who also had muscle weakness and delayed motor development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15580558+15583126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Gloyn, A. L., Cummings, E. A., Edghill, E. L., Harries, L. W., Scott, R., Costa, T., Temple, I. K., Hattersley, A. T., Ellard, S. <strong>Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel.</strong> J. Clin. Endocr. Metab. 89: 3932-3935, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15292329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15292329</a>] [<a href="https://doi.org/10.1210/jc.2004-0568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15292329">Gloyn et al. (2004)</a> described a family in which 2 affected paternal half-sibs were heterozygous for the R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father's leukocyte DNA detected no trace of mutant DNA. These results were consistent with the father being mosaic for the mutation, which was restricted to his germline. <a href="#11" class="mim-tip-reference" title="Gloyn, A. L., Cummings, E. A., Edghill, E. L., Harries, L. W., Scott, R., Costa, T., Temple, I. K., Hattersley, A. T., Ellard, S. <strong>Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel.</strong> J. Clin. Endocr. Metab. 89: 3932-3935, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15292329/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15292329</a>] [<a href="https://doi.org/10.1210/jc.2004-0568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15292329">Gloyn et al. (2004)</a> concluded that the high percentage of permanent neonatal diabetes cases due to de novo KCNJ11 mutations (<a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al., 2004</a>) suggests that germline mosaicism may be common. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15115830+15292329" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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">rs80356617 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356617;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=rs80356617" 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=rs80356617" 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=RCV000009204 OR RCV000020350 OR RCV002227025" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009204, RCV000020350, RCV002227025" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009204...</a>
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<p>In a male patient with permanent neonatal diabetes and neurologic features (ISPAD25) (PNDMNF; see <a href="/entry/618856">618856</a>), <a href="#13" class="mim-tip-reference" title="Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others. <strong>Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.</strong> New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15115830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15115830</a>] [<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15115830">Gloyn et al. (2004)</a> found heterozygosity for a val59-to-gly (V59G) mutation in the KCNJ11 gene. In addition to neonatal diabetes, the patient had muscle weakness, marked motor and mental developmental delay, myoclonic seizures with abnormal EEG, and dysmorphic features, including a downturned mouth, bilateral ptosis, and contractures primarily in the legs at birth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15115830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> noted that 2 mutations in the same residue of Kir6.2, V59M (<a href="#0003">600937.0003</a>) and V59G, are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (<a href="#0002">600937.0002</a>) and R201C (<a href="#0004">600937.0004</a>). <a href="#33" class="mim-tip-reference" title="Proks, P., Antcliff, J. F., Lippiat, J., Gloyn, A. L., Hattersley, A. T., Ashcroft, F. M. <strong>Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.</strong> Proc. Nat. Acad. Sci. 101: 17539-17544, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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.0404756101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15583126">Proks et al. (2004)</a> found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the 'slide helix,' a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15583126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs80356611 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356611;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/rs80356611?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=rs80356611" 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=rs80356611" 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=RCV000009205 OR RCV001089464 OR RCV003335022" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009205, RCV001089464, RCV003335022" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009205...</a>
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<p>In an Italian patient with permanent neonatal diabetes mellitus (PNDM2; <a href="/entry/618856">618856</a>), <a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> identified a 149G-C transversion in the KCNJ11 gene, resulting in an arg50-to-pro (R50P) substitution. The patient had no neurologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356621 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356621;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=rs80356621" 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=rs80356621" 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=RCV000009206 OR RCV001089466 OR RCV002227026" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009206, RCV001089466, RCV002227026" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009206...</a>
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<p>In an Italian patient with permanent neonatal diabetes mellitus (PNDM2; <a href="/entry/618856">618856</a>), <a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> identified a 175G-A transition in the KCNJ11 gene, resulting in a lys170-to-arg (K170R) substitution. The patient had no neurologic abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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, 2</strong>
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KCNJ11, LYS170ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356622 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356622;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=rs80356622" 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=rs80356622" 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=RCV000009207 OR RCV001089467 OR RCV002051780 OR RCV002227027" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009207, RCV001089467, RCV002051780, RCV002227027" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009207...</a>
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<p>In an Italian patient with permanent neonatal diabetes mellitus (PNDM2; <a href="/entry/618856">618856</a>), <a href="#29" class="mim-tip-reference" title="Massa, O., Iafusco, D., D'Amato, E., Gloyn, A. L., Hattersley, A. T., Pasquino, B., Tonini, G., Dammacco, F., Zanette, G., Meschi, F., Porzio, O., Bottazzo, G., Crino, A., Lorini, R., Cerutti, F., Vanelli, M., Barbetti, F. <strong>KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.</strong> Hum. Mutat. 25: 22-27, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15580558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15580558</a>] [<a href="https://doi.org/10.1002/humu.20124" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15580558">Massa et al. (2005)</a> identified a 510G-C transversion in the KCNJ11 gene, resulting in a lys170-to-asn (K170N) substitution. The patient was diagnosed at age 63 days and had delayed mental development; however, this patient also had a brain infarction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15580558" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0009 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
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KCNJ11, TYR12TER
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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> rs104894236 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894236;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/rs104894236?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=rs104894236" 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=rs104894236" 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=RCV000009208 OR RCV001851756 OR RCV002227028" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009208, RCV001851756, RCV002227028" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009208...</a>
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<p>In a Palestinian Arab boy with hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>), born of first-cousin parents, <a href="#31" class="mim-tip-reference" title="Nestorowicz, A., Inagaki, N., Gonoi, T., Schoor, K. P., Wilson, B. A., Glaser, B., Landau, H., Stanley, C. A., Thornton, P. S., Seino, S., Permutt, M. A. <strong>A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.</strong> Diabetes 46: 1743-1748, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9356020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9356020</a>] [<a href="https://doi.org/10.2337/diab.46.11.1743" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9356020">Nestorowicz et al. (1997)</a> identified homozygosity for a 39C-A transversion in the KCNJ11 gene, resulting in a tyr12-to-ter (Y12X) substitution. The mutation is predicted to produce a truncated Kir6.2 polypeptide lacking the putative K+ ion-selective pore region as well as those domains proposed to confer the gating and inward rectification properties of the molecule. In vitro studies in transfected COS-1 cells confirmed the deleterious effect of the mutation on channel activity. The authors noted that this patient was clinically indistinguishable from patients with severe hyperinsulinism caused by mutations in SUR1 (ABCC8; <a href="/entry/600509">600509</a>; see HHF1, <a href="/entry/600509">600509</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9356020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0010 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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">rs387906398 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906398;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=rs387906398" 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=rs387906398" 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=RCV000009209 OR RCV002226639 OR RCV002512936 OR RCV004799736" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009209, RCV002226639, RCV002512936, RCV004799736" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009209...</a>
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<p>In an Israeli Bedouin infant with hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>), <a href="#43" class="mim-tip-reference" title="Tornovsky, S., Crane, A., Cosgrove, K. E., Hussain, K., Lavie, J., Heyman, M., Nesher, Y., Kuchinski, N., Ben-Shushan, E., Shatz, O., Nahari, E., Potikha, T., and 11 others. <strong>Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.</strong> J. Clin. Endocr. Metab. 89: 6224-6234, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579781</a>] [<a href="https://doi.org/10.1210/jc.2004-1233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579781">Tornovsky et al. (2004)</a> identified homozygosity for an 88G-T transversion 5-prime of the transcription start site in the promoter region of the KCNJ11 gene. Functional studies using a luciferase reporter vector revealed a 44% decrease in reporter gene expression for the mutant variant compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0011 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
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KCNJ11, PRO254LEU
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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> rs104894237 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894237;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/rs104894237?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=rs104894237" 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=rs104894237" 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=RCV000009210 OR RCV002226640 OR RCV002512937 OR RCV003466840" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009210, RCV002226640, RCV002512937, RCV003466840" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009210...</a>
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<p>In an Arab infant in whom a prenatal diagnosis of hyperinsulinism was made due to a family history of hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>), <a href="#43" class="mim-tip-reference" title="Tornovsky, S., Crane, A., Cosgrove, K. E., Hussain, K., Lavie, J., Heyman, M., Nesher, Y., Kuchinski, N., Ben-Shushan, E., Shatz, O., Nahari, E., Potikha, T., and 11 others. <strong>Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity.</strong> J. Clin. Endocr. Metab. 89: 6224-6234, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579781</a>] [<a href="https://doi.org/10.1210/jc.2004-1233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579781">Tornovsky et al. (2004)</a> identified homozygosity for a C-T transition at codon 254 in exon 1 of the KCNJ11 gene, resulting in a pro254-to-leu (P254L) substitution. Photolabeling studies after transient transfection into COSm6 cells revealed impaired trafficking of the mutant channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579781" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0012 DIABETES MELLITUS, TRANSIENT NEONATAL, 3</strong>
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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 13, INCLUDED
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356610;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=rs80356610" 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=rs80356610" 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=RCV000009211 OR RCV000020347 OR RCV000170298 OR RCV001851757 OR RCV002226641" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009211, RCV000020347, RCV000170298, RCV001851757, RCV002226641" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009211...</a>
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<p>In affected members of a 4-generation Japanese family with dominantly inherited diabetes mellitus observed in 3 generations, <a href="#45" class="mim-tip-reference" title="Yorifuji, T., Nagashima, K., Kurokawa, K., Kawai, M., Oishi, M., Akazawa, Y., Hosokawa, M., Yamada, Y., Inagaki, N., Nakahata, T. <strong>The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus.</strong> J. Clin. Endocr. Metab. 90: 3174-3178, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15784703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15784703</a>] [<a href="https://doi.org/10.1210/jc.2005-0096" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15784703">Yorifuji et al. (2005)</a> detected a T-to-C transition at nucleotide 124 of the KCNJ11 gene that gave rise to a cys42-to-arg amino acid substitution (C24R). The proband had transient neonatal diabetes (TNDM3; <a href="/entry/610582">610582</a>), and his paternal grandfather had childhood diabetes. The others had early adult-onset diabetes without autoantibodies or insulin resistance (MODY13; <a href="/entry/616329">616329</a>). No affected individual was obese. Patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of the patients. The authors concluded that these results broadened the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggested that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15784703" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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> rs104894248 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894248;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/rs104894248?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=rs104894248" 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=rs104894248" 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=RCV000009213 OR RCV000992253 OR RCV002226642 OR RCV002247279 OR RCV004734505 OR RCV005049325" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009213, RCV000992253, RCV002226642, RCV002247279, RCV004734505, RCV005049325" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009213...</a>
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<p>In a patient with severe congenital hyperinsulinism (HHF2; <a href="/entry/601820">601820</a>), <a href="#28" class="mim-tip-reference" title="Marthinet, E., Bloc, A., Oka, Y., Tanizawa, Y., Wehrle-Haller, B., Bancila, V., Dubuis, J.-M., Philippe, J., Schwitzgebel, V. M. <strong>Severe congenital hyperinsulinism caused by a mutation in the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium channel impairing trafficking and function.</strong> J. Clin. Endocr. Metab. 90: 5401-5406, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15998776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15998776</a>] [<a href="https://doi.org/10.1210/jc.2005-0202" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15998776">Marthinet et al. (2005)</a> identified a homozygous A-to-G transition at nucleotide 776 of the KCNJ11 gene that resulted in a his-259-to-arg substitution (H259R). The patient presented with macrosomia at birth and severe hyperinsulinemic hypoglycemia. Despite medical treatment, the newborn continued to suffer from severe hypoglycemic episodes, and at 4 months of age subtotal pancreatectomy was performed. Coexpression of KCNJ11 H259R with ABCC8 (<a href="/entry/600509">600509</a>) in HEK293T cells completely abolished K(ATP) currents in electrophysiologic recordings. Double immunofluorescence staining revealed that mutant KCNJ11 was partly retained in the endoplasmic reticulum (ER) causing decreased surface expression as observed with total internal reflection fluorescence. Mutation of an ER-retention signal partially rescued the trafficking defect without restoring whole-cell currents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15998776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 RECLASSIFIED - POLYMORPHISM</strong>
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KCNJ11, GLU23LYS
