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Entry
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- *138079 - GLUCOKINASE; GCK
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- OMIM
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<div class="container hidden-print">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*138079</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/138079">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000106633;t=ENST00000403799" 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=2645" 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=138079" 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=ENSG00000106633;t=ENST00000403799" 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_000162,NM_001354800,NM_001354801,NM_001354802,NM_001354803,NM_033507,NM_033508,XM_024446707" 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_000162" 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=138079" 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=00680&isoform_id=00680_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/GCK" 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/179427,183227,183235,547696,2773376,4503951,12804883,15967159,15967161,30582963,51094508,51094509,51094510,119581518,119581519,119581520,152211827,193783792,259477345,300629950,432134608,460239833,460239847,460239860,460239872,460239882,460239890,460239896,460239899,460239909,460239921,460239936,460239948,1236470099,1236471841,1236484112,1237938251,1370509839,2462613627" 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/P35557" 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=2645" 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=ENSG00000106633;t=ENST00000403799" 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=GCK" 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=GCK" 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+2645" 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/GCK" 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:2645" 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/2645" 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=chr7&hgg_gene=ENST00000403799.8&hgg_start=44143213&hgg_end=44189439&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:4195" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/gck" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=138079[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=138079[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/GCK/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/ENSG00000106633" 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=GCK" 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=GCK" 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=GCK" 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="http://www.LOVD.nl/GCK" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=GCK&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/PA28610" 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:4195" 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/FBgn0001186.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:1270854" 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/GCK#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:1270854" 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/2645/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002579/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=2645" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00008780;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-060825-204" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:138079" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:2645" 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=GCK&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> 237604008, 44054006<br />
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<strong>ICD10CM:</strong> E11<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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138079
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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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GLUCOKINASE; GCK
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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">
|
|
GK; GLK<br />
|
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HEXOKINASE 4; HK4<br />
|
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LIVER GLUCOKINASE; LGLK
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=GCK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">GCK</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/7/230?start=-3&limit=10&highlight=230">7p13</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr7:44143213-44189439&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'})">7:44,143,213-44,189,439</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
|
</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</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>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=125853,606176,602485,125851" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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</th>
|
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<th>
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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<a href="/geneMap/7/230?start=-3&limit=10&highlight=230">
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7p13
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</a>
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<span class="mim-font">
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Diabetes mellitus, noninsulin-dependent, late onset
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</span>
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<span class="mim-font">
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<a href="/entry/125853"> 125853 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Diabetes mellitus, permanent neonatal 1
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<span class="mim-font">
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<a href="/entry/606176"> 606176 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Hyperinsulinemic hypoglycemia, familial, 3
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</span>
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<td>
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<span class="mim-font">
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<a href="/entry/602485"> 602485 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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<span class="mim-font">
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MODY, type II
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<td>
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<span class="mim-font">
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<a href="/entry/125851"> 125851 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/138079" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/138079" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>The phosphorylation of glucose at the sixth carbon position is the first step in glycolysis. The reaction is catalyzed by a family of enzymes called hexokinases, types I (<a href="/entry/142600">142600</a>) through IV (glucokinase). Glucokinase (GCK; <a href="https://enzyme.expasy.org/EC/2.7.1.1" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'EC\', \'domain\': \'expasy.org\'})">EC 2.7.1.1</a>) is a structurally and functionally unique member of this family. Glucokinase is expressed only in mammalian liver and pancreatic islet beta cells. Because of its unique functional characteristics, the enzyme plays an important regulatory role in glucose metabolism. The rate of glucose metabolism in liver and pancreas is a function of the activity of the enzyme (summary by <a href="#31" class="mim-tip-reference" title="Matsutani, A., Janssen, R., Donis-Keller, H., Permutt, M. A. <strong>A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7p.</strong> Genomics 12: 319-325, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740341</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90380-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740341">Matsutani et al., 1992</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1740341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Using rat islet glucokinase cDNA to screen a human islet cDNA library, followed by screening a human liver cDNA library and RT-PCR of liver RNA, <a href="#48" class="mim-tip-reference" title="Tanizawa, Y., Koranyi, L. I., Welling, C. M., Permutt, M. A. <strong>Human liver glucokinase gene: cloning and sequence determination of two alternatively spliced cDNAs.</strong> Proc. Nat. Acad. Sci. 88: 7294-7297, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1871135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1871135</a>] [<a href="https://doi.org/10.1073/pnas.88.16.7294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1871135">Tanizawa et al. (1991)</a> cloned 2 GCK splice variants, which they called LGLK1 and LGLK2. LGLK1 encodes a deduced 464-amino acid protein with a calculated molecular mass of 52 kD. LGLK2 encodes a deduced 466-amino acid protein with 16 different N-terminal amino acids compared with LGLK1. LGLK2 shares 98% identity with rat islet glucokinase. Northern blot analysis detected a 2.8-kb transcript in liver total RNA. In vitro translation of LGLK1 cDNA resulted in proteins with apparent molecular masses of 52 and 48 kD by SDS-PAGE. Proteins of similar masses were translated from LGLK2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1871135" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>
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<br />
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimGeneStructureToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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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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<div id="mimGeneStructureFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<p><a href="#44" class="mim-tip-reference" title="Stoffel, M., Froguel, P., Takeda, J., Zouali, H., Vionnet, N., Nishi, S., Weber, I. T., Harrison, R. W., Pilkis, S. J., Lesage, S., Vaxillaire, M., Velho, G., Sun, F., Iris, F., Passa, P., Cohen, D., Bell, G. I. <strong>Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 89: 7698-7702, 1992. Note: Erratum: Proc. Nat. Acad Sci. 89: 10562 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1502186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1502186</a>] [<a href="https://doi.org/10.1073/pnas.89.16.7698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1502186">Stoffel et al. (1992)</a> determined that the GCK gene contains 12 exons. Alternative promoters and alternative splicing encode different-sized proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1502186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>
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<br />
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<div>
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<a id="mapping" class="mim-anchor"></a>
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<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimMappingToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Mapping</strong>
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<p><a href="#31" class="mim-tip-reference" title="Matsutani, A., Janssen, R., Donis-Keller, H., Permutt, M. A. <strong>A polymorphic (CA)n repeat element maps the human glucokinase gene (GCK) to chromosome 7p.</strong> Genomics 12: 319-325, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740341</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90380-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740341">Matsutani et al. (1992)</a> identified a region of compound dinucleotide repeats located approximately 10 kb 3-prime to the GCK gene and used oligonucleotide primers and PCR amplification to demonstrate a number of alleles created by this repeat region. The variable numbers of CT and CA repeats represented altogether 6 alleles that range in length from +10 to -15 nucleotides compared to the most common (Z) allele. Two alleles, Z+10 and Z-15, appeared to be unique to American blacks, while a Z+6 allele was observed only in the Caucasian population studied. Using the PCR assay, they localized the human glucokinase gene to chromosome 7 in a panel of rodent/human somatic cell lines. Genetic analysis in CEPH pedigrees placed the dinucleotide repeat element, and thereby GCK, on 7p between TCRG (see <a href="/entry/186970">186970</a>) and the RFLP locus D7S57. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1740341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Mishra, S. K., Helms, C., Dorsey, D., Permutt, M. A., Donis-Keller, H. <strong>A 2-cM genetic linkage map of human chromosome 7p that includes 47 loci.</strong> Genomics 12: 326-334, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740342</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90381-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740342">Mishra et al. (1992)</a> placed GCK between D7S57 proximally and D7S65 distally. It was estimated to lie about 4.7 cM from D7S65; D7S65 was found to be about 3.4 cM from TCRG, which is located at 7p15-p14. (<a href="#34" class="mim-tip-reference" title="Mishra, S. K., Helms, C., Dorsey, D., Permutt, M. A., Donis-Keller, H. <strong>A 2-cM genetic linkage map of human chromosome 7p that includes 47 loci.</strong> Genomics 12: 326-334, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1740342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1740342</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90381-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1740342">Mishra et al. (1992)</a> gave the location of TCRG as 7p15 in their Figure 2.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1740342" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 id="geneFunction" class="mim-anchor"></a>
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<strong>Gene Function</strong>
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<p><a href="#3" class="mim-tip-reference" title="Byrne, M. M., Sturis, J., Clement, K., Vionnet, N., Pueyo, M. E., Stoffel, M., Takeda, J., Passa, P., Cohen, D., Bell, G. I., Velho, G., Froguel, P., Polonsky, K. S. <strong>Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.</strong> J. Clin. Invest. 93: 1120-1130, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8132752/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8132752</a>] [<a href="https://doi.org/10.1172/JCI117064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8132752">Byrne et al. (1994)</a> studied pancreatic beta-cell function in 4 males and 2 females from kindreds with known GCK mutations and in 6 controls pair-matched for age, weight, and sex. All of the GCK subjects with GCK mutations were found to have elevated fasting and postprandial glucose levels in comparison to the 6 controls. Insulin secretion rates (ISRs) were estimated. The results supported a key role for GCK in determining the in vivo glucose/ISR dose-response relationships and defined the alterations in beta-cell responsiveness that occur in subjects with GCK mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8132752" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Heimberg, H., De Vos, A., Moens, K., Quartier, E., Bouwens, L., Pipeleers, D., Van Schaftingen, E., Madsen, O., Schuit, F. <strong>The glucose sensor protein glucokinase is expressed in glucagon-producing alpha-cells.</strong> Proc. Nat. Acad. Sci. 93: 7036-7041, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8692940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8692940</a>] [<a href="https://doi.org/10.1073/pnas.93.14.7036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8692940">Heimberg et al. (1996)</a> reported the expression of glucokinase in rat glucagon-producing islet alpha cells, which are negatively regulated by glucose. Purified rat alpha cells expressed glucokinase mRNA and protein with the same transcript length, nucleotide sequence, and immunoreactivity as the beta-cell isoform. Glucokinase activity accounted for more than 50% of glucose phosphorylation in extracts of alpha cells and for more than 90% of glucose utilization in intact cells. A glucagon-producing tumor also contained glucokinase mRNA, protein, and enzymatic activity. The data indicated that glucokinase may serve as a metabolic glucose sensor in pancreatic alpha cells and, hence, mediate a mechanism for direct regulation of glucagon release by extracellular glucose. Since the alpha cells do not express GLUT2 (<a href="/entry/138160">138160</a>), <a href="#21" class="mim-tip-reference" title="Heimberg, H., De Vos, A., Moens, K., Quartier, E., Bouwens, L., Pipeleers, D., Van Schaftingen, E., Madsen, O., Schuit, F. <strong>The glucose sensor protein glucokinase is expressed in glucagon-producing alpha-cells.</strong> Proc. Nat. Acad. Sci. 93: 7036-7041, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8692940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8692940</a>] [<a href="https://doi.org/10.1073/pnas.93.14.7036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8692940">Heimberg et al. (1996)</a> suggested that glucose sensing does not necessarily require the coexpression of GLUT2 and glucokinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8692940" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>On the basis of studies in 7 glucokinase-deficient subjects with normal glycosylated hemoglobin and 12 control subjects using (13)C nuclear magnetic spectroscopy during a day in which 3 isocaloric mixed meals were ingested, <a href="#53" class="mim-tip-reference" title="Velho, G., Petersen, K. F., Perseghin, G., Hwang, J.-H., Rothman, D. L., Pueyo, M. E., Cline, G. W., Froguel, P., Shulman, G. I. <strong>Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects.</strong> J. Clin. Invest. 98: 1755-1761, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878425</a>] [<a href="https://doi.org/10.1172/JCI118974" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8878425">Velho et al. (1996)</a> observed results suggesting that in addition to the altered beta-cell function, abnormalities in liver glycogen metabolism play an important role in the pathogenesis of hypoglycemia in patients with maturity-onset diabetes of the young type 2 (MODY2; <a href="/entry/125851">125851</a>). Average fasting hepatic glycogen content was similar in both groups and increased in both after the meals with a continuous pattern throughout the day. However, the net increment in hepatic glycogen content after each meal was 30 to 60% lower in glucokinase-deficient than in control subjects. Glucokinase-deficient subjects had decreased net accumulation of hepatic glycogen and relatively augmented hepatic gluconeogenesis after meals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8878425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#8" class="mim-tip-reference" title="Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J. <strong>BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.