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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> rs5219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5219;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/rs5219?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=rs5219" 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=rs5219" 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=RCV000009214 OR RCV000020356 OR RCV000146116 OR RCV000281825 OR RCV000294608 OR RCV000385348 OR RCV000576501 OR RCV001093985 OR RCV001105584 OR RCV001512207 OR RCV002226643 OR RCV004734506" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009214, RCV000020356, RCV000146116, RCV000281825, RCV000294608, RCV000385348, RCV000576501, RCV001093985, RCV001105584, RCV001512207, RCV002226643, RCV004734506" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009214...</a>
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<p>This variant, formerly titled TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO, with an Included title of EXERCISE STRESS RESPONSE, IMPAIRED, ASSOCIATION WITH, has been reclassified as a polymorphism based on a review of the gnomAD database (v4.1.0) by <a href="#17" class="mim-tip-reference" title="Hamosh, A. <strong>Personal Communication.</strong> Baltimore, Md. 12/4/2024."None>Hamosh (2024)</a>. The E23K variant was present in 1,047,275 of 1,613,446 alleles and in 344,120 homozygotes, with an allele frequency of 0.6491.</p><p><strong><em>Type 2 Diabetes Mellitus, Susceptibility to</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Hani, E. H., Boutin, P., Durand, E., Inoue, H., Permutt, M. A., Velho, G., Froguel, P. <strong>Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians.</strong> Diabetologia 41: 1511-1515, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9867219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9867219</a>] [<a href="https://doi.org/10.1007/s001250051098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9867219">Hani et al. (1998)</a> identified a glu23-to-lys (E23K) amino acid substitution in the KCNJ11 gene by molecular screening using SSCP and direct sequencing in 72 French Caucasian families with type 2 diabetes (<a href="/entry/125853">125853</a>). They genotyped this variant in French cohorts of 191 unrelated type 2 diabetic probands and 119 normoglycemic control subjects and performed association studies. Homozygosity for lys23 (KK) was more frequent in type 2 diabetic than in control subjects (27 vs 14%; p = 0.015). Analyses in a recessive model (KK vs EK/EE) showed a stronger association of the K allele with diabetes. In a metaanalysis of their data for the E23K variant and data obtained from 3 other Caucasian groups, <a href="#18" class="mim-tip-reference" title="Hani, E. H., Boutin, P., Durand, E., Inoue, H., Permutt, M. A., Velho, G., Froguel, P. <strong>Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of type II diabetes mellitus in Caucasians.</strong> Diabetologia 41: 1511-1515, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9867219/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9867219</a>] [<a href="https://doi.org/10.1007/s001250051098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9867219">Hani et al. (1998)</a> found the E23K variant to be significantly associated with type 2 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9867219" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Hansen, S. K., Nielsen, E.-M. D., Ek, J., Andersen, G., Glumer, C., Carstensen, B., Mouritzen, P., Drivsholm, T., Borch-Johnsen, K., Jorgensen, T., Hansen, T., Pedersen, O. <strong>Analysis of separate and combined effects of common variation in KCNJ11 and PPARG on risk of type 2 diabetes.</strong> J. Clin. Endocr. Metab. 90: 3629-3637, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15797964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15797964</a>] [<a href="https://doi.org/10.1210/jc.2004-1942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15797964">Hansen et al. (2005)</a> investigated the separate and combined effects of the PPARG pro12-to-ala (P12A; <a href="/entry/601487#0002">601487.0002</a>) and KCNJ11 E23K polymorphisms on risk of type 2 diabetes. The combined analysis involved 1,164 type 2 diabetic patients and 4,733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of KCNJ11 E23K associated with type 2 diabetes (odds ratio, 1.19; p = 0.0002), whereas PPARG P12A showed no significant association with type 2 diabetes. The combined analysis indicated that the 2 polymorphisms acted in an additive manner to increase the risk of type 2 diabetes, and the authors found no evidence for a synergistic interaction between them. Together, the 2 polymorphisms conferred a population-attributable risk for type 2 diabetes of 28%. The authors concluded that their results showed no evidence of a synergistic interaction between the KCNJ11 E23K and PPARG P12A polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15797964" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Laukkanen, O., Pihlajamaki, J., Lindstrom, J., Eriksson, J., Valle, T. T., Hamalainen, H., Ilanne-Patrikka, P., Keinanen-Kiukaanniemi, S., Tuomilehto, J., Uusitupa, M., Laakso, M., Finnish Diabetes Prevention Study Group. <strong>Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study.</strong> J. Clin. Endocr. Metab. 89: 6286-6290, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15579791/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15579791</a>] [<a href="https://doi.org/10.1210/jc.2004-1204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15579791">Laukkanen et al. (2004)</a> found an additive effect of a high risk ABCC8 (<a href="/entry/600509">600509</a>) haplotype, composed of a silent polymorphism (AGG-AGA; arg1273 to arg) and 3 promoter polymorphisms, and the 23K allele of the KCNJ11 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15579791" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 genomewide association studies of type 2 diabetes involving genotype data from a variety of international consortia, the <a href="#8" class="mim-tip-reference" title="Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research. <strong>Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.</strong> Science 316: 1331-1336, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17463246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17463246</a>] [<a href="https://doi.org/10.1126/science.1142358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17463246">Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007)</a>, <a href="#46" class="mim-tip-reference" title="Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., Barrett, J. C., Shields, B., and 15 others. <strong>Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.</strong> Science 316: 1336-1341, 2007. Note: Erratum: Science 317: 1036 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17463249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17463249</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17463249[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/10.1126/science.1142364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17463249">Zeggini et al. (2007)</a>, and <a href="#37" class="mim-tip-reference" title="Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J., Li, Y., Duren, W. L., Erdos, M. R., Stringham, H. M., Chines, P. S., Jackson, A. U., Prokunina-Olsson, L., Ding, C.-J., and 29 others. <strong>A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.</strong> Science 316: 1341-1345, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17463248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17463248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17463248[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/10.1126/science.1142382" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17463248">Scott et al. (2007)</a> confirmed association of the E23K polymorphism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5219;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5219</a>) with diabetes susceptibility. Although this association was not strongly observed in any single scan, all-data metaanalyses resulted in genomewide significant association (OR = 1.14, p = 6.7 x 10(-11)). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17463246+17463248+17463249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Impaired Exercise Stress Response, Association with</em></strong></p><p>
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<a href="#35" class="mim-tip-reference" title="Reyes, S., Park, S., Johnson, B. D., Terzic, A., Olson, T. M. <strong>K(ATP) channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response.</strong> Hum. Genet. 126: 779-789, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19685080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19685080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19685080[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/10.1007/s00439-009-0731-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19685080">Reyes et al. (2009)</a> found that the E23K polymorphism was overrepresented in 115 individuals with dilated cardiomyopathy (see <a href="/entry/115200">115200</a>) and congestive heart failure (CHF) compared to 2,031 community-based controls (p less than 0.001). In addition, the KK genotype, which was present in 18% of the CHF patients, was associated with abnormal cardiopulmonary exercise stress testing: despite similar baseline heart rates among genotype subgroups, individuals with the KK genotype had a significantly reduced heart rate increase at matched workload, at 75% of maximum oxygen consumption, and at peak VO(2), compared to those with the EE or EK genotypes. Noting that the glu23 residue is located within the functionally relevant intracellular slide helix region, <a href="#35" class="mim-tip-reference" title="Reyes, S., Park, S., Johnson, B. D., Terzic, A., Olson, T. M. <strong>K(ATP) channel Kir6.2 E23K variant overrepresented in human heart failure is associated with impaired exercise stress response.</strong> Hum. Genet. 126: 779-789, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19685080/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19685080</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19685080[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/10.1007/s00439-009-0731-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19685080">Reyes et al. (2009)</a> suggested that E23K might represent a biomarker for impaired stress performance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19685080" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356618;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=rs80356618" 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=rs80356618" 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=RCV000009216 OR RCV000020352 OR RCV002247280" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009216, RCV000020352, RCV002247280" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009216...</a>
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<p>In an infant (NECKER29) with a severe form of permanent neonatal diabetes mellitus with neurologic features (PNDM2; <a href="/entry/618856">618856</a>), <a href="#12" class="mim-tip-reference" title="Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanne-Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., Robert, J. J. <strong>KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.</strong> Europ. J. Hum. Genet. 14: 824-830, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670688</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16670688">Gloyn et al. (2006)</a> identified a heterozygous G-to-T transversion in the KCNJ11 gene, resulting in a cys166-to-phe (C166F) substitution. The infant had feeding problem from birth and was diagnosed with diabetes mellitus at age 3 months. She also had seizures with hypsarrhythmia, progressive neurologic deterioration, diffuse hypotonia, and dysmorphic facial features. She died from aspiration pneumonia at age 6 months. <a href="#12" class="mim-tip-reference" title="Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanne-Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., Robert, J. J. <strong>KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.</strong> Europ. J. Hum. Genet. 14: 824-830, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670688</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16670688">Gloyn et al. (2006)</a> considered this patient to be a case of DEND (developmental delay, epilepsy, and neonatal diabetes). <a href="#12" class="mim-tip-reference" title="Gloyn, A. L., Diatloff-Zito, C., Edghill, E. L., Bellanne-Chantelot, C., Nivot, S., Coutant, R., Ellard, S., Hattersley, A. T., Robert, J. J. <strong>KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features.</strong> Europ. J. Hum. Genet. 14: 824-830, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16670688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16670688</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201629" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16670688">Gloyn et al. (2006)</a> noted that the C166F mutation is predicted to result in a channel with a marked increase in open probability and reduced sensitivity to ATP, which would severely alter the function of the channel in brain, muscle, and nerves, in addition to pancreatic beta cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16670688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356620 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356620;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=rs80356620" 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=rs80356620" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an Italian boy with a severe form of permanent neonatal diabetes with neurologic features (PNDM2; <a href="/entry/618856">618856</a>), <a href="#38" class="mim-tip-reference" title="Shimomura, K., Horster, F., de Wet, H., Flanagan, S. E., Ellard, S., Hattersley, A. T., Wolf, N. I., Ashcroft, F., Ebinger, F. <strong>A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.</strong> Neurology 69: 1342-1349, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17652641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17652641</a>] [<a href="https://doi.org/10.1212/01.wnl.0000268488.51776.53" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17652641">Shimomura et al. (2007)</a> identified a heterozygous de novo 499A-C transversion in the KCNJ11 gene, resulting in an ile167-to-leu (I167L) substitution at the cytoplasmic end of the second transmembrane domain near the internal gate of the channel. In vitro functional expression studies showed that the mutant I167L channel had severely impaired sensitivity to ATP and markedly increased open channel probability. Sulfonylurea treatment resulted in partial blockade of current in the mutant channels, and the patient showed a good response to sulfonylurea treatment, with both improved glycemic control and neurologic improvement. <a href="#38" class="mim-tip-reference" title="Shimomura, K., Horster, F., de Wet, H., Flanagan, S. E., Ellard, S., Hattersley, A. T., Wolf, N. I., Ashcroft, F., Ebinger, F. <strong>A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.</strong> Neurology 69: 1342-1349, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17652641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17652641</a>] [<a href="https://doi.org/10.1212/01.wnl.0000268488.51776.53" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17652641">Shimomura et al. (2007)</a> considered this patient to be a case of DEND (developmental delay, epilepsy, and neonatal diabetes). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17652641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs80356613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356613;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=rs80356613" 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=rs80356613" 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=RCV000009218 OR RCV002226644 OR RCV002250455 OR RCV002250456" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009218, RCV002226644, RCV002250455, RCV002250456" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009218...</a>
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<p>In a sister and brother with transient neonatal diabetes (TNDM3; <a href="/entry/610582">610582</a>), <a href="#14" class="mim-tip-reference" title="Gloyn, A. L., Reimann, F., Girard, C., Edghill, E. L., Proks, P., Pearson, E. R., Temple, I. K., Mackay, D. J. G., Shield, J. P. H., Freedenberg, D., Noyes, K., Ellard, S., Ashcroft, F. M., Gribble, F. M., Hattersley, A. T. <strong>Relapsing diabetes can result from moderately activating mutations in KCNJ11.</strong> Hum. Molec. Genet. 14: 925-934, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15718250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15718250</a>] [<a href="https://doi.org/10.1093/hmg/ddi086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15718250">Gloyn et al. (2005)</a> identified a heterozygous G-to-A transition in the KCNJ11 gene, resulting in a gly53-to-ser (G53S) substitution. The mutation was not identified in 100 control individuals. Both children had insulin-treated diabetes diagnosed in the first 3 weeks of life and went into remission by age 20 months. The affected mother was positive for the mutation but had a milder phenotype, having been diagnosed at age 4 years and requiring only a low dose of insulin for glycemic control. In transformed Xenopus oocytes, the G53S mutation resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15718250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0018 DIABETES MELLITUS, TRANSIENT NEONATAL, 3</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">rs80356613 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356613;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=rs80356613" 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=rs80356613" 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=RCV000009219" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009219" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009219</a>