</strong> Nature 424: 952-956, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12931191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12931191</a>] [<a href="https://doi.org/10.1038/nature01825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12931191">Danial et al. (2003)</a> undertook a proteomic analysis to assess whether BAD (<a href="/entry/603167">603167</a>) might participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A (see <a href="/entry/176911">176911</a>) and protein phosphatase-1 (PP1; see <a href="/entry/176875">176875</a>) catalytic units, WAVE1 (<a href="/entry/605035">605035</a>) as an A kinase-anchoring protein, and glucokinase. Using mitochondria from hepatocytes of Bad-deficient mice, <a href="#8" class="mim-tip-reference" title="Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J. <strong>BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.</strong> Nature 424: 952-956, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12931191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12931191</a>] [<a href="https://doi.org/10.1038/nature01825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12931191">Danial et al. (2003)</a> demonstrated that BAD is required to assemble the complex, the lack of which results in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, <a href="#8" class="mim-tip-reference" title="Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J. <strong>BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.</strong> Nature 424: 952-956, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12931191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12931191</a>] [<a href="https://doi.org/10.1038/nature01825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12931191">Danial et al. (2003)</a> demonstrated that the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient in BAD or bearing a nonphosphorylatable BAD (3SA) mutant (<a href="#9" class="mim-tip-reference" title="Datta, S. R., Ranger, A. M., Lin, M. Z., Sturgill, J. F., Ma, Y.-C., Cowan, C. W., Dikkes, P., Korsmeyer, S. J., Greenberg, M. E. <strong>Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis.</strong> Dev. Cell 3: 631-643, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12431371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12431371</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00326-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12431371">Datta et al., 2002</a>) display abnormal glucose homeostasis, including profound defects in glucose tolerance. <a href="#8" class="mim-tip-reference" title="Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J. <strong>BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.</strong> Nature 424: 952-956, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12931191/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12931191</a>] [<a href="https://doi.org/10.1038/nature01825" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12931191">Danial et al. (2003)</a> concluded that this combination of proteomics, genetics, and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12431371+12931191" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a yeast 2-hybrid assay and other protein interaction assays, <a href="#22" class="mim-tip-reference" title="Hofmeister-Brix, A., Kollmann, K., Langer, S., Schultz, J., Lenzen, S., Baltrusch, S. <strong>Identification of the ubiquitin-like domain of midnolin as a new glucokinase interaction partner.</strong> J. Biol. Chem. 288: 35824-35839, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24187134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24187134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24187134[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.M113.526632" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24187134">Hofmeister-Brix et al. (2013)</a> found that Midn (<a href="/entry/606700">606700</a>), via its the ubiquitin-like domain, bound glucokinase in rat and mouse pancreatic beta cells and cell lines. Binding was strongest at low glucose concentration, when glucokinase exists mainly in its inactive super-open-to-open conformation. Overexpression of fluorescence-tagged Midn inhibited glucokinase activity, reduced the affinity of glucokinase for glucose, and reduced glucose-induced insulin secretion in rat pancreatic MIN6 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24187134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mouse models and the rat INS-1 pancreatic beta cell line, <a href="#27" class="mim-tip-reference" title="Kim, J. Y., Hwang, J.-Y., Lee, D. Y., Song, E. H., Park, K. J., Kim, G. H., Jeong, E. A., Lee, Y. J., Go, M. J., Kim, D. J., Lee, S. S., Kim, B.-J., Song, J., Roh, G. S., Gao, B., Kim, W.-H. <strong>Chronic ethanol consumption inhibits glucokinase transcriptional activity by Atf3 and triggers metabolic syndrome in vivo.</strong> J. Biol. Chem. 289: 27065-27079, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25074928/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25074928</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25074928[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.M114.585653" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25074928">Kim et al. (2014)</a> found that chronic ethanol consumption induced activating transcription factor-3 (ATF3; <a href="/entry/603148">603148</a>), which then inhibited Gck transcriptional activity. Atf3 directly bound to a putative ATF/CREB site in the Gck promoter. Atf3 also counteracted the positive effect of Pdx1 (<a href="/entry/600733">600733</a>) on Gck transcriptional activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25074928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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><strong><em>Maturity-Onset Diabetes of the Young, Type 2</em></strong></p><p>
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In 16 French families with maturity-onset diabetes of the young (MODY2; <a href="/entry/125851">125851</a>), <a href="#11" class="mim-tip-reference" title="Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M. O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J. S., Lathrop, G. M., Passa, P., Permutt, M. A., Cohen, D. <strong>Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.</strong> Nature 356: 162-164, 1992. Note: Erratum: Nature 357: 607 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1545870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1545870</a>] [<a href="https://doi.org/10.1038/356162a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1545870">Froguel et al. (1992)</a> found linkage of the disease with GCK. There was statistically significant evidence of genetic heterogeneity, with an estimated 45 to 95% of the 16 families showing linkage to glucokinase. Because glucokinase is a key enzyme of blood glucose homeostasis, the results suggested a pathogenetic connection. The relationship was clinched by the demonstration by <a href="#54" class="mim-tip-reference" title="Vionnet, N., Stoffel, M., Takeda, J., Yasuda, K., Bell, G. I., Zouali, H., Lesage, S., Velho, G., Iris, F., Passa, P., Froguel, P., Cohen, D. <strong>Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.</strong> Nature 356: 721-722, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570017</a>] [<a href="https://doi.org/10.1038/356721a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570017">Vionnet et al. (1992)</a> of a nonsense mutation in the GCK gene (<a href="#0001">138079.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1545870+1570017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#52" class="mim-tip-reference" title="Velho, G., Froguel, P., Clement, K., Pueyo, M. E., Rakotoambinina, B., Zouali, H., Passa, P., Cohen, D., Robert, J.-J. <strong>Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young.</strong> Lancet 340: 444-448, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1354782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1354782</a>] [<a href="https://doi.org/10.1016/0140-6736(92)91768-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1354782">Velho et al. (1992)</a> studied pancreatic beta-cell secretory function in 9 patients from 4 GCK-linked MODY kindreds. They found that beta-cell secretory response to continuous glucose stimulus during a hyperglycemic glucose clamp was significantly reduced. This finding was different from that for noninsulin-dependent diabetes mellitus with late age of onset or MODY not linked to GCK. Fasting plasma insulin and C-peptide levels in patients were inappropriately low in relation to concomitant plasma glucose level. Furthermore, during a hyperinsulinemic euglycemic clamp, endogenous insulin secretion at euglycemia was suppressed in patients but not in controls. <a href="#52" class="mim-tip-reference" title="Velho, G., Froguel, P., Clement, K., Pueyo, M. E., Rakotoambinina, B., Zouali, H., Passa, P., Cohen, D., Robert, J.-J. <strong>Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young.</strong> Lancet 340: 444-448, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1354782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1354782</a>] [<a href="https://doi.org/10.1016/0140-6736(92)91768-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1354782">Velho et al. (1992)</a> interpreted these results as suggesting that mutant GCK leads to chronic hyperglycemia by raising the threshold of circulating glucose levels which induces insulin secretion. This was the first demonstration of a primary pancreatic secretory defect associated with a form of NIDDM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1354782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J., Passa, P., Permutt, M. A., Beckmann, J. S., Bell, G. I., Cohen, D. <strong>Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus.</strong> New Eng. J. Med. 328: 697-702, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8433729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8433729</a>] [<a href="https://doi.org/10.1056/NEJM199303113281005" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8433729">Froguel et al. (1993)</a> detected 16 mutations of the GCK gene in 18 of 32 families with MODY. An explanation for the way a mutation in glucokinase might cause diabetes follows from the work of <a href="#30" class="mim-tip-reference" title="Matschinsky, F. M. <strong>Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes.</strong> Diabetes 39: 647-652, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2189759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2189759</a>] [<a href="https://doi.org/10.2337/diab.39.6.647" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2189759">Matschinsky (1990)</a>, who developed the concept that glucokinase acts as the glucose sensor of beta cells. According to this concept, the rates of glucose metabolism and insulin secretion are closely linked, with both being determined by the plasma glucose concentration. In beta cells and hepatocytes, the rate of glucose metabolism is determined by the rate of glucose phosphorylation, which is catalyzed by glucokinase. Beta cells and hepatocytes also contain glucose transporter-2 (GLUT2; <a href="/entry/138160">138160</a>), an insulin-independent cellular protein that mediates the transport of glucose into cells. The capacity of GLUT2 to transport glucose is very high, facilitating rapid equilibrium between extracellular and intracellular glucose. Thus, in effect, the extracellular glucose concentrations are sensed by glucokinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8433729+2189759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Randle, P. J. <strong>Glucokinase and candidate genes for type 2 (non-insulin-dependent) diabetes mellitus.</strong> Diabetologia 36: 269-275, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8386682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8386682</a>] [<a href="https://doi.org/10.1007/BF00400227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8386682">Randle (1993)</a> provided a review of glucokinase and candidate genes for type II MODY. <a href="#29" class="mim-tip-reference" title="Matschinsky, F., Liang, Y., Kesavan, P., Wang, L., Froguel, P., Velho, G., Cohen, D., Permutt, M. A., Tanizawa, Y., Jetton, T. L., Niswender, K., Magnuson, M. A. <strong>Glucokinase as pancreatic beta-cell glucose sensor and diabetes gene.</strong> J. Clin. Invest. 92: 2092-2098, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8227324/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8227324</a>] [<a href="https://doi.org/10.1172/JCI116809" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8227324">Matschinsky et al. (1993)</a> also reviewed glucokinase as the pancreatic beta-cell glucose sensor and 'diabetes gene.' They tabulated 16 separate mutations in the GCK gene found in families with MODY. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8227324+8386682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Johansen, A., Ek, J., Mortensen, H. B., Pedersen, O., Hansen, T. <strong>Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1.</strong> J. Clin. Endocr. Metab. 90: 4607-4614, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15928245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15928245</a>] [<a href="https://doi.org/10.1210/jc.2005-0196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15928245">Johansen et al. (2005)</a> examined the prevalence and nature of mutations in the 3 common MODY genes HNF4A (<a href="/entry/600281">600281</a>), GCK, and TCF1 (<a href="/entry/142410">142410</a>) in Danish patients with a clinical diagnosis of MODY and determined metabolic differences in probands with and without mutations in HNF4A, GCK, and TCF1. They identified 29 different mutations in 38 MODY families. Fifteen of the mutations were novel. The variants segregated with diabetes within the families, and none of the variants were found in 100 normal Danish chromosomes. Their findings suggested a relative prevalence of 3% of MODY1 (<a href="/entry/125850">125850</a>) (2 different mutations in 2 families), 10% of MODY2 (7 in 8), and 36% of MODY3 (<a href="/entry/600496">600496</a>) (21 in 28) among Danish kindred clinically diagnosed as MODY. No significant differences in biochemical and anthropometric measurements were observed at baseline examinations. Forty-nine percent of the families carried mutations in the 3 examined MODY genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15928245" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#55" class="mim-tip-reference" title="Vits, L., Beckers, D., Craen, M., de Beaufort, C., Vanfleteren, E., Dahan, K., Nollet, A., Vanhaverbeke, G., Imschoot, S. V., Bourguignon, J.-P., Beauloye, V., Storm, K., Massa, G., Giri, M., Nobels, F., De Schepper, J., Rooman, R., Van den Bruel, A., Mathieu, C., Wuyts, W. <strong>Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. (Letter)</strong> Clin. Genet. 70: 355-359, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965331</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00686.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965331">Vits et al. (2006)</a> identified 19 different GCK mutations, including 11 novel mutations (see, e.g., <a href="#0014">138079.0014</a>), in 33 (26.6%) of 124 Belgian probands with MODY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#39" class="mim-tip-reference" title="Pinterova, D., Ek, J., Kolostova, K., Pruhova, S., Novota, P., Romzova, M., Feigerlova, E., Cerna, M., Lebl, J., Pedersen, O., Hansen, T. <strong>Six novel mutations in the GCK gene in MODY patients. (Letter)</strong> Clin. Genet. 71: 95-96, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17204055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17204055</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00729.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17204055">Pinterova et al. (2007)</a> screened the GCK gene in 92 Czech probands fulfilling classic MODY criteria and identified 15 different missense mutations in 27 (29%) patients; the mutations were not found in 50 unrelated healthy Czech individuals. <a href="#39" class="mim-tip-reference" title="Pinterova, D., Ek, J., Kolostova, K., Pruhova, S., Novota, P., Romzova, M., Feigerlova, E., Cerna, M., Lebl, J., Pedersen, O., Hansen, T. <strong>Six novel mutations in the GCK gene in MODY patients. (Letter)</strong> Clin. Genet. 71: 95-96, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17204055/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17204055</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00729.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17204055">Pinterova et al. (2007)</a> concluded that mutations in GCK are a common cause of MODY in the Czech population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17204055" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mainland Chinese family with a clinical profile similar to that of previously reported MODY2 families, <a href="#42" class="mim-tip-reference" title="Shen, Y., Cai, M., Liang, H., Wang, H., Weng, J. <strong>Insight into the biochemical characteristics of a novel glucokinase gene mutation.</strong> Hum. Genet. 129: 231-238, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21104275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21104275</a>] [<a href="https://doi.org/10.1007/s00439-010-0914-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21104275">Shen et al. (2011)</a> analyzed the GCK gene and identified a heterozygous missense mutation (E339K; <a href="#0016">138079.0016</a>) that segregated with the disease and was not found in 200 controls. Functional analysis indicated that the mutation inactivated enzyme kinetics and severely impaired GCK protein stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21104275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 variable phenotype observed with mutations in the GCK gene includes gestational diabetes mellitus. This fact prompted <a href="#43" class="mim-tip-reference" title="Stoffel, M., Bell, K. L., Blackburn, C. L., Powell, K. L., Seo, T. S., Takeda, J., Vionnet, N., Xiang, K.-S., Gidh-Jain, M., Pilkis, S. J., Ober, C., Bell, G. I. <strong>Identification of glucokinase mutations in subjects with gestational diabetes mellitus.</strong> Diabetes 42: 937-940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8495817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8495817</a>] [<a href="https://doi.org/10.2337/diab.42.6.937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8495817">Stoffel et al. (1993)</a> to screen a group of women with gestational diabetes who also had a first-degree relative with diabetes mellitus for the presence of GCK mutations. Among 40 subjects, they identified 2 with heterozygous mutations (<a href="#0007">138079.0007</a>-<a href="/entry/138070#0008">138070.0008</a>), suggesting a prevalence of approximately 5%. Extrapolating from this result, the prevalence of glucokinase-deficient MODY among Americans may be approximately 1 in 2,500. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8495817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Fetal insulin secretion in response to maternal glycemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. <a href="#19" class="mim-tip-reference" title="Hattersley, A. T., Beards, F., Ballantyne, E., Appleton, M., Harvey, R., Ellard, S. <strong>Mutations in the glucokinase gene of the fetus result in reduced birth weight.</strong> Nature Genet. 