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<p>In a male proband with transient neonatal diabetes (TNDM3; <a href="/entry/610582">610582</a>), <a href="#14" class="mim-tip-reference" title="Gloyn, A. L., Reimann, F., Girard, C., Edghill, E. L., Proks, P., Pearson, E. R., Temple, I. K., Mackay, D. J. G., Shield, J. P. H., Freedenberg, D., Noyes, K., Ellard, S., Ashcroft, F. M., Gribble, F. M., Hattersley, A. T. <strong>Relapsing diabetes can result from moderately activating mutations in KCNJ11.</strong> Hum. Molec. Genet. 14: 925-934, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15718250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15718250</a>] [<a href="https://doi.org/10.1093/hmg/ddi086" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15718250">Gloyn et al. (2005)</a> identified a heterozygous G-to-C transversion in the KCNJ11 gene, resulting in a gly53-to-arg (G53R) substitution. The mutation was not identified in 100 control individuals. The proband had insulin-treated diabetes diagnosed at age 16 weeks and went into remission by 17 months with relapse at age 28 months. The affected mother was positive for the mutation and was diagnosed with diabetes at 11 weeks with no periods of remission. Both mother and son had learning difficulties. In transformed Xenopus oocytes, the G53R mutation resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15718250" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0019 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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> rs74339576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs74339576;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/rs74339576?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=rs74339576" 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=rs74339576" 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=RCV000009220 OR RCV000671339 OR RCV001103550 OR RCV001103551 OR RCV001224980 OR RCV002227030 OR RCV003460444 OR RCV005042016" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009220, RCV000671339, RCV001103550, RCV001103551, RCV001224980, RCV002227030, RCV003460444, RCV005042016" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009220...</a>
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<p>In an infant with focal hyperinsulinism (HHF2; <a href="/entry/601820">601820</a>), <a href="#20" class="mim-tip-reference" title="Henwood, M. J., Kelly, A., MacMullen, C., Bhatia, P., Ganguly, A., Thornton, P. S., Stanley, C. A. <strong>Genotype-phenotype correlations in children with congenital hyperinsulinism due to recessive mutations of the adenosine triphosphate-sensitive potassium channel genes.</strong> J. Clin. Endocr. Metab. 90: 789-794, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15562009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15562009</a>] [<a href="https://doi.org/10.1210/jc.2004-1604" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15562009">Henwood et al. (2005)</a> identified heterozygosity for a paternally derived 902G-A transition in the KCNJ11 gene, resulting in an arg301-to-his (R301H) substitution. KCNJ11 with this mutation retained partial channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15562009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs1404429785 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1404429785;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/rs1404429785?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=rs1404429785" 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=rs1404429785" 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=RCV000009221 OR RCV002243628 OR RCV002243629" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009221, RCV002243628, RCV002243629" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009221...</a>
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<p>In a female proband with hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>), <a href="#32" class="mim-tip-reference" title="Pinney, S. E., MacMullen, C., Becker, S., Lin, Y.-W., Hanna, C., Thornton, P., Ganguly, A., Shyng, S.-L., Stanley, C. A. <strong>Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant K(ATP) channel mutations.</strong> J. Clin. Invest. 118: 2877-2886, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18596924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18596924</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18596924[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/JCI35414" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18596924">Pinney et al. (2008)</a> identified heterozygosity for a gly156-to-arg (G156R) substitution in the KCNJ11 gene. The mutation was also identified in her 34-year-old father, who had symptoms consistent with hypoglycemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18596924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0021 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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">rs80356615 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356615;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=rs80356615" 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=rs80356615" 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=RCV000009222 OR RCV000020349 OR RCV002226645" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009222, RCV000020349, RCV002226645" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009222...</a>
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<p><a href="#23" class="mim-tip-reference" title="Koster, J. C., Cadario, F., Peruzzi, C., Colombo, C., Nichols, C. G., Barbetti, F. <strong>The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy.</strong> J. Clin. Endocr. Metab. 93: 1054-1061, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18073297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18073297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18073297[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2007-1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18073297">Koster et al. (2008)</a> reported a 27-year-old female patient with intermediate developmental delay and neonatal diabetes (PNDM2; <a href="/entry/618856">618856</a>) in whom sequencing revealed a heterozygous gly53-to-asp (G53D) mutation in the KCNJ11 gene. Treatment was progressively transferred from insulin to the inhibitory sulfonylureas (SUs) gliclazide and finally to glibenclamide. The patient demonstrated improved glycemic control and motor coordination with SU treatment, with glibenclamide more effective than gliclazide. Reconstituted G53D channels exhibited reduced ATP sensitivity, which was predicted to suppress electrical activity in vivo. G53D channels coexpressed with the pancreatic and neuronal isoform of the sulfonylurea receptor SUR1 (<a href="/entry/600509">600509</a>) exhibited high-affinity block by gliclazide but were insensitive to block when coexpressed with the skeletal muscle isoform SUR2A (<a href="/entry/601439">601439</a>). <a href="#23" class="mim-tip-reference" title="Koster, J. C., Cadario, F., Peruzzi, C., Colombo, C., Nichols, C. G., Barbetti, F. <strong>The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy.</strong> J. Clin. Endocr. Metab. 93: 1054-1061, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18073297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18073297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18073297[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2007-1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18073297">Koster et al. (2008)</a> concluded that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle ATP-sensitive potassium channel. <a href="#23" class="mim-tip-reference" title="Koster, J. C., Cadario, F., Peruzzi, C., Colombo, C., Nichols, C. G., Barbetti, F. <strong>The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy.</strong> J. Clin. Endocr. Metab. 93: 1054-1061, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18073297/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18073297</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18073297[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1210/jc.2007-1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18073297">Koster et al. (2008)</a> noted that the G53D mutation had been reported by <a href="#9" class="mim-tip-reference" title="Flanagan, S. E., Edghill, E. L., Gloyn, A. L., Ellard, S., Hattersley, A. T. <strong>Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype.</strong> Diabetologia 49: 1190-1197, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16609879/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16609879</a>] [<a href="https://doi.org/10.1007/s00125-006-0246-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16609879">Flanagan et al. (2006)</a> in a patient with 'intermediate DEND,' which included seizures in infancy and abnormal electroencephalogram. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16609879+18073297" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs267607196 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607196;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/rs267607196?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=rs267607196" 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=rs267607196" 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=RCV000009223 OR RCV000763231 OR RCV002226646 OR RCV003466841 OR RCV003555984 OR RCV005042017" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009223, RCV000763231, RCV002226646, RCV003466841, RCV003555984, RCV005042017" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009223...</a>
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<p>In a Swedish patient with hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>) with focal adenomatous hyperplasia, <a href="#40" class="mim-tip-reference" title="Taneja, T. K., Mankouri, J., Karnik, R., Kannan, S., Smith, A. J., Munsey, T., Christesen, H. B. T., Beech, D. J., Sivaprasadarao, A. <strong>Sar1-GTPase-dependent ER exit of K(ATP) channels revealed by a mutation causing congenital hyperinsulinism.</strong> Hum. Molec. Genet. 18: 2400-2413, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19357197/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19357197</a>] [<a href="https://doi.org/10.1093/hmg/ddp179" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19357197">Taneja et al. (2009)</a> identified an 844G-A transition in the KCNJ11 gene, resulting in a glu282-to-lys (E282K) substitution within a diacidic endoplasmic reticulum (ER) exit signal DXE at codons 280 to 282. The paternal E282K mutation abrogated the exit signal and prevented the ER export and surface expression of the channel. Since in focal hyperinsulinemic hypoglycemia, the maternal chromosome containing the K(ATP) channel genes are lost, beta-cells of the patient would lack wildtype Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal chromosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19357197" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0023 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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">rs387906783 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906783;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=rs387906783" 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=rs387906783" 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=RCV000023046 OR RCV002226654" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023046, RCV002226654" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023046...</a>
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<p>In a patient with neonatal diabetes, developmental delay, and epilepsy (PNDM2; <a href="/entry/618856">618856</a>), <a href="#27" class="mim-tip-reference" title="Mannikko, R., Jefferies, C., Flanagan, S. E., Hattersley, A., Ellard, S., Ashcroft, F. M. <strong>Interaction between mutations in the slide helix of Kir6.2 associated with neonatal diabetes and neurological symptoms.</strong> Hum. Molec. Genet. 19: 963-972, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20022885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20022885</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20022885[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp554" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20022885">Mannikko et al. (2010)</a> identified heterozygosity for 2 novel mutations on the same haplotype (cis), phe60 to tyr (F60Y) and val64 to leu (V64L), in the slide helix of Kir6.2 (KCNJ11). Functional analysis revealed that the F60Y mutation increased the intrinsic channel open probability, thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell potassium-ATP currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same, but not a different, subunit. The authors concluded that F60Y is the pathogenic mutation and that interactions between slide helix residues may influence KATP channel gating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20022885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0024 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 13</strong>
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KCNJ11, GLU227LYS
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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> rs587783672 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587783672;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/rs587783672?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=rs587783672" 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=rs587783672" 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=RCV000146115 OR RCV000170299 OR RCV001288659 OR RCV001329964 OR RCV002051813 OR RCV002227076" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000146115, RCV000170299, RCV001288659, RCV001329964, RCV002051813, RCV002227076" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000146115...</a>
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<p><a href="#2" class="mim-tip-reference" title="Bonnefond, A., Philippe, J., Durand, E., Dechaume, A., Huyvaert, M., Montagne, L., Marre, M., Balkau, B., Fajardy, I., Vambergue, A., Vatin, V., Delplanque, J., Le Guilcher, D., De Graeve, F., Lecoeur, C., Sand, O., Vaxillaire, M., Froguel, P. <strong>Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene.</strong> PLoS One 7: e37423, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22701567/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22701567</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22701567[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/10.1371/journal.pone.0037423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22701567">Bonnefond et al. (2012)</a> analyzed a 4-generation French family with maturity-onset diabetes of the young-13 (MODY13; <a href="/entry/616329">616329</a>), including 12 affected individuals; 2 additional individuals had impaired fasting glucose and impaired glucose tolerances, respectively. Twenty-two relatives were unaffected. Whole-exome sequencing was performed on 4 individuals: a patient with diabetes diagnosed at age 17 years, his father who developed diabetes at age 20, an unaffected mother, and a diabetic man diagnosed at age 13. The only mutation that segregated with all family members was a c.679G-A transition (c.679G-A, NM_000525.3) resulting in a glu227-to-lys (E227K) substitution in the KCNJ11 gene. Linkage analysis using a dominant parametric model showed a lod score of 3.68 at KCNJ11 lys227. Lod scores were even higher using nonparametric linkage. This mutation was not found in the dbSNP (build 130) database, in 406 French controls, or in any of 22 French probands with MODY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22701567" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0025 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
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KCNJ11, 3-BP DEL, NT892
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1953574433 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1953574433;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=rs1953574433" 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=rs1953574433" 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=RCV001270679 OR RCV002226762" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001270679, RCV002226762" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001270679...</a>
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<p>In a patient (patient 11-III-a) with hyperinsulinemic hypoglycemia (HHF2; <a href="/entry/601820">601820</a>) who presented on the first day of life, <a href="#3" class="mim-tip-reference" title="Boodhansingh, K. E., Kandasamy, B., Mitteer, L., Givler, S., De Leon, D. D., Shyng, S.-L., Ganguly, A., Stanley, C. A. <strong>Novel dominant K(atp) channel mutations in infants with congenital hyperinsulinism: validation by in vitro expression studies and in vivo carrier phenotyping.</strong> Am. J. Med. Genet. 179A: 2214-2227, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31464105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31464105</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31464105[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/10.1002/ajmg.a.61335" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31464105">Boodhansingh et al. (2019)</a> identified a paternally inherited heterozygous 3-bp deletion (c.892_894del) in the KCNJ11 gene, resulting in the deletion of threonine-298 (thr298del). The mutation was identified by direct gene sequencing and was absent in the gnomAD database. The father did not report symptoms of hypoglycemia, but phenotype testing (fasting test, oral protein tolerance test, oral glucose tolerance test) showed evidence for abnormal regulation of glucose. The rubidium ion efflux assay of Kir6.2 with deletion of thr298 expressed in COSm6 cells demonstrated impaired ATP-dependent potassium channel efflux. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31464105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>REFERENCES</strong>
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Bellanne-Chantelot, C., Saint-Martin, C., Ribeiro, M.-J., Vaury, C., Verkarre, V., Arnoux, J.-B., Valayannopoulos, V., Gobrecht, S., Sempoux, C., Rahier, J., Fournet, J.-C., Jaubert, F., Aigrain, Y., Nihoul-Fekete, C., de Lonlay, P.
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<strong>ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.</strong>
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J. Med. Genet. 47: 752-759, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20685672/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20685672</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20685672" 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/10.1136/jmg.2009.075416" target="_blank">Full Text</a>]
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Bonnefond, A., Philippe, J., Durand, E., Dechaume, A., Huyvaert, M., Montagne, L., Marre, M., Balkau, B., Fajardy, I., Vambergue, A., Vatin, V., Delplanque, J., Le Guilcher, D., De Graeve, F., Lecoeur, C., Sand, O., Vaxillaire, M., Froguel, P.
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<strong>Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene.</strong>
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PLoS One 7: e37423, 2012. Note: Electronic Article.
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[<a href="https://doi.org/10.1056/NEJMoa032922" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi086" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20292" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s001250051098" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/humu.20124" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15583126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15583126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15583126[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=15583126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0404756101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi305" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s00439-009-0731-9" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/S0006-3495(03)74847-4" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17463248/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17463248</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17463248[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=17463248" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1142382" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000268488.51776.53" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2006-0201" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp179" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.11.1809" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2004-1233" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1059829" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1210/jc.2005-0096" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1142364" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 12/04/2024
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 12/17/2020<br>Marla J. F. O'Neill - updated : 06/13/2018<br>Ada Hamosh - updated : 04/20/2015<br>George E. Tiller - updated : 11/10/2011<br>Ada Hamosh - updated : 9/1/2010<br>Marla J. F. O'Neill - updated : 8/25/2010<br>Patricia A. Hartz - updated : 8/2/2010<br>Marla J. F. O'Neill - updated : 4/19/2010<br>George E. Tiller - updated : 3/30/2010<br>John A. Phillips, III - updated : 4/27/2009<br>Marla J. F. O'Neill - updated : 3/20/2009<br>George E. Tiller - updated : 12/10/2008<br>Patricia A. Hartz - updated : 8/22/2008<br>Marla J. F. O'Neill - updated : 5/16/2008<br>George E. Tiller - updated : 4/29/2008<br>Cassandra L. Kniffin - updated : 3/27/2008<br>Ada Hamosh - updated : 7/24/2007<br>John A. Phillips, III - updated : 6/20/2007<br>Cassandra L. Kniffin - updated : 3/2/2007<br>John A. Phillips, III - updated : 11/20/2006<br>John A. Phillips, III - updated : 11/20/2006<br>John A. Phillips, III - updated : 11/20/2006<br>Victor A. McKusick - updated : 4/28/2006<br>Marla J. F. O'Neill - updated : 4/6/2006<br>Marla J. F. O'Neill - updated : 3/21/2006<br>Marla J. F. O'Neill - updated : 3/16/2006<br>John A. Phillips, III - updated : 7/22/2005<br>Marla J. F. O'Neill - updated : 7/8/2005<br>Victor A. McKusick - updated : 2/2/2005<br>Victor A. McKusick - updated : 1/27/2005<br>Victor A. McKusick - updated : 5/6/2004<br>Patricia A. Hartz - updated : 3/11/2003<br>Ada Hamosh - updated : 6/8/2001<br>Stylianos E. Antonarakis - updated : 4/21/2000<br>Moyra Smith - updated : 1/31/1997<br>Perseveranda M. Cagas - updated : 9/23/1996
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott : 11/13/1995
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/04/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/22/2024<br>carol : 12/17/2020<br>alopez : 12/01/2020<br>carol : 09/02/2020<br>alopez : 04/30/2020<br>alopez : 04/30/2020<br>alopez : 06/13/2018<br>carol : 04/06/2017<br>carol : 09/12/2016<br>alopez : 04/20/2015<br>terry : 11/13/2012<br>alopez : 11/15/2011<br>terry : 11/10/2011<br>alopez : 9/2/2010<br>terry : 9/1/2010<br>wwang : 8/26/2010<br>wwang : 8/26/2010<br>terry : 8/25/2010<br>mgross : 8/10/2010<br>terry : 8/2/2010<br>terry : 4/19/2010<br>wwang : 4/6/2010<br>terry : 3/30/2010<br>alopez : 4/27/2009<br>wwang : 3/30/2009<br>terry : 3/20/2009<br>wwang : 12/10/2008<br>mgross : 8/25/2008<br>terry : 8/22/2008<br>carol : 5/16/2008<br>wwang : 5/16/2008<br>wwang : 5/1/2008<br>terry : 4/29/2008<br>wwang : 4/2/2008<br>ckniffin : 3/27/2008<br>alopez : 7/27/2007<br>alopez : 7/27/2007<br>alopez : 7/27/2007<br>alopez : 7/27/2007<br>terry : 7/24/2007<br>carol : 6/20/2007<br>mgross : 4/13/2007<br>wwang : 3/14/2007<br>ckniffin : 3/2/2007<br>carol : 1/25/2007<br>alopez : 11/21/2006<br>alopez : 11/20/2006<br>alopez : 11/20/2006<br>alopez : 11/20/2006<br>carol : 9/27/2006<br>alopez : 8/21/2006<br>alopez : 8/21/2006<br>carol : 8/11/2006<br>carol : 8/11/2006<br>alopez : 5/2/2006<br>terry : 4/28/2006<br>wwang : 4/7/2006<br>terry : 4/6/2006<br>carol : 3/23/2006<br>carol : 3/22/2006<br>carol : 3/21/2006<br>carol : 3/20/2006<br>carol : 3/17/2006<br>carol : 3/16/2006<br>alopez : 7/22/2005<br>alopez : 7/22/2005<br>wwang : 7/14/2005<br>terry : 7/8/2005<br>wwang : 5/11/2005<br>wwang : 4/12/2005<br>carol : 2/17/2005<br>carol : 2/17/2005<br>ckniffin : 2/14/2005<br>carol : 2/14/2005<br>terry : 2/3/2005<br>terry : 2/2/2005<br>terry : 1/27/2005<br>carol : 12/3/2004<br>tkritzer : 12/3/2004<br>terry : 5/6/2004<br>mgross : 3/14/2003<br>terry : 3/11/2003<br>cwells : 6/12/2001<br>cwells : 6/11/2001<br>terry : 6/8/2001<br>mgross : 4/21/2000<br>dkim : 12/10/1998<br>dkim : 12/9/1998<br>alopez : 10/27/1998<br>mark : 9/22/1997<br>terry : 1/31/1997<br>mark : 1/30/1997<br>mark : 9/23/1996<br>mark : 9/23/1996<br>terry : 2/6/1996<br>mark : 11/16/1995
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<h3>
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<span class="mim-font">
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<strong>*</strong> 600937
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<h3>
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<span class="mim-font">
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POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 11; KCNJ11
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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POTASSIUM CHANNEL, INWARDLY RECTIFYING, BIR SUBUNIT<br />
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BETA-CELL INWARD RECTIFIER SUBUNIT; BIR<br />
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INWARDLY RECTIFYING POTASSIUM CHANNEL Kir6.2
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</span>
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</h4>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KCNJ11</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> 609581006;
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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: 11p15.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:17,385,248-17,389,346 </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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<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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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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<tbody>
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<td rowspan="4">
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<span class="mim-font">
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11p15.1
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<td>
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<span class="mim-font">
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Diabetes mellitus, transient neonatal 3
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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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610582
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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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Diabetes, permanent neonatal 2, with or without neurologic features
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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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618856
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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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</span>
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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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Hyperinsulinemic hypoglycemia, familial, 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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601820
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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; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<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 13
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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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616329
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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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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>ATP-sensitive K+ (KATP) channels couple cell metabolism to membrane excitability in various cell types, including pancreatic beta cells, neurons, endocrine cells, and muscle cells. The archetypal KATP channel is an octameric complex of KCNJ11 subunits and either SUR1 (ABCC8; 600509) subunits in pancreatic beta cells and many neurons or SUR2 (ABCC9; 601439) subunits in muscle. Four KCNJ11 subunits form the channel pore, and each is associated with a SUR subunit that contributes to regulation of channel gating (summary by Girard et al., 2009). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Inagaki et al. (1995) cloned a member of the inwardly rectifying potassium channel family, which they called BIR, for 'beta-cell inward rectifier,' or Kir6.2, in the nomenclature of Chandy and Gutman (1993). The channel was expressed in large amounts in rat pancreatic islets and glucose-responsive insulin-secreting cell lines. The sequence showed a single open reading frame encoding a 390-amino acid protein with 2 putative transmembrane segments. The mouse homolog also had a single open reading frame encoding a 390-amino acid protein with 96% amino acid identity with human BIR. </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>Inagaki et al. (1995) determined that KCNJ11, the gene encoding human BIR, is intronless in the protein-coding region. Several other genes encoding inward rectifiers lack introns. </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>By fluorescence in situ hybridization, Inagaki et al. (1995) mapped the BIR gene to 11p15.1. The sequence obtained from 1 lambda clone at the 3-prime end of the SUR gene (ABCC8; 600509) matched a part of the gene encoding BIR; with a sense primer near the 3-prime end of the SUR gene and an antisense primer near the 5-prime end of the BIR gene they PCR-amplified an approximately 4.5-kb fragment. Thus, the authors determined that the 2 genes are clustered at 11p15.1, with the BIR gene immediately 3-prime of the SUR gene. The SUR gene had previously been mapped to 11p15.1 by fluorescence in situ hybridization (Thomas et al., 1995). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In pancreatic beta cells, ATP-potassium channels are crucial for the regulation of glucose-induced insulin secretion and are the target for the sulfonylureas, oral hypoglycemic agents widely used in the treatment of noninsulin-dependent diabetes mellitus (NIDDM; 125853), and for diazoxide, a potassium channel opener. The sulfonylurea receptor (SUR) is a member of the ATP-binding cassette superfamily with multiple transmembrane-spanning domains and 2 potential nucleotide-binding folds. Inagaki et al. (1995) demonstrated that coexpression of BIR with SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to ATP and was inhibited by sulfonylureas and activated by diazoxide. The data indicated to the authors that these pancreatic beta-cell potassium channels are a complex composed of at least 2 subunits: BIR and SUR. </p><p>Inagaki et al. (1996) cloned rat SUR2 (601439) and found that coexpression of SUR2 and BIR in COS-1 cells reconstituted the properties of K(ATP) channels described in cardiac and skeletal muscle. However, they found that the SUR2/BIR channel is less sensitive than the SUR/BIR channel both to ATP and to the sulfonylurea glibenclamide, and is activated by the cardiac K(ATP) channel openers cromakalim and pinacidil but not by diazoxide. The affinity of SUR2 for sulfonylureas is 500 times lower than that of SUR. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Familial Hyperinsulinemic Hypoglycemia 2</em></strong></p><p>