19: 268-270, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662401</a>] [<a href="https://doi.org/10.1038/953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662401">Hattersley et al. (1998)</a> hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycemia after birth. In 58 offspring, where one parent had a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P = 0.002). In 19 of 21 sib pairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P = 0.0002). Maternal hyperglycemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P = 0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. <a href="#19" class="mim-tip-reference" title="Hattersley, A. T., Beards, F., Ballantyne, E., Appleton, M., Harvey, R., Ellard, S. <strong>Mutations in the glucokinase gene of the fetus result in reduced birth weight.</strong> Nature Genet. 19: 268-270, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662401</a>] [<a href="https://doi.org/10.1038/953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662401">Hattersley et al. (1998)</a> proposed that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycemia, by the maternal genotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Dunger, D. B., Ong, K. K. L., Huxtable, S. J., Sherriff, A., Woods, K. A., Ahmed, M. L., Golding, J., Pembrey, M. E., Ring, S., ALSPAC Study Team, Bennett, S. T., Todd, J. A. <strong>Association of the INS VNTR with size at birth.</strong> Nature Genet. 19: 98-100, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590300/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590300</a>] [<a href="https://doi.org/10.1038/ng0598-98" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590300">Dunger et al. (1998)</a> demonstrated an association between the insulin VNTR (variable number tandem repeat) 'locus,' and specifically the VNTR III genotype, and larger size at birth. <a href="#32" class="mim-tip-reference" title="McCarthy, M. <strong>Weighing in on diabetes risk.</strong> Nature Genet. 19: 209-210, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662384/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662384</a>] [<a href="https://doi.org/10.1038/876" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662384">McCarthy (1998)</a> discussed the significance of these observations in relation to the 'thrifty genotype' hypothesis originally proposed by <a href="#36" class="mim-tip-reference" title="Neel, J. V. <strong>Diabetes mellitus: a 'thrifty' genotype rendered detrimental by 'progress'?</strong> Am. J. Hum. Genet. 14: 353-362, 1962.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13937884/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13937884</a>]" pmid="13937884">Neel (1962)</a> and updated by <a href="#35" class="mim-tip-reference" title="Neel, J. V., Weder, A. B., Julius, S. <strong>Type II diabetes, essential hypertension, and obesity as 'syndromes of impaired genetic homeostasis': the 'thrifty genotype' hypothesis enters the 21st century.</strong> Perspect. Biol. Med. 42: 44-74, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9894356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9894356</a>] [<a href="https://doi.org/10.1353/pbm.1998.0060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9894356">Neel et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9662384+9590300+9894356+13937884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 1</em></strong></p><p>
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<a href="#37" class="mim-tip-reference" title="Njolstad, P. R., Sovik, O., Cuesta-Munoz, A., Bjorkhaug, L., Massa, O., Barbetti, F., Undlien, D. E., Shiota, C., Magnuson, M. A., Molven, A., Matschinsky, F. M., Bell, G. I. <strong>Neonatal diabetes mellitus due to complete glucokinase deficiency.</strong> New Eng. J. Med. 344: 1588-1592, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11372010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11372010</a>] [<a href="https://doi.org/10.1056/NEJM200105243442104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11372010">Njolstad et al. (2001)</a> described 2 patients in whom complete deficiency of glucokinase caused permanent neonatal-onset diabetes (PNDM1; <a href="/entry/606176">606176</a>). One patient was homozygous for an M210K mutation (<a href="#0010">138079.0010</a>); the other was homozygous for a T228M mutation (<a href="#0003">138079.0003</a>). Both patients showed total absence of basal insulin release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11372010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Hyperinsulinemic Hypoglycemia</em></strong></p><p>
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In 'family 3' studied by <a href="#50" class="mim-tip-reference" title="Thornton, P. S., Satin-Smith, M. S., Herold, K., Glaser, B., Chiu, K. C., Nestorowicz, A., Permutt, M. A., Baker, L., Stanley, C. A. <strong>Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.</strong> J. Pediat. 132: 9-14, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9469993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9469993</a>] [<a href="https://doi.org/10.1016/s0022-3476(98)70477-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9469993">Thornton et al. (1998)</a>, in which affected members had hyperinsulinemic hypoglycemia (see HHF3, <a href="/entry/602485">602485</a>), <a href="#14" class="mim-tip-reference" title="Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C. A., Thornton, P. S., Permutt, M. A., Matschinsky, F. M., Herold, K. C. <strong>Familial hyperinsulinism caused by an activating glucokinase mutation.</strong> New Eng. J. Med. 338: 226-230, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435328</a>] [<a href="https://doi.org/10.1056/NEJM199801223380404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435328">Glaser et al. (1998)</a> identified heterozygosity for an activating mutation (<a href="#0009">138079.0009</a>) in the GCK gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9469993+9435328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness, <a href="#5" class="mim-tip-reference" title="Christesen, H. B. T., Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F., Barbetti, F. <strong>The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy.</strong> Diabetes 51: 1240-1246, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11916951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11916951</a>] [<a href="https://doi.org/10.2337/diabetes.51.4.1240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11916951">Christesen et al. (2002)</a> identified heterozygosity for an activating mutation in the GCK gene (<a href="#0012">138079.0012</a>). The boy's normal-weight mother, who had asymptomatic fasting hypoglycemia, carried the same mutation. <a href="#5" class="mim-tip-reference" title="Christesen, H. B. T., Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F., Barbetti, F. <strong>The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy.</strong> Diabetes 51: 1240-1246, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11916951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11916951</a>] [<a href="https://doi.org/10.2337/diabetes.51.4.1240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11916951">Christesen et al. (2002)</a> noted the striking contrast in clinical presentation between the mother and son with the same mutation, and recalled a similar situation in the family reported by <a href="#14" class="mim-tip-reference" title="Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C. A., Thornton, P. S., Permutt, M. A., Matschinsky, F. M., Herold, K. C. <strong>Familial hyperinsulinism caused by an activating glucokinase mutation.</strong> New Eng. J. Med. 338: 226-230, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435328</a>] [<a href="https://doi.org/10.1056/NEJM199801223380404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435328">Glaser et al. (1998)</a>, in which the proband was obese and severely hyperinsulinemic, whereas his sister who carried the same mutation was of normal weight, had relatively low insulin levels, and milder clinical symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9435328+11916951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Finnish woman with severe hyperinsulinemic hypoglycemia from birth, who had severe mental retardation and died at age 29 still having hypoglycemic seizures, <a href="#7" class="mim-tip-reference" title="Cuesta-Munoz, A. L., Huopio, H., Otonkoski, T., Gomez-Zumaquero, J. M., Nanto-Salonen, K., Rahier, J., Lopez-Enriquez, S., Garcia-Gimeno, M. A., Sanz, P., Soriguer, F. C., Laakso, M. <strong>Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.</strong> Diabetes 53: 2164-2168, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277402</a>] [<a href="https://doi.org/10.2337/diabetes.53.8.2164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277402">Cuesta-Munoz et al. (2004)</a> identified heterozygosity for a de novo activating mutation in the GCK gene (<a href="#0013">138079.0013</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15277402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kassem, S., Bhandari, S., Rodriguez-Bada, P., Motaghedi, R., Heyman, M., Garcia-Gimeno, M. A., Cobo-Vuilleumier, N., Sanz, P., Maclaren, N. K., Rahier, J., Glaser, B., Cuesta-Munoz, A. L. <strong>Large islets, beta-cell proliferation, and a glucokinase mutation.</strong> New Eng. J. Med. 362: 1348-1350, 2010. Note: Erratum: New Eng. J. Med. 363: 2178 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20375417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20375417</a>] [<a href="https://doi.org/10.1056/NEJMc0909845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20375417">Kassem et al. (2010)</a> reported a young girl with severe neonatal hypoglycemia due to a missense mutation in the GCK gene (<a href="#0015">138079.0015</a>) in whom mean islet cell areas in both the head and the tail of the pancreas were significantly larger than those of 5 age-matched controls and those of 2 age-matched patients with diffuse hypoglycemia due to ABCC8 mutations (<a href="/entry/600509">600509</a>; see HHF1, <a href="/entry/256450">256450</a>). Noting a previously reported HHF3 patient in whom quantitative histologic analysis of pancreatic specimens showed a similar increase in the mean islet profile (<a href="#7" class="mim-tip-reference" title="Cuesta-Munoz, A. L., Huopio, H., Otonkoski, T., Gomez-Zumaquero, J. M., Nanto-Salonen, K., Rahier, J., Lopez-Enriquez, S., Garcia-Gimeno, M. A., Sanz, P., Soriguer, F. C., Laakso, M. <strong>Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.</strong> Diabetes 53: 2164-2168, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277402</a>] [<a href="https://doi.org/10.2337/diabetes.53.8.2164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277402">Cuesta-Munoz et al. (2004)</a>), <a href="#25" class="mim-tip-reference" title="Kassem, S., Bhandari, S., Rodriguez-Bada, P., Motaghedi, R., Heyman, M., Garcia-Gimeno, M. A., Cobo-Vuilleumier, N., Sanz, P., Maclaren, N. K., Rahier, J., Glaser, B., Cuesta-Munoz, A. L. <strong>Large islets, beta-cell proliferation, and a glucokinase mutation.</strong> New Eng. J. Med. 362: 1348-1350, 2010. Note: Erratum: New Eng. J. Med. 363: 2178 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20375417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20375417</a>] [<a href="https://doi.org/10.1056/NEJMc0909845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20375417">Kassem et al. (2010)</a> suggested that histologic findings in infants with hyperinsulinemic hypoglycemia might differ according to the genetic cause of the condition. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20375417+15277402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Penetrance of GCK Mutations in Diabetes</em></strong></p><p>
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<a href="#33" class="mim-tip-reference" title="Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A. <strong>Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.</strong> Am. J. Hum. Genet. 109: 2018-2028, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36257325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36257325</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36257325[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/j.ajhg.2022.09.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36257325">Mirshahi et al. (2022)</a> comprehensively assessed the penetrance and prevalence of pathogenic variants in HNF1A (<a href="/entry/142410">142410</a>), HNF4A (<a href="/entry/600281">600281</a>), and GCK that account for more than 80% of monogenic diabetes. <a href="#33" class="mim-tip-reference" title="Mirshahi, U. L., Colclough, K., Wright, C. F., Wood, A. R., Beaumont, R. N., Tyrrell, J., Laver, T. W., Stahl, R., Golden, A., Goehringer, J. M, Geisinger-Regeneron DiscovEHR Collaboration, Frayling, T. F., Hattersley, A. T., Carey, D. J., Weedon, M. N., Patel, K. A. <strong>Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.</strong> Am. J. Hum. Genet. 109: 2018-2028, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/36257325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">36257325</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=36257325[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/j.ajhg.2022.09.014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="36257325">Mirshahi et al. (2022)</a> analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort of 132,194 individuals, and a UK population-based cohort of 198,748 individuals, and found that 1 in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of pathogenic GCK variants was similar (89 to 97%) across all cohorts. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts, highlighting the role of environment/ other genetic factors. The authors suggested that for HNF1A and HNF4A, genetic interpretation and counseling should be tailored to the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=36257325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Other Associations</em></strong></p><p>
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<a href="#41" class="mim-tip-reference" title="Rowe, R. E., Wapelhorst, B., Bell, G. I., Risch, N., Spielman, R. S., Concannon, P. <strong>Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7.</strong> Nature Genet. 10: 240-245, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663523</a>] [<a href="https://doi.org/10.1038/ng0695-240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663523">Rowe et al. (1995)</a> evaluated 35 microsatellite marker loci on human chromosome 7 for linkage to insulin-dependent diabetes mellitus (IDDM) in 339 affected sib-pair families. Increased sharing of parental haplotypes in affected sib pairs was detected for 2 microsatellite markers flanking GCK. Preferential transmission of alleles to affected offspring was observed at one of these marker loci, GCK3, indicating linkage disequilibrium between the marker and the disease susceptibility locus. This combination of linkage and disease association suggested to <a href="#41" class="mim-tip-reference" title="Rowe, R. E., Wapelhorst, B., Bell, G. I., Risch, N., Spielman, R. S., Concannon, P. <strong>Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7.</strong> Nature Genet. 10: 240-245, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663523</a>] [<a href="https://doi.org/10.1038/ng0695-240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663523">Rowe et al. (1995)</a> that glucokinase, or a gene in the vicinity, plays an important role in IDDM susceptibility. (<a href="#41" class="mim-tip-reference" title="Rowe, R. E., Wapelhorst, B., Bell, G. I., Risch, N., Spielman, R. S., Concannon, P. <strong>Linkage and association between insulin-dependent diabetes mellitus (IDDM) susceptibility and markers near the glucokinase gene on chromosome 7.</strong> Nature Genet. 10: 240-245, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7663523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7663523</a>] [<a href="https://doi.org/10.1038/ng0695-240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7663523">Rowe et al. (1995)</a> used the designations GCK1, GCK2, and GCK3 for 3 modestly polymorphic microsatellite markers near the GCK gene (<a href="#6" class="mim-tip-reference" title="Concannon, P. <strong>Personal Communication.</strong> Seattle, Wash. 7/26/1995."None>Concannon, 1995</a>). These are not symbols for separate glucokinase genes; there is only a single GCK gene on 7p, although as a result of alternative, tissue-specific promoters, there are islet- and liver-specific forms that differ in their amino-terminal sequences.) <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7663523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#46" class="mim-tip-reference" title="Stone, L. M., Kahn, S. E., Fujimoto, W. Y., Deeb, S. S., Porte, D. Jr. <strong>A variation at position -30 of the beta-cell glucokinase gene promoter is associated with reduced beta-cell function in middle-aged Japanese-American men.</strong> Diabetes 45: 422-428, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8603762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8603762</a>] [<a href="https://doi.org/10.2337/diab.45.4.422" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8603762">Stone et al. (1996)</a> used SSCP analysis to determine whether a G-to-A variant at position -30 of the beta-cell promoter of the GCK gene is associated with impaired beta-cell function. The variant was observed more frequently in Japanese-American men with impaired glucose tolerance than in Japanese-American men with normal glucose tolerance. Beta-cell function was assessed using the ratio of the incremental response in immunoreactive insulin to that of glucose during the first 30 minutes of the oral glucose tolerance test. They concluded that the -30 promoter variant is associated with reduced beta-cell function in middle-aged Japanese-American men and may contribute to the high risk of abnormal glucose tolerance in this population. They noted that the polymorphism has been observed in other populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8603762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#28" class="mim-tip-reference" title="Marz, W., Nauck, M., Hoffmann, M. M., Nagel, D., Boehm, B. O., Koenig, W., Rothenbacher, D., Winkelmann, B. R. <strong>G(-30)A polymorphism in the pancreatic promoter of the glucokinase gene associated with angiographic coronary artery disease and type 2 diabetes mellitus.</strong> Circulation 109: 2844-2849, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15173029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15173029</a>] [<a href="https://doi.org/10.1161/01.CIR.0000129306.44085.C4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15173029">Marz et al. (2004)</a> analyzed the GCK -30G-A variant in 2,567 patients with and in 731 individuals without coronary artery disease (CAD; see CHDS1, <a href="/entry/607339">607339</a>) by angiography and found that the A allele of the pancreatic GCK promoter increased the risk of CAD in individuals both with and without type II diabetes mellitus (ORs, 1.92 and 1.27, respectively). The A allele was also associated with an increased prevalence of type II diabetes mellitus, particularly among CAD patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15173029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>For discussion of an association between variation in the GCK gene and fasting plasma glucose levels, see FGQTL2 (<a href="/entry/613219">613219</a>).</p>