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Thomas et al. (1996) screened genomic DNA from members of 15 families with hyperinsulinemic hypoglycemia (HHF2; 601820) for mutations in the KCNJ11 gene. In a male infant with profound hypoglycemia, born of consanguineous Iranian parents, Thomas et al. (1996) identified homozygosity for a 649T-C mutation (600937.0001). His parents were heterozygous for the mutation. </p><p>Using SSCP and nucleotide sequence analysis, Nestorowicz et al. (1997) screened 78 patients with hyperinsulinism for mutations in the KCNJ11 gene and identified homozygosity for a nonsense mutation (600937.0009) in 1 patient. </p><p>De Lonlay et al. (1997) showed that in cases of the focal form, but not those of the diffuse form, of hyperinsulinemic hypoglycemia there was specific loss of maternal alleles of the imprinted chromosome region 11p15 in cells of the hyperplastic area of the pancreas but not in normal pancreatic cells. This somatic event was consistent with a proliferative monoclonal lesion. It involves disruption of the balance between monoallelic expression of several maternally and paternally expressed genes. Thus, they provided the first molecular explanation for the heterogeneity of sporadic forms of PHHI such that it is possible to perform only partial pancreatectomy, limited to the focal somatic lesion, so as to avoid iatrogenic diabetes in patients with focal adenomatous hyperplasia. It is possible that in these cases of somatic loss of maternal 11p15.1, there is reduction to homozygosity for a recessive ABCC8 or KCNJ11 mutation on the paternal allele, since both ABCC8 and KCNJ11 are located in the 11p15.1 region. </p><p>Tornovsky et al. (2004) screened 15 patients with neonatal hyperinsulinemic hypoglycemia for mutations in the ABCC8 and KCNJ11 genes and identified 12 mutations in 11 patients. Homozygosity for a mutation in the promoter (600937.0010) and in exon 1 (600937.0011) of the KCNJ11 gene were identified in an Israeli Bedouin and an Arab patient, respectively. </p><p>Henwood et al. (2005) measured acute insulin responses (AIRs) to calcium, leucine, glucose, and tolbutamide in 22 infants with recessive ABCC8 or KCNJ11 mutations (see, e.g., 600937.0019), 8 of whom had diffuse hyperinsulinism and 14 of whom had focal hyperinsulinism. Of the 24 total mutations, 7 showed evidence of residual K(ATP) channel function: 2 of the patients with partial defects were homozygous and 4 heterozygous for amino acid substitutions or insertions, and 1 was a compound heterozygote for 2 premature stop codons. </p><p>Lin et al. (2008) investigated the mechanisms by which hyperinsulinism-associated mutations of arg301 (R301) in KCNJ11 (e.g., R301H; 600937.0019) lead to channel dysfunction. They found that R301 mutations in rat Kcnj11 resulted in reduced channel expression at the cell surface in transfected cells and caused rapid, spontaneous current decay, or inactivation. Mutagenesis studies indicated that R301 is near the Kcnj11 subunit-subunit interface and likely stabilizes channel activity. To evaluate the effects of channel inactivation on beta cell function, Lin et al. (2008) expressed an alternative R301 mutation, R301A, which induces channel inactivation without affecting channel surface expression, in a rat insulinoma cell line. Expression of Kcnj11 with R301A resulted in more depolarized membrane potential and elevated insulin secretion at basal glucose concentration compared with cells expressing wildtype channels. Lin et al. (2008) concluded that mutations at R301 may cause channel inactivation by disrupting subunit-subunit interactions, and that this gating defect is sufficient to cause loss of channel function and hyperinsulinism. </p><p>Pinney et al. (2008) identified 14 different dominantly inherited K(ATP) channel mutations in 16 unrelated families, 13 with mutations in the ABCC8 gene (see, e.g., 600509.0011) and 3 with mutations in the KCNJ11 gene (see, e.g., 600937.0020). Unlike recessive mutations, dominantly inherited K(ATP) mutant subunits trafficked normally to the plasma membrane when expressed in simian kidney cells; dominant mutations also resulted in different channel-gating defects, with dominant ABCC8 mutations diminishing channel responses to magnesium adenosine diphosphate or diazoxide and dominant KCNJ11 mutations impairing channel opening even in the absence of nucleotides. Pinney et al. (2008) concluded that there are distinctive features of dominant K(ATP) hyperinsulinism compared to the more common and more severe recessive form, including retention of normal subunit trafficking, impaired channel activity, and a milder hypoglycemia phenotype that may escape detection in infancy and is often responsive to diazoxide medical therapy. </p><p>Taneja et al. (2009) reported that the Kir6.2 channel contains a diacidic ER exit signal DXE at codons 280 to 282, which promotes concentration of the channel into COPII-enriched ER exit sites prior to ER export via a process that requires Sar1-GTPase (607690). They identified an E282K mutation (600937.0022) in a Swedish patient with HHF2 with focal adenomatous hyperplasia. The E282K mutation abrogated the ER exit signal and prevented ER export and surface expression of the channel. When coexpressed, the E282K-mutant subunit was able to associate with the wildtype Kir6.2 and form functional channels, and unlike most mutations did not cause protein misfolding. Since in focal congenital hyperinsulinism, the maternal chromosome containing the K(ATP) channel genes is lost, beta-cells of the patient lacked wildtype Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal chromosome. The resultant absence of functional KATP channels leads to insulin hypersecretion. Taneja et al. (2009) concluded that surface expression of K(ATP) channels is critically dependent on the Sar1-GTPase-dependent ER exit mechanism, and abrogation of the diacidic ER exit signal leads to congenital hyperinsulinism. </p><p>Bellanne-Chantelot et al. (2010) analyzed the ABCC8 and KCNJ11 genes in 109 diazoxide-unresponsive patients with congenital hyperinsulinism and identified mutations in 89 (82%) of the probands. A total of 118 mutations were found, including 106 (90%) in ABCC8 and 12 (10%) in KCNJ11; 94 of the 118 were different mutations, and 41 had previously been reported. The 37 patients diagnosed with focal disease all had heterozygous mutations, whereas 30 (47%) of 64 patients known or suspected to have diffuse disease had homozygous or compound heterozygous mutations, 22 (34%) had a heterozygous mutation, and 12 (19%) had no mutation in the ABCC8 or KCNJ11 genes. </p><p><strong><em>Diabetes Mellitus Type 2 Susceptibility</em></strong></p><p>
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Hani et al. (1998) identified an association between an E23K variant in the KCNJ11 gene (600937.0014) and type 2 diabetes mellitus (T2D; 125853) in French families. </p><p>Hansen et al. (2005) studied the effects of the E23K polymorphism and a PPARG P12A polymorphism (601487.0002) on the risk of type 2 diabetes and found that the polymorphisms may act in an additive manner to increase the risk of type 2 diabetes. </p><p><strong><em>Permanent Neonatal Diabetes Mellitus 2</em></strong></p><p>
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Because ATP-sensitive potassium channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, Gloyn et al. (2004) hypothesized that activating mutations in the KCNJ11 gene might cause neonatal diabetes. They studied 29 patients with permanent neonatal diabetes (PNDM2; 618856) characterized by ketoacidosis or marked hyperglycemia who were treated with insulin. The patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; 3 of them also had epilepsy and mild dysmorphic features (DEND). Gloyn et al. (2004) sequenced the KCNJ11 gene in all 29 patients and identified 6 novel, heterozygous missense mutations in 10. In 4 of the 10 families, the mutation was an arg201-to-his (R201H) substitution (600937.0002). In 2 patients, the diabetes was familial. In 8 patients, the diabetes arose from a spontaneous mutation (see, e.g., V59M; 600937.0003). When the most common mutation, R201H, was coexpressed with SUR in Xenopus oocytes, the ability of ATP to block mutant ATP-sensitive potassium channels was greatly reduced. Thus, whereas inactivating mutations of KCNJ11 lead to uncontrolled insulin secretion and congenital hyperinsulinism, activating mutations cause neonatal diabetes. Gloyn et al. (2004) concluded that heterozygous activating mutations of the KCNJ11 gene are a common cause (approximately 34%) of permanent neonatal diabetes. In a high proportion (80%) of subjects studied in their series, the mutation occurred de novo. </p><p>Gloyn et al. (2005) identified 3 novel heterozygous mutations (see, e.g., 600937.0017-600937.0018) in 3 of 11 probands with clinically defined TNDM who did not have chromosome 6q24 abnormalities. The mutations cosegregated with diabetes in 2 families and were not found in 100 controls. All 3 probands had insulin-treated diabetes diagnosed in the first 4 months of life and went into remission by 7 to 17 months of age. In transformed Xenopus oocytes, all 3 heterozygous mutations resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated mutations. Gloyn et al. (2005) concluded that mutations in KCNJ11 can cause both remitting and permanent diabetes, suggesting that a fixed ion channel abnormality may result in a fluctuating glycemic phenotype. </p><p>Proks et al. (2005) studied the MgATP sensitivity of neonatal diabetes-causing KCNJ11-mutant K(ATP) channels expressed in Xenopus oocytes. In contrast to wildtype channels, Mg(2+) dramatically reduced the ATP sensitivity of heterozygous R201C (600937.0004), R201H, V59M, and V59G (600937.0005) channels. This effect was predominantly mediated via the nucleotide-binding domains of SUR1 (ABCC8; 600509) and resulted from an enhanced stimulatory action of MgATP. Proks et al. (2005) concluded that KCNJ11 mutations increase the current magnitude of heterozygous K(ATP) channels by increasing MgATP activation and by decreasing ATP inhibition. The fraction of unblocked K(ATP) current at physiologic MgATP concentrations correlated with the severity of the clinical phenotype. </p><p><strong><em>Transient Neonatal Diabetes Mellitus 3</em></strong></p><p>
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Yorifuji et al. (2005) found a missense mutation in the KCNJ11 gene (600937.0012) in a 4-generation family with dominantly inherited diabetes mellitus observed in 3 generations. The onset and severity of the diabetes were variable: transient neonatal diabetes (TNDM3; 610582), childhood-onset diabetes, gestational diabetes, or maturity-onset diabetes of the young. </p><p>In a 20-year-old woman who had transient neonatal diabetes mellitus that recurred at age 7 years, Colombo et al. (2005) identified heterozygosity for a de novo R201H mutation in the KCNJ11 gene. </p><p><strong><em>Maturity-Onset Diabetes of the Young 13</em></strong></p><p>
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Yorifuji et al. (2005) and Bonnefond et al. (2012) reported families in which affected members had autosomal dominant early-onset diabetes that was responsive to sulfonylureas. The disease usually manifested before age 25 years and occurred in nonobese individuals, suggesting a diagnosis of maturity-onset diabetes of the young (MODY13; 616329). </p><p><strong><em>Association with Impaired Exercise Stress Response</em></strong></p><p>
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Reyes et al. (2009) found that the E23K polymorphism (600937.0014) was overrepresented in individuals with dilated cardiomyopathy (see 115200) and congestive heart failure (CHF) compared to controls, and that the KK genotype was associated with abnormal cardiopulmonary exercise stress testing. Reyes et al. (2009) suggested that E23K might represent a biomarker for impaired stress performance. </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>Genotype/Phenotype Correlations</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>To determine why some mutations in the KCNJ11 gene cause PNDM in isolation whereas others cause PNDM associated with marked developmental delay, muscle weakness, and epilepsy, Proks et al. (2004) expressed wildtype or mutant Kir6.2/sulfonylurea receptor-1 channels in Xenopus oocytes. All of the mutations investigated (R201C, Q52R, and V59G) increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but in the simulated heterozygous state, the mutation causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). These findings suggested that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extra pancreatic cell function. Proks et al. (2004) also found that mutations causing PNDM alone impaired ATP sensitivity directly (at the binding site), whereas those associated with severe disease acted indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflected the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. The results showed that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating and suggesting that the efficacy of sulfonylurea therapy in PNDM may vary with genotype. </p><p>Massa et al. (2005) screened the KCNJ11 gene in 18 Italian patients with what they termed 'permanent diabetes mellitus of infancy' (PDMI), including 12 patients with onset within 3 months after birth and 6 with onset between 3 months to 1 year of age. Five different heterozygous mutations were identified in 8 patients with diabetes diagnosed between day 3 and day 182. Two of these mutations were novel. Four of the 8 patients also had motor and/or developmental delay. Massa et al. (2005) concluded that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. </p><p>The beta-cell ATP-sensitive potassium channel is a key component of stimulus-secretion coupling in the pancreatic beta cell. The channel couples metabolism to membrane electrical events, bringing about insulin secretion. Given the critical role of this channel in glucose homeostasis, it is not surprising that mutations in the genes encoding the 2 essential subunits of the channel, KCNJ11 and ABCC8, can result in either hypoglycemia or hyperglycemia. Gloyn et al. (2006) reviewed the loss-of-function mutations in KCNJ11 and ABCC8, which can cause oversecretion of insulin and result in hyperinsulinemia of infancy. They reviewed the management of patients in whom mutations in these genes are found. </p><p>From a study of 49 patients with activating Kir6.2 mutations, Slingerland and Hattersley (2006) concluded that these mutations cause a severe reduction in fetal insulin secretion and hence fetal growth but that this is independent of mutation severity. Postnatal catch-up required insulin treatment but was complete, except in those with epilepsy. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Miki et al. (1997) generated transgenic mice expressing a dominant-negative mutation within the conserved gly-tyr-gly motif of the putative K(+)-permeable domain of Kcnj11. The gene was inserted downstream of the human insulin promoter region for selective expression in pancreatic beta cells. Transgenic mice developed hypoglycemia with hyperinsulinemia as neonates and hyperglycemia with hypoinsulinemia and decreased beta cell numbers as adults. Kcnj11 function was impaired in the beta cells of transgenic mice with hyperglycemia, and both resting membrane potential and basal calcium concentrations were significantly elevated in transgenic mice. Miki et al. (1997) also observed a high frequency of apoptotic beta cells prior to the development of hyperglycemia, suggesting a role for Kcnj11 in cell survival as well as in regulating insulin secretion. </p><p>Koster et al. (2000) generated transgenic mice expressing pancreatic beta-cell K(ATP) channels with reduced ATP sensitivity. They used transgenes with truncation of the N-terminal 30 amino acids of the Kir6.2 subunit, and a double mutant with the 30-amino acid truncation and a lys185-to-gln mutation. These transgenes were fused at the C terminus with the green fluorescent protein to allow for detection under ultraviolet illumination. Transgenic animals developed severe hyperglycemia, hypoinsulinemia, and ketoacidosis within 2 days, and typically died within 5 days. Nevertheless, islet morphology, insulin localization, and alpha- and beta-cell distributions were normal (before day 3), pointing to reduced insulin secretion as causal. The data indicated that normal K(ATP) channel activity is critical for maintenance of euglycemia and that overactivity can cause diabetes by inhibiting insulin secretion. </p><p>In mice with a conditional deletion of Hnf4a (600281) in pancreatic beta cells, Gupta et al. (2005) observed hyperinsulinemia in fasted and fed animals but also impaired glucose tolerance. Islet perfusion and calcium-imaging studies showed abnormal beta cell responses to stimulation by glucose and sulfonylureas, explainable in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. Cotransfection assays revealed that the Kir6.2 gene is a transcriptional target of HNF4A. Gupta et al. (2005) concluded that HNF4A is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel. </p><p>ATP-sensitive potassium channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata, the area with the highest expression of ATP-sensitive potassium channels in the brain, plays a pivotal role in the control of seizures. Yamada et al. (2001) studied mutant mice lacking the Kir6.2 subunit of ATP-sensitive potassium channels and found that they were susceptible to generalized seizures after brief hypoxia. In normal mice, the substantia nigra pars reticulata neuron activity was inactivated during hypoxia by the opening of the postsynaptic ATP-sensitive potassium channels, whereas in knockout mice, the activity of these neurons was enhanced. ATP-sensitive potassium channels exert a depressant effect on substantia nigra pars reticulata neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures. </p><p>Girard et al. (2009) created a mouse strain conditionally expressing the human Kir6.2 V59M mutation (600937.0003) specifically in pancreatic beta cells. Kir6.2(V59M) mRNA was expressed at a level comparable to that of endogenous wildtype Kir6.2 mRNA. Mutant mice (beta-V59M mice) developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Isolated beta-V59M islets displayed a reduced percentage of beta cells, abnormal morphology, abnormal calcium oscillations, lower insulin content, and decreased expression of Kir6.2, Sur1, and insulin mRNA. Beta-V59M islets secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose than wildtype islets, which was due to reduced sensitivity of Kir6.2(V69M) channels to ATP or glucose. Current and secretion events downstream of channel closure remained intact. </p><p>By using mice carrying the human V59M mutation in Kir6.2 (600937.0003) targeted to either muscle or nerve, Clark et al. (2010) showed that analogous motor impairments originate in the central nervous system rather than in muscle or peripheral nerves. Clark et al. (2010) also identified locomotor hyperactivity as a feature of K(ATP) channel overactivity. Clark et al. (2010) concluded that their finding suggested that drugs targeted against neuronal, rather than muscle, K(ATP) channels are needed to treat the motor deficits and that such drugs require high blood-brain barrier permeability. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>25 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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KCNJ11, LEU147PRO
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SNP: rs28936678,
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gnomAD: rs28936678,
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ClinVar: RCV000009197, RCV002227020, RCV005089216
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<span class="mim-text-font">
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<p>In a male infant with profound hypoglycemia (HHF2; 601820), born of consanguineous Iranian parents, Thomas et al. (1996) identified homozygosity for a 649T-C mutation in the KCNJ11 gene, resulting in a leu147-to-pro (L147P) substitution predicted to cause disruption of the M2 alpha-helical transmembrane domain of the protein. His parents were heterozygous for the mutation. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 DIABETES MELLITUS, PERMANENT NEONATAL, 2</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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DIABETES MELLITUS, TRANSIENT NEONATAL, 3, INCLUDED
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</span>
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</div>
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<span class="mim-text-font">
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KCNJ11, ARG201HIS
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<br />
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SNP: rs80356624,
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gnomAD: rs80356624,
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ClinVar: RCV000009198, RCV000009200, RCV000146114, RCV000712160, RCV001089463, RCV002051777, RCV002227021
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</span>
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<span class="mim-text-font">
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<p />
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<p><strong><em>Permanent Neonatal Diabetes Mellitus 2</em></strong></p><p>
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In 4 unrelated patients with permanent neonatal diabetes (PNDM2; 618856), Gloyn et al. (2004) identified a heterozygous arg201-to-his (R201H) mutation in the KCNJ11 gene. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (Ribalet et al., 2003). In 1 family reported by Gloyn et al. (2004), 2 brothers and the father were affected. Diabetes in the brothers was diagnosed under the age of 3 or 4 weeks, and in the father at the age of 12 weeks. The father was age 46 years at the time of report. In another family, mother and son were affected. The diagnosis had been made at birth in the son and at age 6 weeks in the mother, who was 36 years old at the time of report. None of the patients with the R201H mutation had muscle weakness, neurologic abnormalities, or dysmorphic features. The arginine residue at position 201 of Kir6.2 lies close to the ATP-binding site and was previously implicated in ATP sensing. </p><p>By functional expression studies in Xenopus oocytes, Proks et al. (2004) found that mutations at the arg201 residue (see also R201C; 600937.0004) caused a decrease in ATP sensitivity by altering the ATP-binding site. However, the decreased sensitivity found in cells with a mutation at arg201 was not as severe as that found in cells with a mutation at val59 (see V59M, 600937.0003 and V59G, 600937.0005). </p><p>Gloyn et al. (2006) reported 2 unrelated infants with PNDM and the R201H mutation. The male infant (family NECKER4) also had dysmorphic facial features and neurologic involvement, including seizures, developmental delay, and axial hypotonia. On the basis of clinical and neuroimaging findings, the neurological involvement was thought to represent acute cerebral edema, which is a known complication of severe ketoacidosis in young children. The facial dysmorphism was considered to be unlike the classical features reported in other cases of syndromic PNDM. In contrast, the other infant (family NECKER6) did not have neurologic involvement, and her mother, who also carried the mutation, had severe diabetes mellitus without neurologic involvement. </p><p><strong><em>Transient Neonatal Diabetes Mellitus 3</em></strong></p><p>
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In a 20-year-old woman with transient neonatal diabetes mellitus (TNDM3; 610582) in whom diabetes remitted at age 29 months and recurred at age 7 years, Colombo et al. (2005) identified heterozygosity for a de novo 602G-A (R201H) mutation in the KCNJ11 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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<h4>
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<span class="mim-font">
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<strong>.0003 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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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KCNJ11, VAL59MET
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<br />
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SNP: rs80356616,
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ClinVar: RCV000009201, RCV000030665, RCV000146104, RCV000724752, RCV002051778, RCV002227022
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated males (ISPAD54 and ISPAD55) with permanent neonatal diabetes (PNDM2; 618856), Gloyn et al. (2004) found heterozygosity for a val59-to-met (V59M) mutation in the KCNJ11 gene. One of the patients (ISPAD55) had muscle weakness and delayed motor and mental development. </p><p>Proks et al. (2004) noted that 2 mutations in the same residue of Kir6.2, V59M and V59G (600937.0005), are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (600937.0002) and R201C (600937.0004). They found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the 'slide helix,' a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel. </p><p>Massa et al. (2005) found the V59M mutation in 4 unrelated Italian patients with PNDM. Two of the patients had motor and mental developmental delay. One of the patients was diagnosed at over 6 months of age (182 days). Massa et al. (2005) suggested that the designation 'permanent diabetes mellitus of infancy' (PDMI) replace 'permanent neonatal diabetes mellitus.' </p><p>Gloyn et al. (2006) reported a patient (ANGERS1) with the V59M mutation who had PNDM and neurologic features, including mild motor developmental delay and axial hypotonia. </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 DIABETES MELLITUS, PERMANENT NEONATAL, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ11, ARG201CYS
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<br />
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SNP: rs80356625,
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ClinVar: RCV000009202, RCV000146113, RCV001089465, RCV001530196, RCV001851755, RCV002051779, RCV002227023, RCV002227024, RCV005051732
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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 permanent neonatal diabetes mellitus (PNDM2; 618856), Gloyn et al. (2004) identified a heterozygous arg201-to-cys (R201C) mutation in the Kir6.2 gene. The patient was diagnosed at 4 weeks of age and had no additional neurologic or dysmorphic features. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (Ribalet et al., 2003). </p><p>Proks et al. (2004) stated that the 2 mutations in residue arg201, R201H (600937.0002) and R201C, which lie in the ATP-binding site of Kir6.2, cause milder PNDM disease without neurologic features; however, Massa et al. (2005) identified the R201C mutation in a patient with PNDM who also had muscle weakness and delayed motor development. </p><p>Gloyn et al. (2004) described a family in which 2 affected paternal half-sibs were heterozygous for the R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father's leukocyte DNA detected no trace of mutant DNA. These results were consistent with the father being mosaic for the mutation, which was restricted to his germline. Gloyn et al. (2004) concluded that the high percentage of permanent neonatal diabetes cases due to de novo KCNJ11 mutations (Gloyn et al., 2004) suggests that germline mosaicism may be common. </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 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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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KCNJ11, VAL59GLY
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<br />
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SNP: rs80356617,
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ClinVar: RCV000009204, RCV000020350, RCV002227025
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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 male patient with permanent neonatal diabetes and neurologic features (ISPAD25) (PNDMNF; see 618856), Gloyn et al. (2004) found heterozygosity for a val59-to-gly (V59G) mutation in the KCNJ11 gene. In addition to neonatal diabetes, the patient had muscle weakness, marked motor and mental developmental delay, myoclonic seizures with abnormal EEG, and dysmorphic features, including a downturned mouth, bilateral ptosis, and contractures primarily in the legs at birth. </p><p>Proks et al. (2004) noted that 2 mutations in the same residue of Kir6.2, V59M (600937.0003) and V59G, are associated with a more severe form of PNDM that may be accompanied by developmental delay, muscle weakness, and epilepsy, compared to PNDM caused by the mutations R201H (600937.0002) and R201C (600937.0004). Proks et al. (2004) found that residue val59 lies some distance from the ATP-binding site, within the N-terminal region of the protein; moreover, val59 lies within the 'slide helix,' a domain postulated to be involved in the opening and closing (gating) of Kir channels. Functional expression studies in Xenopus oocytes indicated that the V59M and V59G mutations decreased ATP sensitivity indirectly by favoring the open conformation of the channel. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 DIABETES MELLITUS, PERMANENT NEONATAL, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ11, ARG50PRO
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<br />
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SNP: rs80356611,
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gnomAD: rs80356611,
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ClinVar: RCV000009205, RCV001089464, RCV003335022
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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 an Italian patient with permanent neonatal diabetes mellitus (PNDM2; 618856), Massa et al. (2005) identified a 149G-C transversion in the KCNJ11 gene, resulting in an arg50-to-pro (R50P) substitution. The patient had no neurologic abnormalities. </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 DIABETES MELLITUS, PERMANENT NEONATAL, 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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KCNJ11, LYS170ARG
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<br />
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SNP: rs80356621,
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ClinVar: RCV000009206, RCV001089466, RCV002227026
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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 an Italian patient with permanent neonatal diabetes mellitus (PNDM2; 618856), Massa et al. (2005) identified a 175G-A transition in the KCNJ11 gene, resulting in a lys170-to-arg (K170R) substitution. The patient had no neurologic abnormalities. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0008 DIABETES MELLITUS, PERMANENT NEONATAL, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ11, LYS170ASN
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<br />
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SNP: rs80356622,
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ClinVar: RCV000009207, RCV001089467, RCV002051780, RCV002227027
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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 an Italian patient with permanent neonatal diabetes mellitus (PNDM2; 618856), Massa et al. (2005) identified a 510G-C transversion in the KCNJ11 gene, resulting in a lys170-to-asn (K170N) substitution. The patient was diagnosed at age 63 days and had delayed mental development; however, this patient also had a brain infarction. </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>.0009 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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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KCNJ11, TYR12TER