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<p><a href="#16" class="mim-tip-reference" title="Gloyn, A. L. <strong>Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.</strong> Hum. Mutat. 22: 353-362, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14517946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14517946</a>] [<a href="https://doi.org/10.1002/humu.10277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14517946">Gloyn (2003)</a> stated that given the central role of glucokinase in the regulation of insulin release, it is understandable that mutations in the GCK gene can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause MODY, characterized by mild hyperglycemia, which is present at birth, but is often only detected later in life. Homozygous inactivating GCK mutations result in a more severe phenotype, presenting at birth as permanent neonatal diabetes mellitus. Several heterozygous activating GCK mutations causing hypoglycemia had been reported as instances of familial hyperinsulinism (see HHF3, <a href="/entry/602485">602485</a>). <a href="#16" class="mim-tip-reference" title="Gloyn, A. L. <strong>Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.</strong> Hum. Mutat. 22: 353-362, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14517946/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14517946</a>] [<a href="https://doi.org/10.1002/humu.10277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14517946">Gloyn (2003)</a> tabulated 195 mutations in the GCK gene, found in 285 families. There were no common mutations and the mutations were distributed throughout the gene. Mutations causing hypoglycemia are located in various exons in a discrete region of the protein termed the heterotropic allosteric activator site. Patients with MODY type 2 (due to GCK mutations) rarely need pharmacologic treatment and most are managed on diet alone. During pregnancy, some women with GCK mutations are treated with insulin, which, due to its role in fetal growth, can result in babies that are large for gestational age if they do not also have the GCK mutation (<a href="#19" class="mim-tip-reference" title="Hattersley, A. T., Beards, F., Ballantyne, E., Appleton, M., Harvey, R., Ellard, S. <strong>Mutations in the glucokinase gene of the fetus result in reduced birth weight.</strong> Nature Genet. 19: 268-270, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662401</a>] [<a href="https://doi.org/10.1038/953" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662401">Hattersley et al., 1998</a>). Microvascular complications are rare in MODY2. These patients do not need to be followed in a diabetes clinic, but should have an HbA1c checked annually. Some patients with hyperinsulinism due to GCK mutations may not require pharmacologic intervention and may be able to control their symptoms by eating regularly. Patients with hyperinsulinism due to mutation in the ABCC8 gene (<a href="/entry/600509">600509</a>) or the KCNJ11 gene (<a href="/entry/600937">600937</a>) respond poorly or are totally refractory to the potassium channel opener diazoxide, which is used to inhibit insulin secretion. Conversely, patients with hyperinsulinism resulting from GCK mutations respond well or tolerated diazoxide (<a href="#15" class="mim-tip-reference" title="Gloyn, A. L., Noordam, K., Willemsen, M. A. A. P., Ellard, S., Lam, W. W. K., Campbell, I. W., Midgley, P., Shiota, C., Buettger, C., Magnuson, M. A., Matschinsky, F. M., Hattersley, A. T. <strong>Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations.</strong> Diabetes 52: 2433-2440, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12941786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12941786</a>] [<a href="https://doi.org/10.2337/diabetes.52.9.2433" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12941786">Gloyn et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12941786+9662401+14517946" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Using homologous recombination in mouse embryonic stem cells to disrupt the glucokinase gene, <a href="#2" class="mim-tip-reference" title="Bali, D., Svetlanov, A., Lee, H.-W., Fusco-DeMane, D., Leiser, M., Li, B., Barzilai, N., Surana, M., Hou, H., Fleischer, N., DePinho, R., Rossetti, L., Efrat, S. <strong>Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene.</strong> J. Biol. Chem. 270: 21464-21467, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7665557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7665557</a>] [<a href="https://doi.org/10.1074/jbc.270.37.21464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7665557">Bali et al. (1995)</a> showed that heterozygous mice showed a phenotype similar to MODY. Reduced islet glucokinase activity caused mildly elevated fasting blood glucose levels. Hyperglycemic clamp studies revealed decreased glucose tolerance and abnormal liver glucose metabolism. These findings demonstrated a key role for glucokinase in glucose homeostasis and implicated both islets and liver in the MODY disease. <a href="#1" class="mim-tip-reference" title="Aizawa, T., Asanuma, N., Terauchi, Y., Suzuki, N., Komatsu, M., Itoh, N., Nakabayashi, T., Hidaka, H., Ohnota, H., Yamauchi, K., Yasuda, K., Yazaki, Y., Kadowaki, T., Hashizume, K. <strong>Analysis of the pancreatic beta cell in the mouse with targeted disruption of the pancreatic beta cell-specific glucokinase gene.</strong> Biochem. Biophys. Res. Commun. 229: 460-465, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954920</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1826" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954920">Aizawa et al. (1996)</a> made a detailed study of pancreatic beta-cell function in the isolated pancreatic islets of heterozygous GCK knockout mice. The beta cells of these mice displayed impaired glucose sensitivity, poor discrimination of alpha- and beta-glucose anomers, and normal activity of the ATP-sensitive K+ channel. The mice displayed impaired insulin release after insulin treatment and age-related worsening of glucose tolerance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8954920+7665557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Understanding how the beta cells of the pancreatic islet sense an alteration in glucose levels is critical to understanding how glucose homeostasis is maintained. <a href="#18" class="mim-tip-reference" title="Grupe, A., Hultgren, B., Ryan, A., Ma, Y. H., Bauer, M., Stewart, T. A. <strong>Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis.</strong> Cell 83: 69-78, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553875</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90235-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553875">Grupe et al. (1995)</a> noted that glucose sensing is mediated through an increase in the rate of intracellular catabolism of glucose rather than a ligand-receptor interaction. However, it is likely that there is still a need for a rate-limiting step in glucose catabolism to serve the role of glucose sensor. A compelling case can be made for glucokinase fulfilling this role, since phosphorylation by GLK appears to be the rate-limiting step for glucose catabolism in beta cells. To test this possibility and to resolve the relative roles of liver and beta-cell GLK in maintaining glucose levels, <a href="#18" class="mim-tip-reference" title="Grupe, A., Hultgren, B., Ryan, A., Ma, Y. H., Bauer, M., Stewart, T. A. <strong>Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis.</strong> Cell 83: 69-78, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7553875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7553875</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90235-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7553875">Grupe et al. (1995)</a> generated mice completely deficient in GLK and transgenic mice in which GLK is expressed only in beta cells. In mice with only 1 GLK allele, blood glucose levels were elevated and insulin secretion was reduced. GLK-deficient mice died perinatally with severe hyperglycemia. Expression of GLK in beta cells in the absence of expression in the liver is sufficient for survival. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7553875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Grimsby, J., Sarabu, R., Corbett, W. L., Haynes, N.-E., Bizzarro, F. T., Coffey, J. W., Guertin, K. R., Hilliard, D. W., Kester, R. F., Mahaney, P. E., Marcus, L., Qi, L., Spence, C. L., Tengi, J., Magnuson, M. A., Chu, C. A., Dvorozniak, M. T., Matschinsky, F. M., Grippo, J. F. <strong>Allosteric activators of glucokinase: potential role in diabetes therapy.</strong> Science 301: 370-373, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12869762/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12869762</a>] [<a href="https://doi.org/10.1126/science.1084073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12869762">Grimsby et al. (2003)</a> identified a class of antidiabetic agents that act as nonessential, mixed-type glucokinase activators that increase the glucose affinity and maximum velocity of glucokinase. Glucokinase activators augmented both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of glucokinase in both cell types. In several rodent models of NIDDM, glucokinase activators lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12869762" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 N-ethyl-N-nitrosourea (ENU) mutagenesis, <a href="#23" class="mim-tip-reference" title="Inoue, M., Sakuraba, Y., Motegi, H., Kubota, N., Toki, H., Matsui, J., Toyoda, Y., Miwa, I., Terauchi, Y., Kadowaki, T., Shigeyama, Y., Kasuga, M. <strong>A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program.</strong> Hum. Molec. Genet. 13: 1147-1157, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15102714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15102714</a>] [<a href="https://doi.org/10.1093/hmg/ddh133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15102714">Inoue et al. (2004)</a> generated diabetic mice. The authors screened 9,375 animals and identified 11 mutations in the glucokinase (Gk) gene that were associated with hyperglycemia. Four had previously been found in human MODY2 (<a href="/entry/125851">125851</a>) patients, and 1 was found previously in a patient with permanent neonatal diabetes mellitus (PNDM; <a href="/entry/606176">606176</a>). Some of the Gk mutant lines displayed impaired glucose-responsive insulin secretion, and the mutations had different effects on Gk mRNA levels and/or the stability of the GK protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15102714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#49" class="mim-tip-reference" title="Terauchi, Y., Takamoto, I., Kubota, N., Matsui, J., Suzuki, R., Komeda, K., Hara, A., Toyoda, Y., Miwa, I., Aizawa, S., Tsutsumi, S., Tsubamoto, Y., Hashimoto, S., Eto, K., Nakamura, A., Noda, M., Tobe, K., Aburatani, H., Nagai, R., Kadowaki, T. <strong>Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.</strong> J. Clin. Invest. 117: 246-257, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200721[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/JCI17645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200721">Terauchi et al. (2007)</a> generated mice with haploinsufficiency of beta cell-specific Gck and observed that on a high-fat diet, Gck +/- mice had decreased beta cell replication and insufficient beta cell hyperplasia compared to wildtype mice despite a similar degree of insulin resistance. On a high-fat diet, Gck +/- mouse islets showed decreased insulin receptor substrate-2 (Irs2; <a href="/entry/600797">600797</a>) expression compared with wildtype islets. Overexpression of Irs2 in beta cells of Gck +/- mice partially prevented diabetes by increasing beta cell mass. <a href="#49" class="mim-tip-reference" title="Terauchi, Y., Takamoto, I., Kubota, N., Matsui, J., Suzuki, R., Komeda, K., Hara, A., Toyoda, Y., Miwa, I., Aizawa, S., Tsutsumi, S., Tsubamoto, Y., Hashimoto, S., Eto, K., Nakamura, A., Noda, M., Tobe, K., Aburatani, H., Nagai, R., Kadowaki, T. <strong>Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.</strong> J. Clin. Invest. 117: 246-257, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200721[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/JCI17645" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17200721">Terauchi et al. (2007)</a> suggested that both GCK and IRS2 are critical for beta cell hyperplasia to occur in response to high-fat diet-induced insulin resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17200721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<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> rs104894005 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894005;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/rs104894005?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=rs104894005" 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=rs104894005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In the process of single-strand conformation polymorphism (SSCP) analysis of exon 7 in a French family with GCK-linked MODY (MODY2; <a href="/entry/125851">125851</a>), previously studied by <a href="#11" class="mim-tip-reference" title="Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M. O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J. S., Lathrop, G. M., Passa, P., Permutt, M. A., Cohen, D. <strong>Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.</strong> Nature 356: 162-164, 1992. Note: Erratum: Nature 357: 607 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1545870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1545870</a>] [<a href="https://doi.org/10.1038/356162a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1545870">Froguel et al. (1992)</a>, <a href="#54" class="mim-tip-reference" title="Vionnet, N., Stoffel, M., Takeda, J., Yasuda, K., Bell, G. I., Zouali, H., Lesage, S., Velho, G., Iris, F., Passa, P., Froguel, P., Cohen, D. <strong>Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.</strong> Nature 356: 721-722, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570017</a>] [<a href="https://doi.org/10.1038/356721a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1570017">Vionnet et al. (1992)</a> demonstrated a G-to-T substitution in codon 279 which changed GAG (glutamic acid) to TAG, an amber termination codon. An individual in this family who had noninsulin-dependent diabetes mellitus (NIDDM) did not show linkage to GCK; moreover, she did not have the nonsense mutation in codon 279. Thus, there were 2 forms of NIDDM in this kindred. <a href="#20" class="mim-tip-reference" title="Hattersley, A. T., Turner, R. C., Permutt, M. A., Patel, P., Tanizawa, Y., Chiu, K. C., O'Rahilly, S., Watkins, P. J., Wainscoat, J. S. <strong>Linkage of type 2 diabetes to the glucokinase gene.</strong> Lancet 339: 1307-1310, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1349989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1349989</a>] [<a href="https://doi.org/10.1016/0140-6736(92)91958-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1349989">Hattersley et al. (1992)</a> likewise found tight linkage of MODY to a macrosatellite polymorphism associated with the GCK locus; peak lod = 4.60 at theta = 0.0. In a second MODY pedigree, they excluded linkage; lod = -7.36 at theta = 0.0. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1545870+1570017+1349989" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs104894006 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894006;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/rs104894006?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=rs104894006" 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=rs104894006" 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=RCV000017513 OR RCV000516235 OR RCV002225072 OR RCV002345246" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017513, RCV000516235, RCV002225072, RCV002345246" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017513...</a>
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<p>In a Japanese family, <a href="#26" class="mim-tip-reference" title="Katagiri, H., Asano, T., Ishihara, H., Inukai, K., Anai, M., Miyazaki, J., Tsukuda, K., Kikuchi, M., Yazaki, Y., Oka, Y. <strong>Nonsense mutation of glucokinase gene in late-onset non-insulin-dependent diabetes mellitus.</strong> Lancet 340: 1316-1317, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1360036/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1360036</a>] [<a href="https://doi.org/10.1016/0140-6736(92)92494-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1360036">Katagiri et al. (1992)</a> found a correlation between the presence of late-onset noninsulin-dependent diabetes mellitus (<a href="/entry/125853">125853</a>) or impaired glucose tolerance and a nonsense mutation in exon 5 of the glucokinase gene: a C-to-T transition changing codon 186 from CGA (arginine) to TGA (an amber termination codon). The mutation was predicted to delete 60% of the amino acid residues of the glucokinase derived from the affected allele. The family was detected through a 59-year-old woman who was the twenty-third subject screened. <a href="#12" class="mim-tip-reference" title="Froguel, P., Velho, G. <strong>Non-sense mutation of glucokinase gene. (Letter)</strong> Lancet 341: 385 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094163</a>]" pmid="8094163">Froguel and Velho (1993)</a> raised the question as to whether the Japanese family may in fact have had MODY, because in their experience in French families carrying mutations in GCK, hyperglycemia often went undiagnosed for a long time. <a href="#4" class="mim-tip-reference" title="Chiu, K. C., Tanizawa, Y., Permutt, M. A. <strong>Non-sense mutation of glucokinase gene. (Letter)</strong> Lancet 341: 385-386, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094164</a>]" pmid="8094164">Chiu et al. (1993)</a> likewise questioned whether the disorder in the Japanese families should be termed NIDDM and pointed out that in young patients with glucokinase mutations the degree of hyperglycemia is so mild that values often do not exceed the renal threshold. Therefore, absence of glycosuria cannot be used as a criterion for distinguishing MODY from NIDDM. <a href="#38" class="mim-tip-reference" title="Permutt, M. A., Chiu, K. C., Tanizawa, Y. <strong>Glucokinase and NIDDM: a candidate gene that paid off.</strong> Diabetes 41: 1367-1372, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1397713/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1397713</a>] [<a href="https://doi.org/10.2337/diab.41.11.1367" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1397713">Permutt et al. (1992)</a> pointed out that structural mutations in the GCK gene are very rare (less than 2%) in American black and Caucasian NIDDM patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8094163+1360036+8094164+1397713" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs80356655 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356655;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/rs80356655?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=rs80356655" 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=rs80356655" 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=RCV000020167 OR RCV000498792 OR RCV001269032 OR RCV002362586 OR RCV003147295 OR RCV003147296 OR RCV003883118 OR RCV004751212" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020167, RCV000498792, RCV001269032, RCV002362586, RCV003147295, RCV003147296, RCV003883118, RCV004751212" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020167...</a>