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<br />
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SNP: rs104894236,
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gnomAD: rs104894236,
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ClinVar: RCV000009208, RCV001851756, RCV002227028
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|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Palestinian Arab boy with hyperinsulinemic hypoglycemia (HHF2; 601820), born of first-cousin parents, Nestorowicz et al. (1997) identified homozygosity for a 39C-A transversion in the KCNJ11 gene, resulting in a tyr12-to-ter (Y12X) substitution. The mutation is predicted to produce a truncated Kir6.2 polypeptide lacking the putative K+ ion-selective pore region as well as those domains proposed to confer the gating and inward rectification properties of the molecule. In vitro studies in transfected COS-1 cells confirmed the deleterious effect of the mutation on channel activity. The authors noted that this patient was clinically indistinguishable from patients with severe hyperinsulinism caused by mutations in SUR1 (ABCC8; 600509; see HHF1, 600509). </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>.0010 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ11, 88G-T, PROMOTER REGION
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<br />
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SNP: rs387906398,
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ClinVar: RCV000009209, RCV002226639, RCV002512936, RCV004799736
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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 an Israeli Bedouin infant with hyperinsulinemic hypoglycemia (HHF2; 601820), Tornovsky et al. (2004) identified homozygosity for an 88G-T transversion 5-prime of the transcription start site in the promoter region of the KCNJ11 gene. Functional studies using a luciferase reporter vector revealed a 44% decrease in reporter gene expression for the mutant variant compared to wildtype. </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>.0011 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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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|
KCNJ11, PRO254LEU
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<br />
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SNP: rs104894237,
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|
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gnomAD: rs104894237,
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|
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|
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ClinVar: RCV000009210, RCV002226640, RCV002512937, RCV003466840
|
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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 an Arab infant in whom a prenatal diagnosis of hyperinsulinism was made due to a family history of hyperinsulinemic hypoglycemia (HHF2; 601820), Tornovsky et al. (2004) identified homozygosity for a C-T transition at codon 254 in exon 1 of the KCNJ11 gene, resulting in a pro254-to-leu (P254L) substitution. Photolabeling studies after transient transfection into COSm6 cells revealed impaired trafficking of the mutant channel. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DIABETES MELLITUS, TRANSIENT NEONATAL, 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 13, INCLUDED
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ11, CYS42ARG
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|
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|
|
|
<br />
|
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|
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SNP: rs80356610,
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|
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|
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ClinVar: RCV000009211, RCV000020347, RCV000170298, RCV001851757, RCV002226641
|
|
|
|
|
|
</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 4-generation Japanese family with dominantly inherited diabetes mellitus observed in 3 generations, Yorifuji et al. (2005) detected a T-to-C transition at nucleotide 124 of the KCNJ11 gene that gave rise to a cys42-to-arg amino acid substitution (C24R). The proband had transient neonatal diabetes (TNDM3; 610582), and his paternal grandfather had childhood diabetes. The others had early adult-onset diabetes without autoantibodies or insulin resistance (MODY13; 616329). No affected individual was obese. Patch-clamp experiments using the mutated KCNJ11 showed that the mutation causes increased spontaneous open probability and reduced ATP sensitivity. The effect, however, was partially compensated by the reduction of functional ATP-sensitive potassium channel expression at the cell surface, which could account for the milder phenotype of the patients. The authors concluded that these results broadened the spectrum of diabetes phenotypes caused by mutations of KCNJ11 and suggested that mutations in this gene should be taken into consideration for not only permanent neonatal diabetes but also other forms of diabetes with milder phenotypes and later onset. </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>.0013 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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">
|
|
|
|
KCNJ11, HIS259ARG
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<br />
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|
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SNP: rs104894248,
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|
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|
|
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gnomAD: rs104894248,
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|
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|
|
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ClinVar: RCV000009213, RCV000992253, RCV002226642, RCV002247279, RCV004734505, RCV005049325
|
|
|
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|
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</span>
|
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a patient with severe congenital hyperinsulinism (HHF2; 601820), Marthinet et al. (2005) identified a homozygous A-to-G transition at nucleotide 776 of the KCNJ11 gene that resulted in a his-259-to-arg substitution (H259R). The patient presented with macrosomia at birth and severe hyperinsulinemic hypoglycemia. Despite medical treatment, the newborn continued to suffer from severe hypoglycemic episodes, and at 4 months of age subtotal pancreatectomy was performed. Coexpression of KCNJ11 H259R with ABCC8 (600509) in HEK293T cells completely abolished K(ATP) currents in electrophysiologic recordings. Double immunofluorescence staining revealed that mutant KCNJ11 was partly retained in the endoplasmic reticulum (ER) causing decreased surface expression as observed with total internal reflection fluorescence. Mutation of an ER-retention signal partially rescued the trafficking defect without restoring whole-cell currents. </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>.0014 RECLASSIFIED - POLYMORPHISM</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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KCNJ11, GLU23LYS
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<br />
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SNP: rs5219,
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gnomAD: rs5219,
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ClinVar: RCV000009214, RCV000020356, RCV000146116, RCV000281825, RCV000294608, RCV000385348, RCV000576501, RCV001093985, RCV001105584, RCV001512207, RCV002226643, RCV004734506
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>This variant, formerly titled TYPE 2 DIABETES MELLITUS, SUSCEPTIBILITY TO, with an Included title of EXERCISE STRESS RESPONSE, IMPAIRED, ASSOCIATION WITH, has been reclassified as a polymorphism based on a review of the gnomAD database (v4.1.0) by Hamosh (2024). The E23K variant was present in 1,047,275 of 1,613,446 alleles and in 344,120 homozygotes, with an allele frequency of 0.6491.</p><p><strong><em>Type 2 Diabetes Mellitus, Susceptibility to</em></strong></p><p>
|
|
Hani et al. (1998) identified a glu23-to-lys (E23K) amino acid substitution in the KCNJ11 gene by molecular screening using SSCP and direct sequencing in 72 French Caucasian families with type 2 diabetes (125853). They genotyped this variant in French cohorts of 191 unrelated type 2 diabetic probands and 119 normoglycemic control subjects and performed association studies. Homozygosity for lys23 (KK) was more frequent in type 2 diabetic than in control subjects (27 vs 14%; p = 0.015). Analyses in a recessive model (KK vs EK/EE) showed a stronger association of the K allele with diabetes. In a metaanalysis of their data for the E23K variant and data obtained from 3 other Caucasian groups, Hani et al. (1998) found the E23K variant to be significantly associated with type 2 diabetes. </p><p>Hansen et al. (2005) investigated the separate and combined effects of the PPARG pro12-to-ala (P12A; 601487.0002) and KCNJ11 E23K polymorphisms on risk of type 2 diabetes. The combined analysis involved 1,164 type 2 diabetic patients and 4,733 middle-aged, glucose-tolerant subjects. In the separate analyses, the K allele of KCNJ11 E23K associated with type 2 diabetes (odds ratio, 1.19; p = 0.0002), whereas PPARG P12A showed no significant association with type 2 diabetes. The combined analysis indicated that the 2 polymorphisms acted in an additive manner to increase the risk of type 2 diabetes, and the authors found no evidence for a synergistic interaction between them. Together, the 2 polymorphisms conferred a population-attributable risk for type 2 diabetes of 28%. The authors concluded that their results showed no evidence of a synergistic interaction between the KCNJ11 E23K and PPARG P12A polymorphisms, but indicated that they may act in an additive manner to increase the risk of type 2 diabetes. </p><p>Laukkanen et al. (2004) found an additive effect of a high risk ABCC8 (600509) haplotype, composed of a silent polymorphism (AGG-AGA; arg1273 to arg) and 3 promoter polymorphisms, and the 23K allele of the KCNJ11 gene. </p><p>In genomewide association studies of type 2 diabetes involving genotype data from a variety of international consortia, the Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) confirmed association of the E23K polymorphism (rs5219) with diabetes susceptibility. Although this association was not strongly observed in any single scan, all-data metaanalyses resulted in genomewide significant association (OR = 1.14, p = 6.7 x 10(-11)). </p><p><strong><em>Impaired Exercise Stress Response, Association with</em></strong></p><p>
|
|
Reyes et al. (2009) found that the E23K polymorphism was overrepresented in 115 individuals with dilated cardiomyopathy (see 115200) and congestive heart failure (CHF) compared to 2,031 community-based controls (p less than 0.001). In addition, the KK genotype, which was present in 18% of the CHF patients, was associated with abnormal cardiopulmonary exercise stress testing: despite similar baseline heart rates among genotype subgroups, individuals with the KK genotype had a significantly reduced heart rate increase at matched workload, at 75% of maximum oxygen consumption, and at peak VO(2), compared to those with the EE or EK genotypes. Noting that the glu23 residue is located within the functionally relevant intracellular slide helix region, Reyes et al. (2009) suggested that E23K might represent a biomarker for impaired stress performance. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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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KCNJ11, CYS166PHE
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<br />
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SNP: rs80356618,
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ClinVar: RCV000009216, RCV000020352, RCV002247280
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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 an infant (NECKER29) with a severe form of permanent neonatal diabetes mellitus with neurologic features (PNDM2; 618856), Gloyn et al. (2006) identified a heterozygous G-to-T transversion in the KCNJ11 gene, resulting in a cys166-to-phe (C166F) substitution. The infant had feeding problem from birth and was diagnosed with diabetes mellitus at age 3 months. She also had seizures with hypsarrhythmia, progressive neurologic deterioration, diffuse hypotonia, and dysmorphic facial features. She died from aspiration pneumonia at age 6 months. Gloyn et al. (2006) considered this patient to be a case of DEND (developmental delay, epilepsy, and neonatal diabetes). Gloyn et al. (2006) noted that the C166F mutation is predicted to result in a channel with a marked increase in open probability and reduced sensitivity to ATP, which would severely alter the function of the channel in brain, muscle, and nerves, in addition to pancreatic beta cells. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0016 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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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KCNJ11, ILE167LEU
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<br />
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SNP: rs80356620,
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ClinVar: RCV000009217, RCV000020353, RCV002227029
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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 an Italian boy with a severe form of permanent neonatal diabetes with neurologic features (PNDM2; 618856), Shimomura et al. (2007) identified a heterozygous de novo 499A-C transversion in the KCNJ11 gene, resulting in an ile167-to-leu (I167L) substitution at the cytoplasmic end of the second transmembrane domain near the internal gate of the channel. In vitro functional expression studies showed that the mutant I167L channel had severely impaired sensitivity to ATP and markedly increased open channel probability. Sulfonylurea treatment resulted in partial blockade of current in the mutant channels, and the patient showed a good response to sulfonylurea treatment, with both improved glycemic control and neurologic improvement. Shimomura et al. (2007) considered this patient to be a case of DEND (developmental delay, epilepsy, and neonatal 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>
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<span class="mim-font">
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<strong>.0017 DIABETES MELLITUS, TRANSIENT NEONATAL, 3</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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KCNJ11, GLY53SER
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<br />
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SNP: rs80356613,
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ClinVar: RCV000009218, RCV002226644, RCV002250455, RCV002250456
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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 sister and brother with transient neonatal diabetes (TNDM3; 610582), Gloyn et al. (2005) identified a heterozygous G-to-A transition in the KCNJ11 gene, resulting in a gly53-to-ser (G53S) substitution. The mutation was not identified in 100 control individuals. Both children had insulin-treated diabetes diagnosed in the first 3 weeks of life and went into remission by age 20 months. The affected mother was positive for the mutation but had a milder phenotype, having been diagnosed at age 4 years and requiring only a low dose of insulin for glycemic control. In transformed Xenopus oocytes, the G53S mutation resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated 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>
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<span class="mim-font">
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<strong>.0018 DIABETES MELLITUS, TRANSIENT NEONATAL, 3</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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KCNJ11, GLY53ARG
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<br />
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SNP: rs80356613,
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ClinVar: RCV000009219
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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 male proband with transient neonatal diabetes (TNDM3; 610582), Gloyn et al. (2005) identified a heterozygous G-to-C transversion in the KCNJ11 gene, resulting in a gly53-to-arg (G53R) substitution. The mutation was not identified in 100 control individuals. The proband had insulin-treated diabetes diagnosed at age 16 weeks and went into remission by 17 months with relapse at age 28 months. The affected mother was positive for the mutation and was diagnosed with diabetes at 11 weeks with no periods of remission. Both mother and son had learning difficulties. In transformed Xenopus oocytes, the G53R mutation resulted in a reduction in sensitivity to ATP when compared with wildtype; however, the effect was less than that of PNDM-associated 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>
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<span class="mim-font">
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<strong>.0019 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ11, ARG301HIS
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<br />
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SNP: rs74339576,
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gnomAD: rs74339576,
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ClinVar: RCV000009220, RCV000671339, RCV001103550, RCV001103551, RCV001224980, RCV002227030, RCV003460444, RCV005042016
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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 an infant with focal hyperinsulinism (HHF2; 601820), Henwood et al. (2005) identified heterozygosity for a paternally derived 902G-A transition in the KCNJ11 gene, resulting in an arg301-to-his (R301H) substitution. KCNJ11 with this mutation retained partial channel function. </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>.0020 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KCNJ11, GLY156ARG
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<br />
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SNP: rs1404429785,
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gnomAD: rs1404429785,
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ClinVar: RCV000009221, RCV002243628, RCV002243629
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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 female proband with hyperinsulinemic hypoglycemia (HHF2; 601820), Pinney et al. (2008) identified heterozygosity for a gly156-to-arg (G156R) substitution in the KCNJ11 gene. The mutation was also identified in her 34-year-old father, who had symptoms consistent with hypoglycemia. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</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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KCNJ11, GLY53ASP
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<br />
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SNP: rs80356615,
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ClinVar: RCV000009222, RCV000020349, RCV002226645
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Koster et al. (2008) reported a 27-year-old female patient with intermediate developmental delay and neonatal diabetes (PNDM2; 618856) in whom sequencing revealed a heterozygous gly53-to-asp (G53D) mutation in the KCNJ11 gene. Treatment was progressively transferred from insulin to the inhibitory sulfonylureas (SUs) gliclazide and finally to glibenclamide. The patient demonstrated improved glycemic control and motor coordination with SU treatment, with glibenclamide more effective than gliclazide. Reconstituted G53D channels exhibited reduced ATP sensitivity, which was predicted to suppress electrical activity in vivo. G53D channels coexpressed with the pancreatic and neuronal isoform of the sulfonylurea receptor SUR1 (600509) exhibited high-affinity block by gliclazide but were insensitive to block when coexpressed with the skeletal muscle isoform SUR2A (601439). Koster et al. (2008) concluded that SUs can resolve motor dysfunction in an adult with intermediate DEND and that this improvement is due to inhibition of the neuronal but not skeletal muscle ATP-sensitive potassium channel. Koster et al. (2008) noted that the G53D mutation had been reported by Flanagan et al. (2006) in a patient with 'intermediate DEND,' which included seizures in infancy and abnormal electroencephalogram. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ11, GLU282LYS
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<br />
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|
|
SNP: rs267607196,
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|
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|
|
gnomAD: rs267607196,
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|
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|
|
ClinVar: RCV000009223, RCV000763231, RCV002226646, RCV003466841, RCV003555984, RCV005042017
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Swedish patient with hyperinsulinemic hypoglycemia (HHF2; 601820) with focal adenomatous hyperplasia, Taneja et al. (2009) identified an 844G-A transition in the KCNJ11 gene, resulting in a glu282-to-lys (E282K) substitution within a diacidic endoplasmic reticulum (ER) exit signal DXE at codons 280 to 282. The paternal E282K mutation abrogated the exit signal and prevented the ER export and surface expression of the channel. Since in focal hyperinsulinemic hypoglycemia, the maternal chromosome containing the K(ATP) channel genes are lost, beta-cells of the patient would lack wildtype Kir6.2 to rescue the mutant Kir6.2 subunit expressed from the paternal chromosome. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 DIABETES MELLITUS, PERMANENT NEONATAL, 2, WITH NEUROLOGIC FEATURES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ11, PHE60TYR
|
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|
|
<br />
|
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|
|
SNP: rs387906783,
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|
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|
|
|
|
|
ClinVar: RCV000023046, RCV002226654
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with neonatal diabetes, developmental delay, and epilepsy (PNDM2; 618856), Mannikko et al. (2010) identified heterozygosity for 2 novel mutations on the same haplotype (cis), phe60 to tyr (F60Y) and val64 to leu (V64L), in the slide helix of Kir6.2 (KCNJ11). Functional analysis revealed that the F60Y mutation increased the intrinsic channel open probability, thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell potassium-ATP currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same, but not a different, subunit. The authors concluded that F60Y is the pathogenic mutation and that interactions between slide helix residues may influence KATP channel gating. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 13</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KCNJ11, GLU227LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587783672,
|
|
|
|
|
|
gnomAD: rs587783672,
|
|
|
|
|
|
ClinVar: RCV000146115, RCV000170299, RCV001288659, RCV001329964, RCV002051813, RCV002227076
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Bonnefond et al. (2012) analyzed a 4-generation French family with maturity-onset diabetes of the young-13 (MODY13; 616329), including 12 affected individuals; 2 additional individuals had impaired fasting glucose and impaired glucose tolerances, respectively. Twenty-two relatives were unaffected. Whole-exome sequencing was performed on 4 individuals: a patient with diabetes diagnosed at age 17 years, his father who developed diabetes at age 20, an unaffected mother, and a diabetic man diagnosed at age 13. The only mutation that segregated with all family members was a c.679G-A transition (c.679G-A, NM_000525.3) resulting in a glu227-to-lys (E227K) substitution in the KCNJ11 gene. Linkage analysis using a dominant parametric model showed a lod score of 3.68 at KCNJ11 lys227. Lod scores were even higher using nonparametric linkage. This mutation was not found in the dbSNP (build 130) database, in 406 French controls, or in any of 22 French probands with MODY. </p>
|
|
</span>
|
|
</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
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|
KCNJ11, 3-BP DEL, NT892
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<br />
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SNP: rs1953574433,
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|
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ClinVar: RCV001270679, RCV002226762
|
|
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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 patient (patient 11-III-a) with hyperinsulinemic hypoglycemia (HHF2; 601820) who presented on the first day of life, Boodhansingh et al. (2019) identified a paternally inherited heterozygous 3-bp deletion (c.892_894del) in the KCNJ11 gene, resulting in the deletion of threonine-298 (thr298del). The mutation was identified by direct gene sequencing and was absent in the gnomAD database. The father did not report symptoms of hypoglycemia, but phenotype testing (fasting test, oral protein tolerance test, oral glucose tolerance test) showed evidence for abnormal regulation of glucose. The rubidium ion efflux assay of Kir6.2 with deletion of thr298 expressed in COSm6 cells demonstrated impaired ATP-dependent potassium channel efflux. </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>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
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<p class="mim-text-font">
|
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Bellanne-Chantelot, C., Saint-Martin, C., Ribeiro, M.-J., Vaury, C., Verkarre, V., Arnoux, J.-B., Valayannopoulos, V., Gobrecht, S., Sempoux, C., Rahier, J., Fournet, J.-C., Jaubert, F., Aigrain, Y., Nihoul-Fekete, C., de Lonlay, P.
|
|
<strong>ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.</strong>
|
|
J. Med. Genet. 47: 752-759, 2010.
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[PubMed: 20685672]
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[Full Text: https://doi.org/10.1136/jmg.2009.075416]
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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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Bonnefond, A., Philippe, J., Durand, E., Dechaume, A., Huyvaert, M., Montagne, L., Marre, M., Balkau, B., Fajardy, I., Vambergue, A., Vatin, V., Delplanque, J., Le Guilcher, D., De Graeve, F., Lecoeur, C., Sand, O., Vaxillaire, M., Froguel, P.
|
|
<strong>Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene.</strong>
|
|
PLoS One 7: e37423, 2012. Note: Electronic Article.
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|
|
[PubMed: 22701567]
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[Full Text: https://doi.org/10.1371/journal.pone.0037423]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Boodhansingh, K. E., Kandasamy, B., Mitteer, L., Givler, S., De Leon, D. D., Shyng, S.-L., Ganguly, A., Stanley, C. A.
|
|
<strong>Novel dominant K(atp) channel mutations in infants with congenital hyperinsulinism: validation by in vitro expression studies and in vivo carrier phenotyping.</strong>
|
|
Am. J. Med. Genet. 179A: 2214-2227, 2019.
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|
[PubMed: 31464105]
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[Full Text: https://doi.org/10.1002/ajmg.a.61335]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chandy, K. G., Gutman, G. A.
|
|
<strong>Nomenclature for mammalian potassium channel genes.</strong>
|
|
Trends Pharm. Sci. 14: 434, 1993.
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[PubMed: 8122319]
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[Full Text: https://doi.org/10.1016/0165-6147(93)90181-i]
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</p>
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</li>
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<li>
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Ada Hamosh - updated : 12/04/2024<br>Hilary J. Vernon - updated : 12/17/2020<br>Marla J. F. O'Neill - updated : 06/13/2018<br>Ada Hamosh - updated : 04/20/2015<br>George E. Tiller - updated : 11/10/2011<br>Ada Hamosh - updated : 9/1/2010<br>Marla J. F. O'Neill - updated : 8/25/2010<br>Patricia A. Hartz - updated : 8/2/2010<br>Marla J. F. O'Neill - updated : 4/19/2010<br>George E. Tiller - updated : 3/30/2010<br>John A. Phillips, III - updated : 4/27/2009<br>Marla J. F. O'Neill - updated : 3/20/2009<br>George E. Tiller - updated : 12/10/2008<br>Patricia A. Hartz - updated : 8/22/2008<br>Marla J. F. O'Neill - updated : 5/16/2008<br>George E. Tiller - updated : 4/29/2008<br>Cassandra L. Kniffin - updated : 3/27/2008<br>Ada Hamosh - updated : 7/24/2007<br>John A. Phillips, III - updated : 6/20/2007<br>Cassandra L. Kniffin - updated : 3/2/2007<br>John A. Phillips, III - updated : 11/20/2006<br>John A. Phillips, III - updated : 11/20/2006<br>John A. Phillips, III - updated : 11/20/2006<br>Victor A. McKusick - updated : 4/28/2006<br>Marla J. F. O'Neill - updated : 4/6/2006<br>Marla J. F. O'Neill - updated : 3/21/2006<br>Marla J. F. O'Neill - updated : 3/16/2006<br>John A. Phillips, III - updated : 7/22/2005<br>Marla J. F. O'Neill - updated : 7/8/2005<br>Victor A. McKusick - updated : 2/2/2005<br>Victor A. McKusick - updated : 1/27/2005<br>Victor A. McKusick - updated : 5/6/2004<br>Patricia A. Hartz - updated : 3/11/2003<br>Ada Hamosh - updated : 6/8/2001<br>Stylianos E. Antonarakis - updated : 4/21/2000<br>Moyra Smith - updated : 1/31/1997<br>Perseveranda M. Cagas - updated : 9/23/1996
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