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<p><strong><em>Maturity-Onset Diabetes of the Young, Type 2</em></strong></p><p>
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<a href="#44" class="mim-tip-reference" title="Stoffel, M., Froguel, P., Takeda, J., Zouali, H., Vionnet, N., Nishi, S., Weber, I. T., Harrison, R. W., Pilkis, S. J., Lesage, S., Vaxillaire, M., Velho, G., Sun, F., Iris, F., Passa, P., Cohen, D., Bell, G. I. <strong>Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 89: 7698-7702, 1992. Note: Erratum: Proc. Nat. Acad Sci. 89: 10562 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1502186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1502186</a>] [<a href="https://doi.org/10.1073/pnas.89.16.7698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1502186">Stoffel et al. (1992)</a> stated that DNA polymorphisms in the GCK gene has been shown to be tightly linked to MODY (MODY2; <a href="/entry/125851">125851</a>) in approximately 80% of French families. They identified 2 further missense mutations in exon 7 in families with MODY: thr228 to met (T228M) and gly261 to arg (G261R; <a href="#0004">138079.0004</a>). A TGC-to-TAC change at codon 228 and a CCC-to-TCC change at codon 261 were responsible. Using computer-assisted modeling and the crystal structure of the related yeast hexokinase B as a simple model for human beta-cell glucokinase, <a href="#44" class="mim-tip-reference" title="Stoffel, M., Froguel, P., Takeda, J., Zouali, H., Vionnet, N., Nishi, S., Weber, I. T., Harrison, R. W., Pilkis, S. J., Lesage, S., Vaxillaire, M., Velho, G., Sun, F., Iris, F., Passa, P., Cohen, D., Bell, G. I. <strong>Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 89: 7698-7702, 1992. Note: Erratum: Proc. Nat. Acad Sci. 89: 10562 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1502186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1502186</a>] [<a href="https://doi.org/10.1073/pnas.89.16.7698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1502186">Stoffel et al. (1992)</a> obtained data which suggested to them that mutation of thr228 affects affinity for ATP and mutation of gly261 alters glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset noninsulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1502186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#51" class="mim-tip-reference" title="Velho, G., Blanche, H., Vaxillaire, M., Bellane-Chantelot, C., Pardini, V. C., Timsit, J., Passa, P., Deschamps, I., Robert, J.-J., Weber, I. T., Marotta, D., Pilkis, S. J., Lipkind, G. M., Bell, G. I., Froguel, P. <strong>Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.</strong> Diabetologia 40: 217-224, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9049484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9049484</a>] [<a href="https://doi.org/10.1007/s001250050666" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9049484">Velho et al. (1997)</a> identified the T228M mutation in affected members of a family with glucokinase-related MODY. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9049484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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, Permanent Neonatal 1</em></strong></p><p>
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In an 8-year-old girl of Italian ancestry, <a href="#37" class="mim-tip-reference" title="Njolstad, P. R., Sovik, O., Cuesta-Munoz, A., Bjorkhaug, L., Massa, O., Barbetti, F., Undlien, D. E., Shiota, C., Magnuson, M. A., Molven, A., Matschinsky, F. M., Bell, G. I. <strong>Neonatal diabetes mellitus due to complete glucokinase deficiency.</strong> New Eng. J. Med. 344: 1588-1592, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11372010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11372010</a>] [<a href="https://doi.org/10.1056/NEJM200105243442104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11372010">Njolstad et al. (2001)</a> identified homozygosity for the T228M mutation in the GCK gene as the cause of neonatal-onset diabetes mellitus (PNDM1; <a href="/entry/606176">606176</a>). The child had shown hyperglycemia and marked growth retardation at birth. Her father had impaired glucose tolerance and her mother had impaired fasting glycemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11372010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs104894008 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894008;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/rs104894008?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=rs104894008" 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=rs104894008" 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=RCV000017515 OR RCV000426797 OR RCV001507008 OR RCV003325940 OR RCV003445078" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017515, RCV000426797, RCV001507008, RCV003325940, RCV003445078" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017515...</a>
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<p><a href="#44" class="mim-tip-reference" title="Stoffel, M., Froguel, P., Takeda, J., Zouali, H., Vionnet, N., Nishi, S., Weber, I. T., Harrison, R. W., Pilkis, S. J., Lesage, S., Vaxillaire, M., Velho, G., Sun, F., Iris, F., Passa, P., Cohen, D., Bell, G. I. <strong>Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 89: 7698-7702, 1992. Note: Erratum: Proc. Nat. Acad Sci. 89: 10562 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1502186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1502186</a>] [<a href="https://doi.org/10.1073/pnas.89.16.7698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1502186">Stoffel et al. (1992)</a> identified missense mutations in exon 7 of the GCK gene in families with maturity diabetes of the young (MODY2; <a href="/entry/125851">125851</a>): thr228 to met (T228M; <a href="#0003">138079.0003</a>) and gly261 to arg (G261R). A TGC-to-TAC change at codon 228 and a CCC-to-TCC change at codon 261 were responsible. Using computer-assisted modeling and the crystal structure of the related yeast hexokinase B as a simple model for human beta-cell glucokinase, <a href="#44" class="mim-tip-reference" title="Stoffel, M., Froguel, P., Takeda, J., Zouali, H., Vionnet, N., Nishi, S., Weber, I. T., Harrison, R. W., Pilkis, S. J., Lesage, S., Vaxillaire, M., Velho, G., Sun, F., Iris, F., Passa, P., Cohen, D., Bell, G. I. <strong>Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus.</strong> Proc. Nat. Acad. Sci. 89: 7698-7702, 1992. Note: Erratum: Proc. Nat. Acad Sci. 89: 10562 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1502186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1502186</a>] [<a href="https://doi.org/10.1073/pnas.89.16.7698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1502186">Stoffel et al. (1992)</a> obtained data which suggested to them that mutation of thr228 affects affinity for ATP and mutation of gly261 alters glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset noninsulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1502186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894009 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894009;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=rs104894009" 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=rs104894009" 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=RCV000017516 OR RCV001288185" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017516, RCV001288185" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017516...</a>
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<p>In a large British pedigree with many cases of MODY (MODY2; <a href="/entry/125851">125851</a>) in 5 generations, <a href="#45" class="mim-tip-reference" title="Stoffel, M., Patel, P., Lo, Y.-M. D., Hattersley, A. T., Lucassen, A. M., Page, R., Bell, J. I., Bell, G. I., Turner, R. C., Wainscoat, J. S. <strong>Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes.</strong> Nature Genet. 2: 153-156, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303265/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303265</a>] [<a href="https://doi.org/10.1038/ng1092-153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303265">Stoffel et al. (1992)</a> demonstrated a G-to-C transversion in the GCK gene, which converted codon 266 from glycine to arginine. The mutation also created a HhaI site which allowed them to construct a rapid PCR test for the mutation. Applying this to cases of classic late-onset type 2 diabetes mellitus, they found the same mutation in 1 of 50 patients. All 9 relatives of this patient who had inherited the mutation had type 2 diabetes, although 6 others without the mutation also had diabetes. MODY had not previously been considered in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1303265" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 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">rs1583601110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1583601110;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=rs1583601110" 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=rs1583601110" 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=RCV000992052 OR RCV002286425 OR RCV003106086" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000992052, RCV002286425, RCV003106086" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000992052...</a>
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<p><a href="#47" class="mim-tip-reference" title="Sun, F., Knebelmann, B., Pueyo, M. E., Zouali, H., Lesage, S., Vaxillaire, M., Passa, P., Cohen, D., Velho, G., Antignac, C., Froguel, P. <strong>Deletion of the donor splice site of intron 4 in the glucokinase gene causes maturity-onset diabetes of the young.</strong> J. Clin. Invest. 92: 1174-1180, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8376578/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8376578</a>] [<a href="https://doi.org/10.1172/JCI116687" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8376578">Sun et al. (1993)</a> analyzed the nucleotide sequence of exon 4 and its flanking intronic regions of the GCK gene in 4 hyperglycemic members of a MODY (MODY2; <a href="/entry/125851">125851</a>) family and found a deletion of 15 bp, which removed the T of the GT in the donor splice site of intron 4 and the following 14 basepairs. This deletion resulted in 2 aberrant transcripts: one with exon 5 missing and the other with activation of a cryptic splice site leading to the removal of the last 8 codons of exon 4. This intronic deletion seemed to cause a more severe form of glucose intolerance than did the missense and nonsense mutations previously reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8376578" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0007 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
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GCK, SER131PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894010 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894010;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=rs104894010" 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=rs104894010" 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=RCV000017518 OR RCV002513078 OR RCV003147297 OR RCV003147298 OR RCV003147299 OR RCV004730847" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017518, RCV002513078, RCV003147297, RCV003147298, RCV003147299, RCV004730847" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017518...</a>
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<p><a href="#43" class="mim-tip-reference" title="Stoffel, M., Bell, K. L., Blackburn, C. L., Powell, K. L., Seo, T. S., Takeda, J., Vionnet, N., Xiang, K.-S., Gidh-Jain, M., Pilkis, S. J., Ober, C., Bell, G. I. <strong>Identification of glucokinase mutations in subjects with gestational diabetes mellitus.</strong> Diabetes 42: 937-940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8495817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8495817</a>] [<a href="https://doi.org/10.2337/diab.42.6.937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8495817">Stoffel et al. (1993)</a> found heterozygosity for a ser131-to-pro mutation in the GCK gene in an obese 31-year-old Puerto Rican woman with gestational diabetes (MODY2; <a href="/entry/125851">125851</a>) in her first pregnancy. She reportedly had borderline elevated blood glucose levels at age 26. <a href="#43" class="mim-tip-reference" title="Stoffel, M., Bell, K. L., Blackburn, C. L., Powell, K. L., Seo, T. S., Takeda, J., Vionnet, N., Xiang, K.-S., Gidh-Jain, M., Pilkis, S. J., Ober, C., Bell, G. I. <strong>Identification of glucokinase mutations in subjects with gestational diabetes mellitus.</strong> Diabetes 42: 937-940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8495817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8495817</a>] [<a href="https://doi.org/10.2337/diab.42.6.937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8495817">Stoffel et al. (1993)</a> showed defective enzymatic properties of the enzyme carrying the ser131-to-pro mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8495817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
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GCK, GLU265TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894011 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894011;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=rs104894011" 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=rs104894011" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017519 OR RCV000517435" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017519, RCV000517435" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017519...</a>
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<p><a href="#43" class="mim-tip-reference" title="Stoffel, M., Bell, K. L., Blackburn, C. L., Powell, K. L., Seo, T. S., Takeda, J., Vionnet, N., Xiang, K.-S., Gidh-Jain, M., Pilkis, S. J., Ober, C., Bell, G. I. <strong>Identification of glucokinase mutations in subjects with gestational diabetes mellitus.</strong> Diabetes 42: 937-940, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8495817/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8495817</a>] [<a href="https://doi.org/10.2337/diab.42.6.937" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8495817">Stoffel et al. (1993)</a> found a glu265-to-ter mutation in a thin 32-year-old Caucasian woman with gestational diabetes mellitus (MODY2; <a href="/entry/125851">125851</a>) who was in her second pregnancy. She reportedly had elevated fasting blood glucose levels since age 16. The subject's mother and 2 sisters had diabetes mellitus treated with diet or oral hypoglycemic agents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8495817" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 3</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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GCK, VAL455MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104894012 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894012;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=rs104894012" 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=rs104894012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017520 OR RCV002513079" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017520, RCV002513079" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017520...</a>
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<p>In a 31-year-old man and his 36-year-old sister from the 3-generation 'family 3' with autosomal dominant hyperinsulinemic hypoglycemia (<a href="/entry/602485">602485</a>) previously studied by <a href="#50" class="mim-tip-reference" title="Thornton, P. S., Satin-Smith, M. S., Herold, K., Glaser, B., Chiu, K. C., Nestorowicz, A., Permutt, M. A., Baker, L., Stanley, C. A. <strong>Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.</strong> J. Pediat. 132: 9-14, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9469993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9469993</a>] [<a href="https://doi.org/10.1016/s0022-3476(98)70477-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9469993">Thornton et al. (1998)</a>, <a href="#14" class="mim-tip-reference" title="Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C. A., Thornton, P. S., Permutt, M. A., Matschinsky, F. M., Herold, K. C. <strong>Familial hyperinsulinism caused by an activating glucokinase mutation.</strong> New Eng. J. Med. 338: 226-230, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435328</a>] [<a href="https://doi.org/10.1056/NEJM199801223380404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9435328">Glaser et al. (1998)</a> identified a val455-to-met (V455M) mutation in the glucokinase gene. When expressed in vitro, the V455M mutation increased the affinity of glucokinase for glucose, resulting in higher rates of glycolysis at low glucose concentrations and therefore a higher rate of insulin secretion at any plasma glucose concentration. The finding confirmed the importance of glucokinase as a primary regulator of glucose-controlled insulin secretion in beta cells. This mutation was not found in 37 unrelated white families with hyperinsulinism, including 6 with an apparently autosomal dominant form. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9469993+9435328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 DIABETES MELLITUS, PERMANENT NEONATAL, 1</strong>
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MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2, INCLUDED
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GCK, MET210LYS
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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> rs80356654 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356654;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/rs80356654?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=rs80356654" 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=rs80356654" 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=RCV000017521 OR RCV000190348 OR RCV001281107 OR RCV003318493" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017521, RCV000190348, RCV001281107, RCV003318493" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017521...</a>
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<p><a href="#37" class="mim-tip-reference" title="Njolstad, P. R., Sovik, O., Cuesta-Munoz, A., Bjorkhaug, L., Massa, O., Barbetti, F., Undlien, D. E., Shiota, C., Magnuson, M. A., Molven, A., Matschinsky, F. M., Bell, G. I. <strong>Neonatal diabetes mellitus due to complete glucokinase deficiency.</strong> New Eng. J. Med. 344: 1588-1592, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11372010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11372010</a>] [<a href="https://doi.org/10.1056/NEJM200105243442104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11372010">Njolstad et al. (2001)</a> described an infant girl of Norwegian ancestry with neonatal diabetes mellitus (PNDM1; <a href="/entry/606176">606176</a>) that persisted thereafter. The parents were first cousins, and both had glucose intolerance. At 5 years of age, the patient developed epilepsy, probably as a sequela of a neonatal brain abscess. A sister had typical type I diabetes developing at the age of 7 years. The mother had a diagnosis of gestational diabetes at the age of 25 years. The father had impaired fasting glycemia that was treated with diet. After excluding other candidate genes, <a href="#37" class="mim-tip-reference" title="Njolstad, P. R., Sovik, O., Cuesta-Munoz, A., Bjorkhaug, L., Massa, O., Barbetti, F., Undlien, D. E., Shiota, C., Magnuson, M. A., Molven, A., Matschinsky, F. M., Bell, G. I. <strong>Neonatal diabetes mellitus due to complete glucokinase deficiency.</strong> New Eng. J. Med. 344: 1588-1592, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11372010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11372010</a>] [<a href="https://doi.org/10.1056/NEJM200105243442104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11372010">Njolstad et al. (2001)</a> found that the child was homozygous for a T-to-A transversion (ATG-AAG) at nucleotide 629 in exon 6 of the GCK gene, resulting in a met210-to-lys mutation (M210K). Her parents and sister were heterozygous for the mutation, which cosegregated with diabetes or hyperglycemia in other members of the family. Thus, in this family, heterozygosity caused GCK-related MODY (MODY2; <a href="/entry/125851">125851</a>) and homozygosity caused neonatal-onset diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11372010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894014 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894014;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=rs104894014" 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=rs104894014" 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=RCV000017525 OR RCV001818166" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017525, RCV001818166" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017525...</a>
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<p>In a 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness (see HHF3, <a href="/entry/602485">602485</a>), <a href="#5" class="mim-tip-reference" title="Christesen, H. B. T., Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F., Barbetti, F. <strong>The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy.</strong> Diabetes 51: 1240-1246, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11916951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11916951</a>] [<a href="https://doi.org/10.2337/diabetes.51.4.1240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11916951">Christesen et al. (2002)</a> identified heterozygosity for an ala456-to-val (A456V) substitution in exon 10 of the GCK gene. Kinetic analysis showed this to be an activating mutation. The boy's normal-weight mother, who had asymptomatic fasting hypoglycemia, carried the same mutation; the mutation was not found in his normoglycemic brother nor in 80 controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11916951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs104894015 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894015;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=rs104894015" 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=rs104894015" 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=RCV000017526 OR RCV005089266" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017526, RCV005089266" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017526...</a>
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<p>In a Finnish woman with severe hyperinsulinemic hypoglycemia from birth (<a href="/entry/602485">602485</a>), who had severe mental retardation and was still having hypoglycemic seizures when she died at age 29, <a href="#7" class="mim-tip-reference" title="Cuesta-Munoz, A. L., Huopio, H., Otonkoski, T., Gomez-Zumaquero, J. M., Nanto-Salonen, K., Rahier, J., Lopez-Enriquez, S., Garcia-Gimeno, M. A., Sanz, P., Soriguer, F. C., Laakso, M. <strong>Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.</strong> Diabetes 53: 2164-2168, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277402</a>] [<a href="https://doi.org/10.2337/diabetes.53.8.2164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277402">Cuesta-Munoz et al. (2004)</a> identified heterozygosity for a de novo tyr214-to-cys (Y214C) substitution in exon 6 of the GCK gene. Although paternity was confirmed, the mutation was not found in her parents or her 2 healthy sisters. Kinetic analysis revealed that this mutation had the highest activity index (130-fold over wildtype) of all naturally occurring activating GCK mutations described. <a href="#7" class="mim-tip-reference" title="Cuesta-Munoz, A. L., Huopio, H., Otonkoski, T., Gomez-Zumaquero, J. M., Nanto-Salonen, K., Rahier, J., Lopez-Enriquez, S., Garcia-Gimeno, M. A., Sanz, P., Soriguer, F. C., Laakso, M. <strong>Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.</strong> Diabetes 53: 2164-2168, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15277402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15277402</a>] [<a href="https://doi.org/10.2337/diabetes.53.8.2164" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15277402">Cuesta-Munoz et al. (2004)</a> noted that this phenotype was considerably more severe than that of previously reported patients (see <a href="#0009">138079.0009</a> and <a href="#0012">138079.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15277402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 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> rs104894016 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104894016;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/rs104894016?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=rs104894016" 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=rs104894016" 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=RCV000017527 OR RCV002513080 OR RCV003325941" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017527, RCV002513080, RCV003325941" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017527...</a>
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<p>In affected members from 5 Belgian families with MODY2 (<a href="/entry/125851">125851</a>), <a href="#55" class="mim-tip-reference" title="Vits, L., Beckers, D., Craen, M., de Beaufort, C., Vanfleteren, E., Dahan, K., Nollet, A., Vanhaverbeke, G., Imschoot, S. V., Bourguignon, J.-P., Beauloye, V., Storm, K., Massa, G., Giri, M., Nobels, F., De Schepper, J., Rooman, R., Van den Bruel, A., Mathieu, C., Wuyts, W. <strong>Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. (Letter)</strong> Clin. Genet. 70: 355-359, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965331</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00686.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16965331">Vits et al. (2006)</a> identified a 1132G-A transition in exon 9 of the GCK gene, resulting in an ala378-to-thr (A378T) substitution. All the probands originated from the Belgian province of West Flanders, suggesting a founder mutation; this was confirmed in 3 families by haplotype analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965331" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 3</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000017528" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000017528" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000017528</a>
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<p><a href="#25" class="mim-tip-reference" title="Kassem, S., Bhandari, S., Rodriguez-Bada, P., Motaghedi, R., Heyman, M., Garcia-Gimeno, M. A., Cobo-Vuilleumier, N., Sanz, P., Maclaren, N. K., Rahier, J., Glaser, B., Cuesta-Munoz, A. L. <strong>Large islets, beta-cell proliferation, and a glucokinase mutation.</strong> New Eng. J. Med. 362: 1348-1350, 2010. Note: Erratum: New Eng. J. Med. 363: 2178 only, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20375417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20375417</a>] [<a href="https://doi.org/10.1056/NEJMc0909845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20375417">Kassem et al. (2010)</a> studied a young girl with severe neonatal hypoglycemia-3 (<a href="/entry/602485">602485</a>) due to a val91-to-leu (V91L) missense mutation in the GCK gene. Her father had a similar clinical course but neither his DNA nor pancreatic tissue was available for study. Quantitative histologic examination after subtotal pancreatectomy due to refractory disease revealed abnormally large islets, with some beta cells containing a large nucleus, and mean islet cell areas in both the head and the tail of the pancreas were significantly larger than those of 5 age-matched controls and those of 2 age-matched HHF1 (<a href="/entry/256450">256450</a>) patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20375417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs397514580 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514580;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=rs397514580" 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=rs397514580" 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=RCV000032978 OR RCV003883126 OR RCV005089333" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032978, RCV003883126, RCV005089333" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032978...</a>
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<p>In 5 affected members over 3 generations of a mainland Chinese family with type 2 maturity-onset diabetes of the young (MODY2; <a href="/entry/125851">125851</a>), <a href="#42" class="mim-tip-reference" title="Shen, Y., Cai, M., Liang, H., Wang, H., Weng, J. <strong>Insight into the biochemical characteristics of a novel glucokinase gene mutation.</strong> Hum. Genet. 129: 231-238, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21104275/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21104275</a>] [<a href="https://doi.org/10.1007/s00439-010-0914-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21104275">Shen et al. (2011)</a> identified heterozygosity for a G-A transition in exon 8 of the GCK gene, resulting in a glu339-to-lys (E339K) substitution. The mutation was not found in unaffected family members or in 200 controls. SDS-PAGE analysis of a bacterial expression system demonstrated that the protein yield of mutant GCK was significantly lower than wildtype; kinetic analysis showed that the E339K mutant had 1.4-fold and 9.9-fold lower affinity for glucose and ATP, respectively, compared to wildtype. The mutant GCK also exhibited thermal instability, with a dramatic decrease in activity at 45 degrees centigrade compared to 55 degrees centigrade for wildtype; in addition, wildtype GCK maintained 50% activity at 55 degrees centigrade for 30 minutes, whereas wildtype lost 97% of activity within 30 minutes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21104275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Christesen, H. B. T., Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F., Barbetti, F.
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[<a href="https://doi.org/10.2337/diabetes.53.8.2164" target="_blank">Full Text</a>]
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Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J.
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[<a href="https://doi.org/10.1038/nature01825" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng0598-98" target="_blank">Full Text</a>]
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Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M. O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J. S., Lathrop, G. M., Passa, P., Permutt, M. A., Cohen, D.
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[<a href="https://doi.org/10.1038/356162a0" target="_blank">Full Text</a>]
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<a id="Froguel1993" class="mim-anchor"></a>
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<strong>Non-sense mutation of glucokinase gene. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8094163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8094163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8094163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Froguel1993" class="mim-anchor"></a>
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Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J., Passa, P., Permutt, M. A., Beckmann, J. S., Bell, G. I., Cohen, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8433729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8433729</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8433729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199303113281005" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9435328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9435328</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9435328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1056/NEJM199801223380404" target="_blank">Full Text</a>]
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<a id="Gloyn2003" class="mim-anchor"></a>
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<div class="">
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Gloyn, A. L., Noordam, K., Willemsen, M. A. A. P., Ellard, S., Lam, W. W. K., Campbell, I. W., Midgley, P., Shiota, C., Buettger, C., Magnuson, M. A., Matschinsky, F. M., Hattersley, A. T.
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<strong>Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations.</strong>
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[<a href="https://doi.org/10.2337/diabetes.52.9.2433" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0888-7543(92)90380-b" target="_blank">Full Text</a>]
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Tanizawa, Y., Koranyi, L. I., Welling, C. M., Permutt, M. A.
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<strong>Human liver glucokinase gene: cloning and sequence determination of two alternatively spliced cDNAs.</strong>
|
|
Proc. Nat. Acad. Sci. 88: 7294-7297, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1871135/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1871135</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1871135" 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.88.16.7294" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="49" class="mim-anchor"></a>
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<a id="Terauchi2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Terauchi, Y., Takamoto, I., Kubota, N., Matsui, J., Suzuki, R., Komeda, K., Hara, A., Toyoda, Y., Miwa, I., Aizawa, S., Tsutsumi, S., Tsubamoto, Y., Hashimoto, S., Eto, K., Nakamura, A., Noda, M., Tobe, K., Aburatani, H., Nagai, R., Kadowaki, T.
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<strong>Glucokinase and IRS-2 are required for compensatory beta cell hyperplasia in response to high-fat diet-induced insulin resistance.</strong>
|
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J. Clin. Invest. 117: 246-257, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17200721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17200721</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17200721[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=17200721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI17645" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="50" class="mim-anchor"></a>
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<a id="Thornton1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thornton, P. S., Satin-Smith, M. S., Herold, K., Glaser, B., Chiu, K. C., Nestorowicz, A., Permutt, M. A., Baker, L., Stanley, C. A.
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|
<strong>Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.</strong>
|
|
J. Pediat. 132: 9-14, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9469993/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9469993</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9469993" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0022-3476(98)70477-9" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="51" class="mim-anchor"></a>
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<a id="Velho1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Velho, G., Blanche, H., Vaxillaire, M., Bellane-Chantelot, C., Pardini, V. C., Timsit, J., Passa, P., Deschamps, I., Robert, J.-J., Weber, I. T., Marotta, D., Pilkis, S. J., Lipkind, G. M., Bell, G. I., Froguel, P.
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<strong>Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.</strong>
|
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Diabetologia 40: 217-224, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9049484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9049484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9049484" 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/10.1007/s001250050666" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="52" class="mim-anchor"></a>
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<a id="Velho1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Velho, G., Froguel, P., Clement, K., Pueyo, M. E., Rakotoambinina, B., Zouali, H., Passa, P., Cohen, D., Robert, J.-J.
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<strong>Primary pancreatic beta-cell secretory defect caused by mutations in glucokinase gene in kindreds of maturity onset diabetes of the young.</strong>
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Lancet 340: 444-448, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1354782/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1354782</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1354782" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0140-6736(92)91768-4" target="_blank">Full Text</a>]
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<li>
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<a id="53" class="mim-anchor"></a>
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<a id="Velho1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Velho, G., Petersen, K. F., Perseghin, G., Hwang, J.-H., Rothman, D. L., Pueyo, M. E., Cline, G. W., Froguel, P., Shulman, G. I.
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<strong>Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects.</strong>
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J. Clin. Invest. 98: 1755-1761, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8878425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8878425</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8878425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1172/JCI118974" target="_blank">Full Text</a>]
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<li>
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<a id="54" class="mim-anchor"></a>
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<a id="Vionnet1992" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vionnet, N., Stoffel, M., Takeda, J., Yasuda, K., Bell, G. I., Zouali, H., Lesage, S., Velho, G., Iris, F., Passa, P., Froguel, P., Cohen, D.
|
|
<strong>Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.</strong>
|
|
Nature 356: 721-722, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1570017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1570017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1570017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/356721a0" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="55" class="mim-anchor"></a>
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<a id="Vits2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vits, L., Beckers, D., Craen, M., de Beaufort, C., Vanfleteren, E., Dahan, K., Nollet, A., Vanhaverbeke, G., Imschoot, S. V., Bourguignon, J.-P., Beauloye, V., Storm, K., Massa, G., Giri, M., Nobels, F., De Schepper, J., Rooman, R., Van den Bruel, A., Mathieu, C., Wuyts, W.
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<strong>Identification of novel and recurrent glucokinase mutations in Belgian and Luxembourg maturity onset diabetes of the young patients. (Letter)</strong>
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Clin. Genet. 70: 355-359, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16965331/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16965331</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16965331" 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/10.1111/j.1399-0004.2006.00686.x" target="_blank">Full Text</a>]
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</ol>
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<br />
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</div>
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<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 : 01/17/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 02/14/2018<br>Patricia A. Hartz - updated : 6/24/2014<br>Marla J. F. O'Neill - updated : 11/2/2012<br>Patricia A. Hartz - updated : 4/15/2010<br>Marla J. F. O'Neill - reorganized : 4/14/2010<br>Marla J. F. O'Neill - updated : 4/14/2010<br>Ada Hamosh - updated : 1/15/2010<br>Victor A. McKusick - updated : 5/23/2007<br>Marla J. F. O'Neill - updated : 4/17/2007<br>Marla J. F. O'Neill - updated : 3/9/2007<br>Victor A. McKusick - updated : 11/28/2006<br>Cassandra L. Kniffin - updated : 11/2/2006<br>John A. Phillips, III - updated : 10/19/2006<br>George E. Tiller - updated : 8/31/2006<br>Marla J. F. O'Neill - updated : 3/17/2006<br>Marla J. F. O'Neill - updated : 1/25/2006<br>Victor A. McKusick - updated : 11/19/2003<br>Ada Hamosh - updated : 9/16/2003<br>Ada Hamosh - updated : 8/5/2003<br>Ada Hamosh - updated : 10/18/2001<br>Ada Hamosh - updated : 8/23/2001<br>Victor A. McKusick - updated : 6/25/2001<br>Victor A. McKusick - updated : 2/2/1999<br>Victor A. McKusick - updated : 6/25/1998<br>Victor A. McKusick - updated : 4/15/1998<br>Jennifer P. Macke - updated : 9/2/1997
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 2/1/1992
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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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alopez : 01/17/2023
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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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alopez : 12/01/2020<br>carol : 09/02/2020<br>carol : 07/14/2020<br>alopez : 04/30/2020<br>mgross : 02/14/2018<br>alopez : 08/04/2016<br>carol : 08/12/2015<br>carol : 8/12/2015<br>mgross : 6/24/2014<br>mgross : 10/7/2013<br>mgross : 10/7/2013<br>terry : 4/4/2013<br>carol : 11/6/2012<br>terry : 11/2/2012<br>terry : 7/5/2012<br>carol : 12/15/2010<br>alopez : 4/22/2010<br>mgross : 4/16/2010<br>terry : 4/15/2010<br>carol : 4/14/2010<br>carol : 4/14/2010<br>wwang : 2/3/2010<br>alopez : 1/27/2010<br>alopez : 1/26/2010<br>terry : 1/15/2010<br>terry : 9/11/2009<br>joanna : 9/4/2009<br>alopez : 5/29/2007<br>terry : 5/23/2007<br>wwang : 4/17/2007<br>wwang : 3/13/2007<br>terry : 3/9/2007<br>alopez : 12/8/2006<br>terry : 11/28/2006<br>carol : 11/3/2006<br>ckniffin : 11/2/2006<br>alopez : 10/19/2006<br>alopez : 8/31/2006<br>carol : 3/17/2006<br>carol : 3/16/2006<br>carol : 3/16/2006<br>carol : 3/16/2006<br>carol : 3/16/2006<br>wwang : 2/2/2006<br>terry : 1/25/2006<br>carol : 12/3/2004<br>carol : 12/3/2004<br>tkritzer : 12/30/2003<br>tkritzer : 12/18/2003<br>tkritzer : 11/24/2003<br>terry : 11/19/2003<br>alopez : 9/16/2003<br>alopez : 8/7/2003<br>terry : 8/5/2003<br>terry : 6/27/2002<br>carol : 10/18/2001<br>carol : 8/23/2001<br>mcapotos : 7/6/2001<br>mcapotos : 6/29/2001<br>terry : 6/25/2001<br>carol : 12/26/2000<br>mgross : 3/16/1999<br>carol : 2/15/1999<br>carol : 2/15/1999<br>terry : 2/2/1999<br>dkim : 12/10/1998<br>alopez : 6/29/1998<br>terry : 6/25/1998<br>carol : 4/20/1998<br>terry : 4/15/1998<br>mark : 10/20/1997<br>mark : 10/17/1997<br>alopez : 10/7/1997<br>alopez : 10/7/1997<br>alopez : 10/6/1997<br>terry : 11/25/1996<br>terry : 11/12/1996<br>terry : 11/1/1996<br>terry : 9/17/1996<br>marlene : 8/15/1996<br>terry : 11/2/1995<br>mark : 8/18/1995<br>mimadm : 9/24/1994<br>jason : 7/14/1994<br>carol : 5/10/1994<br>carol : 12/7/1993
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<h3>
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<span class="mim-font">
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<strong>*</strong> 138079
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<div>
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<h3>
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<span class="mim-font">
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GLUCOKINASE; GCK
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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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<h4>
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<span class="mim-font">
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GK; GLK<br />
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HEXOKINASE 4; HK4<br />
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LIVER GLUCOKINASE; LGLK
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: GCK</em></strong>
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<strong>SNOMEDCT:</strong> 237604008, 44054006;
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<strong>ICD10CM:</strong> E11;
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<strong>
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<em>
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Cytogenetic location: 7p13
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Genomic coordinates <span class="small">(GRCh38)</span> : 7:44,143,213-44,189,439 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="4">
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<span class="mim-font">
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7p13
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</span>
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</td>
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<td>
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<span class="mim-font">
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Diabetes mellitus, noninsulin-dependent, late onset
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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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125853
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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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Diabetes mellitus, permanent neonatal 1
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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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606176
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Hyperinsulinemic hypoglycemia, familial, 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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602485
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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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MODY, type II
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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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125851
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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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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The phosphorylation of glucose at the sixth carbon position is the first step in glycolysis. The reaction is catalyzed by a family of enzymes called hexokinases, types I (142600) through IV (glucokinase). Glucokinase (GCK; EC 2.7.1.1) is a structurally and functionally unique member of this family. Glucokinase is expressed only in mammalian liver and pancreatic islet beta cells. Because of its unique functional characteristics, the enzyme plays an important regulatory role in glucose metabolism. The rate of glucose metabolism in liver and pancreas is a function of the activity of the enzyme (summary by Matsutani et al., 1992). </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>Using rat islet glucokinase cDNA to screen a human islet cDNA library, followed by screening a human liver cDNA library and RT-PCR of liver RNA, Tanizawa et al. (1991) cloned 2 GCK splice variants, which they called LGLK1 and LGLK2. LGLK1 encodes a deduced 464-amino acid protein with a calculated molecular mass of 52 kD. LGLK2 encodes a deduced 466-amino acid protein with 16 different N-terminal amino acids compared with LGLK1. LGLK2 shares 98% identity with rat islet glucokinase. Northern blot analysis detected a 2.8-kb transcript in liver total RNA. In vitro translation of LGLK1 cDNA resulted in proteins with apparent molecular masses of 52 and 48 kD by SDS-PAGE. Proteins of similar masses were translated from LGLK2. </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>Stoffel et al. (1992) determined that the GCK gene contains 12 exons. Alternative promoters and alternative splicing encode different-sized proteins. </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>Matsutani et al. (1992) identified a region of compound dinucleotide repeats located approximately 10 kb 3-prime to the GCK gene and used oligonucleotide primers and PCR amplification to demonstrate a number of alleles created by this repeat region. The variable numbers of CT and CA repeats represented altogether 6 alleles that range in length from +10 to -15 nucleotides compared to the most common (Z) allele. Two alleles, Z+10 and Z-15, appeared to be unique to American blacks, while a Z+6 allele was observed only in the Caucasian population studied. Using the PCR assay, they localized the human glucokinase gene to chromosome 7 in a panel of rodent/human somatic cell lines. Genetic analysis in CEPH pedigrees placed the dinucleotide repeat element, and thereby GCK, on 7p between TCRG (see 186970) and the RFLP locus D7S57. </p><p>Mishra et al. (1992) placed GCK between D7S57 proximally and D7S65 distally. It was estimated to lie about 4.7 cM from D7S65; D7S65 was found to be about 3.4 cM from TCRG, which is located at 7p15-p14. (Mishra et al. (1992) gave the location of TCRG as 7p15 in their Figure 2.) </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>Byrne et al. (1994) studied pancreatic beta-cell function in 4 males and 2 females from kindreds with known GCK mutations and in 6 controls pair-matched for age, weight, and sex. All of the GCK subjects with GCK mutations were found to have elevated fasting and postprandial glucose levels in comparison to the 6 controls. Insulin secretion rates (ISRs) were estimated. The results supported a key role for GCK in determining the in vivo glucose/ISR dose-response relationships and defined the alterations in beta-cell responsiveness that occur in subjects with GCK mutations. </p><p>Heimberg et al. (1996) reported the expression of glucokinase in rat glucagon-producing islet alpha cells, which are negatively regulated by glucose. Purified rat alpha cells expressed glucokinase mRNA and protein with the same transcript length, nucleotide sequence, and immunoreactivity as the beta-cell isoform. Glucokinase activity accounted for more than 50% of glucose phosphorylation in extracts of alpha cells and for more than 90% of glucose utilization in intact cells. A glucagon-producing tumor also contained glucokinase mRNA, protein, and enzymatic activity. The data indicated that glucokinase may serve as a metabolic glucose sensor in pancreatic alpha cells and, hence, mediate a mechanism for direct regulation of glucagon release by extracellular glucose. Since the alpha cells do not express GLUT2 (138160), Heimberg et al. (1996) suggested that glucose sensing does not necessarily require the coexpression of GLUT2 and glucokinase. </p><p>On the basis of studies in 7 glucokinase-deficient subjects with normal glycosylated hemoglobin and 12 control subjects using (13)C nuclear magnetic spectroscopy during a day in which 3 isocaloric mixed meals were ingested, Velho et al. (1996) observed results suggesting that in addition to the altered beta-cell function, abnormalities in liver glycogen metabolism play an important role in the pathogenesis of hypoglycemia in patients with maturity-onset diabetes of the young type 2 (MODY2; 125851). Average fasting hepatic glycogen content was similar in both groups and increased in both after the meals with a continuous pattern throughout the day. However, the net increment in hepatic glycogen content after each meal was 30 to 60% lower in glucokinase-deficient than in control subjects. Glucokinase-deficient subjects had decreased net accumulation of hepatic glycogen and relatively augmented hepatic gluconeogenesis after meals. </p><p>Danial et al. (2003) undertook a proteomic analysis to assess whether BAD (603167) might participate in mitochondrial physiology. In liver mitochondria, BAD resides in a functional holoenzyme complex together with protein kinase A (see 176911) and protein phosphatase-1 (PP1; see 176875) catalytic units, WAVE1 (605035) as an A kinase-anchoring protein, and glucokinase. Using mitochondria from hepatocytes of Bad-deficient mice, Danial et al. (2003) demonstrated that BAD is required to assemble the complex, the lack of which results in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose. Glucose deprivation results in dephosphorylation of BAD, and BAD-dependent cell death. Moreover, Danial et al. (2003) demonstrated that the phosphorylation status of BAD helps regulate glucokinase activity. Mice deficient in BAD or bearing a nonphosphorylatable BAD (3SA) mutant (Datta et al., 2002) display abnormal glucose homeostasis, including profound defects in glucose tolerance. Danial et al. (2003) concluded that this combination of proteomics, genetics, and physiology indicates an unanticipated role for BAD in integrating pathways of glucose metabolism and apoptosis. </p><p>Using a yeast 2-hybrid assay and other protein interaction assays, Hofmeister-Brix et al. (2013) found that Midn (606700), via its the ubiquitin-like domain, bound glucokinase in rat and mouse pancreatic beta cells and cell lines. Binding was strongest at low glucose concentration, when glucokinase exists mainly in its inactive super-open-to-open conformation. Overexpression of fluorescence-tagged Midn inhibited glucokinase activity, reduced the affinity of glucokinase for glucose, and reduced glucose-induced insulin secretion in rat pancreatic MIN6 cells. </p><p>Using mouse models and the rat INS-1 pancreatic beta cell line, Kim et al. (2014) found that chronic ethanol consumption induced activating transcription factor-3 (ATF3; 603148), which then inhibited Gck transcriptional activity. Atf3 directly bound to a putative ATF/CREB site in the Gck promoter. Atf3 also counteracted the positive effect of Pdx1 (600733) on Gck transcriptional activity. </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>Maturity-Onset Diabetes of the Young, Type 2</em></strong></p><p>
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In 16 French families with maturity-onset diabetes of the young (MODY2; 125851), Froguel et al. (1992) found linkage of the disease with GCK. There was statistically significant evidence of genetic heterogeneity, with an estimated 45 to 95% of the 16 families showing linkage to glucokinase. Because glucokinase is a key enzyme of blood glucose homeostasis, the results suggested a pathogenetic connection. The relationship was clinched by the demonstration by Vionnet et al. (1992) of a nonsense mutation in the GCK gene (138079.0001). </p><p>Velho et al. (1992) studied pancreatic beta-cell secretory function in 9 patients from 4 GCK-linked MODY kindreds. They found that beta-cell secretory response to continuous glucose stimulus during a hyperglycemic glucose clamp was significantly reduced. This finding was different from that for noninsulin-dependent diabetes mellitus with late age of onset or MODY not linked to GCK. Fasting plasma insulin and C-peptide levels in patients were inappropriately low in relation to concomitant plasma glucose level. Furthermore, during a hyperinsulinemic euglycemic clamp, endogenous insulin secretion at euglycemia was suppressed in patients but not in controls. Velho et al. (1992) interpreted these results as suggesting that mutant GCK leads to chronic hyperglycemia by raising the threshold of circulating glucose levels which induces insulin secretion. This was the first demonstration of a primary pancreatic secretory defect associated with a form of NIDDM. </p><p>Froguel et al. (1993) detected 16 mutations of the GCK gene in 18 of 32 families with MODY. An explanation for the way a mutation in glucokinase might cause diabetes follows from the work of Matschinsky (1990), who developed the concept that glucokinase acts as the glucose sensor of beta cells. According to this concept, the rates of glucose metabolism and insulin secretion are closely linked, with both being determined by the plasma glucose concentration. In beta cells and hepatocytes, the rate of glucose metabolism is determined by the rate of glucose phosphorylation, which is catalyzed by glucokinase. Beta cells and hepatocytes also contain glucose transporter-2 (GLUT2; 138160), an insulin-independent cellular protein that mediates the transport of glucose into cells. The capacity of GLUT2 to transport glucose is very high, facilitating rapid equilibrium between extracellular and intracellular glucose. Thus, in effect, the extracellular glucose concentrations are sensed by glucokinase. </p><p>Randle (1993) provided a review of glucokinase and candidate genes for type II MODY. Matschinsky et al. (1993) also reviewed glucokinase as the pancreatic beta-cell glucose sensor and 'diabetes gene.' They tabulated 16 separate mutations in the GCK gene found in families with MODY. </p><p>Johansen et al. (2005) examined the prevalence and nature of mutations in the 3 common MODY genes HNF4A (600281), GCK, and TCF1 (142410) in Danish patients with a clinical diagnosis of MODY and determined metabolic differences in probands with and without mutations in HNF4A, GCK, and TCF1. They identified 29 different mutations in 38 MODY families. Fifteen of the mutations were novel. The variants segregated with diabetes within the families, and none of the variants were found in 100 normal Danish chromosomes. Their findings suggested a relative prevalence of 3% of MODY1 (125850) (2 different mutations in 2 families), 10% of MODY2 (7 in 8), and 36% of MODY3 (600496) (21 in 28) among Danish kindred clinically diagnosed as MODY. No significant differences in biochemical and anthropometric measurements were observed at baseline examinations. Forty-nine percent of the families carried mutations in the 3 examined MODY genes. </p><p>Vits et al. (2006) identified 19 different GCK mutations, including 11 novel mutations (see, e.g., 138079.0014), in 33 (26.6%) of 124 Belgian probands with MODY. </p><p>Pinterova et al. (2007) screened the GCK gene in 92 Czech probands fulfilling classic MODY criteria and identified 15 different missense mutations in 27 (29%) patients; the mutations were not found in 50 unrelated healthy Czech individuals. Pinterova et al. (2007) concluded that mutations in GCK are a common cause of MODY in the Czech population. </p><p>In a mainland Chinese family with a clinical profile similar to that of previously reported MODY2 families, Shen et al. (2011) analyzed the GCK gene and identified a heterozygous missense mutation (E339K; 138079.0016) that segregated with the disease and was not found in 200 controls. Functional analysis indicated that the mutation inactivated enzyme kinetics and severely impaired GCK protein stability. </p><p>The variable phenotype observed with mutations in the GCK gene includes gestational diabetes mellitus. This fact prompted Stoffel et al. (1993) to screen a group of women with gestational diabetes who also had a first-degree relative with diabetes mellitus for the presence of GCK mutations. Among 40 subjects, they identified 2 with heterozygous mutations (138079.0007-138070.0008), suggesting a prevalence of approximately 5%. Extrapolating from this result, the prevalence of glucokinase-deficient MODY among Americans may be approximately 1 in 2,500. </p><p>Fetal insulin secretion in response to maternal glycemia plays a key role in fetal growth, and adult insulin secretion is a primary determinant of glucose tolerance. Hattersley et al. (1998) hypothesized that a defect in the sensing of glucose by the pancreas, caused by a heterozygous mutation in the glucokinase gene, could reduce fetal growth and birth weight in addition to causing hyperglycemia after birth. In 58 offspring, where one parent had a glucokinase mutation, the inheritance of a glucokinase mutation by the fetus resulted in a mean reduction of birth weight of 533 g (P = 0.002). In 19 of 21 sib pairs discordant for the presence of a glucokinase mutation, the child with the mutation had a lower birth weight, with a mean difference of 521 g (P = 0.0002). Maternal hyperglycemia due to a glucokinase mutation resulted in a mean increase in birth weight of 601 g (P = 0.001). The effects of maternal and fetal glucokinase mutations on birth weight were additive. Hattersley et al. (1998) proposed that these changes in birth weight reflect changes in fetal insulin secretion which are influenced directly by the fetal genotype and indirectly, through maternal hyperglycemia, by the maternal genotype. </p><p>Dunger et al. (1998) demonstrated an association between the insulin VNTR (variable number tandem repeat) 'locus,' and specifically the VNTR III genotype, and larger size at birth. McCarthy (1998) discussed the significance of these observations in relation to the 'thrifty genotype' hypothesis originally proposed by Neel (1962) and updated by Neel et al. (1998). </p><p><strong><em>Permanent Neonatal Diabetes Mellitus 1</em></strong></p><p>
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Njolstad et al. (2001) described 2 patients in whom complete deficiency of glucokinase caused permanent neonatal-onset diabetes (PNDM1; 606176). One patient was homozygous for an M210K mutation (138079.0010); the other was homozygous for a T228M mutation (138079.0003). Both patients showed total absence of basal insulin release. </p><p><strong><em>Hyperinsulinemic Hypoglycemia</em></strong></p><p>
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In 'family 3' studied by Thornton et al. (1998), in which affected members had hyperinsulinemic hypoglycemia (see HHF3, 602485), Glaser et al. (1998) identified heterozygosity for an activating mutation (138079.0009) in the GCK gene. </p><p>In a 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness, Christesen et al. (2002) identified heterozygosity for an activating mutation in the GCK gene (138079.0012). The boy's normal-weight mother, who had asymptomatic fasting hypoglycemia, carried the same mutation. Christesen et al. (2002) noted the striking contrast in clinical presentation between the mother and son with the same mutation, and recalled a similar situation in the family reported by Glaser et al. (1998), in which the proband was obese and severely hyperinsulinemic, whereas his sister who carried the same mutation was of normal weight, had relatively low insulin levels, and milder clinical symptoms. </p><p>In a Finnish woman with severe hyperinsulinemic hypoglycemia from birth, who had severe mental retardation and died at age 29 still having hypoglycemic seizures, Cuesta-Munoz et al. (2004) identified heterozygosity for a de novo activating mutation in the GCK gene (138079.0013). </p><p>Kassem et al. (2010) reported a young girl with severe neonatal hypoglycemia due to a missense mutation in the GCK gene (138079.0015) in whom mean islet cell areas in both the head and the tail of the pancreas were significantly larger than those of 5 age-matched controls and those of 2 age-matched patients with diffuse hypoglycemia due to ABCC8 mutations (600509; see HHF1, 256450). Noting a previously reported HHF3 patient in whom quantitative histologic analysis of pancreatic specimens showed a similar increase in the mean islet profile (Cuesta-Munoz et al. (2004)), Kassem et al. (2010) suggested that histologic findings in infants with hyperinsulinemic hypoglycemia might differ according to the genetic cause of the condition. </p><p><strong><em>Penetrance of GCK Mutations in Diabetes</em></strong></p><p>
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Mirshahi et al. (2022) comprehensively assessed the penetrance and prevalence of pathogenic variants in HNF1A (142410), HNF4A (600281), and GCK that account for more than 80% of monogenic diabetes. Mirshahi et al. (2022) analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort of 132,194 individuals, and a UK population-based cohort of 198,748 individuals, and found that 1 in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of pathogenic GCK variants was similar (89 to 97%) across all cohorts. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts, highlighting the role of environment/ other genetic factors. The authors suggested that for HNF1A and HNF4A, genetic interpretation and counseling should be tailored to the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. </p><p><strong><em>Other Associations</em></strong></p><p>
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Rowe et al. (1995) evaluated 35 microsatellite marker loci on human chromosome 7 for linkage to insulin-dependent diabetes mellitus (IDDM) in 339 affected sib-pair families. Increased sharing of parental haplotypes in affected sib pairs was detected for 2 microsatellite markers flanking GCK. Preferential transmission of alleles to affected offspring was observed at one of these marker loci, GCK3, indicating linkage disequilibrium between the marker and the disease susceptibility locus. This combination of linkage and disease association suggested to Rowe et al. (1995) that glucokinase, or a gene in the vicinity, plays an important role in IDDM susceptibility. (Rowe et al. (1995) used the designations GCK1, GCK2, and GCK3 for 3 modestly polymorphic microsatellite markers near the GCK gene (Concannon, 1995). These are not symbols for separate glucokinase genes; there is only a single GCK gene on 7p, although as a result of alternative, tissue-specific promoters, there are islet- and liver-specific forms that differ in their amino-terminal sequences.) </p><p>Stone et al. (1996) used SSCP analysis to determine whether a G-to-A variant at position -30 of the beta-cell promoter of the GCK gene is associated with impaired beta-cell function. The variant was observed more frequently in Japanese-American men with impaired glucose tolerance than in Japanese-American men with normal glucose tolerance. Beta-cell function was assessed using the ratio of the incremental response in immunoreactive insulin to that of glucose during the first 30 minutes of the oral glucose tolerance test. They concluded that the -30 promoter variant is associated with reduced beta-cell function in middle-aged Japanese-American men and may contribute to the high risk of abnormal glucose tolerance in this population. They noted that the polymorphism has been observed in other populations. </p><p>Marz et al. (2004) analyzed the GCK -30G-A variant in 2,567 patients with and in 731 individuals without coronary artery disease (CAD; see CHDS1, 607339) by angiography and found that the A allele of the pancreatic GCK promoter increased the risk of CAD in individuals both with and without type II diabetes mellitus (ORs, 1.92 and 1.27, respectively). The A allele was also associated with an increased prevalence of type II diabetes mellitus, particularly among CAD patients. </p><p>For discussion of an association between variation in the GCK gene and fasting plasma glucose levels, see FGQTL2 (613219).</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>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>Gloyn (2003) stated that given the central role of glucokinase in the regulation of insulin release, it is understandable that mutations in the GCK gene can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause MODY, characterized by mild hyperglycemia, which is present at birth, but is often only detected later in life. Homozygous inactivating GCK mutations result in a more severe phenotype, presenting at birth as permanent neonatal diabetes mellitus. Several heterozygous activating GCK mutations causing hypoglycemia had been reported as instances of familial hyperinsulinism (see HHF3, 602485). Gloyn (2003) tabulated 195 mutations in the GCK gene, found in 285 families. There were no common mutations and the mutations were distributed throughout the gene. Mutations causing hypoglycemia are located in various exons in a discrete region of the protein termed the heterotropic allosteric activator site. Patients with MODY type 2 (due to GCK mutations) rarely need pharmacologic treatment and most are managed on diet alone. During pregnancy, some women with GCK mutations are treated with insulin, which, due to its role in fetal growth, can result in babies that are large for gestational age if they do not also have the GCK mutation (Hattersley et al., 1998). Microvascular complications are rare in MODY2. These patients do not need to be followed in a diabetes clinic, but should have an HbA1c checked annually. Some patients with hyperinsulinism due to GCK mutations may not require pharmacologic intervention and may be able to control their symptoms by eating regularly. Patients with hyperinsulinism due to mutation in the ABCC8 gene (600509) or the KCNJ11 gene (600937) respond poorly or are totally refractory to the potassium channel opener diazoxide, which is used to inhibit insulin secretion. Conversely, patients with hyperinsulinism resulting from GCK mutations respond well or tolerated diazoxide (Gloyn et al., 2003). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using homologous recombination in mouse embryonic stem cells to disrupt the glucokinase gene, Bali et al. (1995) showed that heterozygous mice showed a phenotype similar to MODY. Reduced islet glucokinase activity caused mildly elevated fasting blood glucose levels. Hyperglycemic clamp studies revealed decreased glucose tolerance and abnormal liver glucose metabolism. These findings demonstrated a key role for glucokinase in glucose homeostasis and implicated both islets and liver in the MODY disease. Aizawa et al. (1996) made a detailed study of pancreatic beta-cell function in the isolated pancreatic islets of heterozygous GCK knockout mice. The beta cells of these mice displayed impaired glucose sensitivity, poor discrimination of alpha- and beta-glucose anomers, and normal activity of the ATP-sensitive K+ channel. The mice displayed impaired insulin release after insulin treatment and age-related worsening of glucose tolerance. </p><p>Understanding how the beta cells of the pancreatic islet sense an alteration in glucose levels is critical to understanding how glucose homeostasis is maintained. Grupe et al. (1995) noted that glucose sensing is mediated through an increase in the rate of intracellular catabolism of glucose rather than a ligand-receptor interaction. However, it is likely that there is still a need for a rate-limiting step in glucose catabolism to serve the role of glucose sensor. A compelling case can be made for glucokinase fulfilling this role, since phosphorylation by GLK appears to be the rate-limiting step for glucose catabolism in beta cells. To test this possibility and to resolve the relative roles of liver and beta-cell GLK in maintaining glucose levels, Grupe et al. (1995) generated mice completely deficient in GLK and transgenic mice in which GLK is expressed only in beta cells. In mice with only 1 GLK allele, blood glucose levels were elevated and insulin secretion was reduced. GLK-deficient mice died perinatally with severe hyperglycemia. Expression of GLK in beta cells in the absence of expression in the liver is sufficient for survival. </p><p>Grimsby et al. (2003) identified a class of antidiabetic agents that act as nonessential, mixed-type glucokinase activators that increase the glucose affinity and maximum velocity of glucokinase. Glucokinase activators augmented both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of glucokinase in both cell types. In several rodent models of NIDDM, glucokinase activators lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. </p><p>Using N-ethyl-N-nitrosourea (ENU) mutagenesis, Inoue et al. (2004) generated diabetic mice. The authors screened 9,375 animals and identified 11 mutations in the glucokinase (Gk) gene that were associated with hyperglycemia. Four had previously been found in human MODY2 (125851) patients, and 1 was found previously in a patient with permanent neonatal diabetes mellitus (PNDM; 606176). Some of the Gk mutant lines displayed impaired glucose-responsive insulin secretion, and the mutations had different effects on Gk mRNA levels and/or the stability of the GK protein. </p><p>Terauchi et al. (2007) generated mice with haploinsufficiency of beta cell-specific Gck and observed that on a high-fat diet, Gck +/- mice had decreased beta cell replication and insufficient beta cell hyperplasia compared to wildtype mice despite a similar degree of insulin resistance. On a high-fat diet, Gck +/- mouse islets showed decreased insulin receptor substrate-2 (Irs2; 600797) expression compared with wildtype islets. Overexpression of Irs2 in beta cells of Gck +/- mice partially prevented diabetes by increasing beta cell mass. Terauchi et al. (2007) suggested that both GCK and IRS2 are critical for beta cell hyperplasia to occur in response to high-fat diet-induced insulin resistance. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 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 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 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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GCK, GLU279TER
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<br />
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SNP: rs104894005,
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gnomAD: rs104894005,
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ClinVar: RCV000017512
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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 the process of single-strand conformation polymorphism (SSCP) analysis of exon 7 in a French family with GCK-linked MODY (MODY2; 125851), previously studied by Froguel et al. (1992), Vionnet et al. (1992) demonstrated a G-to-T substitution in codon 279 which changed GAG (glutamic acid) to TAG, an amber termination codon. An individual in this family who had noninsulin-dependent diabetes mellitus (NIDDM) did not show linkage to GCK; moreover, she did not have the nonsense mutation in codon 279. Thus, there were 2 forms of NIDDM in this kindred. Hattersley et al. (1992) likewise found tight linkage of MODY to a macrosatellite polymorphism associated with the GCK locus; peak lod = 4.60 at theta = 0.0. In a second MODY pedigree, they excluded linkage; lod = -7.36 at theta = 0.0. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 TYPE 2 DIABETES MELLITUS</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GCK, ARG186TER
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<br />
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SNP: rs104894006,
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gnomAD: rs104894006,
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ClinVar: RCV000017513, RCV000516235, RCV002225072, RCV002345246
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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 Japanese family, Katagiri et al. (1992) found a correlation between the presence of late-onset noninsulin-dependent diabetes mellitus (125853) or impaired glucose tolerance and a nonsense mutation in exon 5 of the glucokinase gene: a C-to-T transition changing codon 186 from CGA (arginine) to TGA (an amber termination codon). The mutation was predicted to delete 60% of the amino acid residues of the glucokinase derived from the affected allele. The family was detected through a 59-year-old woman who was the twenty-third subject screened. Froguel and Velho (1993) raised the question as to whether the Japanese family may in fact have had MODY, because in their experience in French families carrying mutations in GCK, hyperglycemia often went undiagnosed for a long time. Chiu et al. (1993) likewise questioned whether the disorder in the Japanese families should be termed NIDDM and pointed out that in young patients with glucokinase mutations the degree of hyperglycemia is so mild that values often do not exceed the renal threshold. Therefore, absence of glycosuria cannot be used as a criterion for distinguishing MODY from NIDDM. Permutt et al. (1992) pointed out that structural mutations in the GCK gene are very rare (less than 2%) in American black and Caucasian NIDDM patients. </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>.0003 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 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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DIABETES MELLITUS, PERMANENT NEONATAL, 1, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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GCK, THR228MET
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<br />
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SNP: rs80356655,
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gnomAD: rs80356655,
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ClinVar: RCV000020167, RCV000498792, RCV001269032, RCV002362586, RCV003147295, RCV003147296, RCV003883118, RCV004751212
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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 />
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<p><strong><em>Maturity-Onset Diabetes of the Young, Type 2</em></strong></p><p>
|
|
Stoffel et al. (1992) stated that DNA polymorphisms in the GCK gene has been shown to be tightly linked to MODY (MODY2; 125851) in approximately 80% of French families. They identified 2 further missense mutations in exon 7 in families with MODY: thr228 to met (T228M) and gly261 to arg (G261R; 138079.0004). A TGC-to-TAC change at codon 228 and a CCC-to-TCC change at codon 261 were responsible. Using computer-assisted modeling and the crystal structure of the related yeast hexokinase B as a simple model for human beta-cell glucokinase, Stoffel et al. (1992) obtained data which suggested to them that mutation of thr228 affects affinity for ATP and mutation of gly261 alters glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset noninsulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. </p><p>Velho et al. (1997) identified the T228M mutation in affected members of a family with glucokinase-related MODY. </p><p><strong><em>Diabetes Mellitus, Permanent Neonatal 1</em></strong></p><p>
|
|
In an 8-year-old girl of Italian ancestry, Njolstad et al. (2001) identified homozygosity for the T228M mutation in the GCK gene as the cause of neonatal-onset diabetes mellitus (PNDM1; 606176). The child had shown hyperglycemia and marked growth retardation at birth. Her father had impaired glucose tolerance and her mother had impaired fasting glycemia. </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>.0004 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 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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|
|
|
GCK, GLY261ARG
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<br />
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|
|
SNP: rs104894008,
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gnomAD: rs104894008,
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|
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|
|
ClinVar: RCV000017515, RCV000426797, RCV001507008, RCV003325940, RCV003445078
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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>Stoffel et al. (1992) identified missense mutations in exon 7 of the GCK gene in families with maturity diabetes of the young (MODY2; 125851): thr228 to met (T228M; 138079.0003) and gly261 to arg (G261R). A TGC-to-TAC change at codon 228 and a CCC-to-TCC change at codon 261 were responsible. Using computer-assisted modeling and the crystal structure of the related yeast hexokinase B as a simple model for human beta-cell glucokinase, Stoffel et al. (1992) obtained data which suggested to them that mutation of thr228 affects affinity for ATP and mutation of gly261 alters glucose binding. The identification of mutations in glucokinase, a protein that plays an important role in hepatic and beta-cell glucose metabolism, indicates that early-onset noninsulin-dependent diabetes mellitus may be primarily a disorder of carbohydrate metabolism. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCK, GLY299ARG
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|
|
<br />
|
|
|
|
SNP: rs104894009,
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|
|
|
|
|
|
|
ClinVar: RCV000017516, RCV001288185
|
|
|
|
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a large British pedigree with many cases of MODY (MODY2; 125851) in 5 generations, Stoffel et al. (1992) demonstrated a G-to-C transversion in the GCK gene, which converted codon 266 from glycine to arginine. The mutation also created a HhaI site which allowed them to construct a rapid PCR test for the mutation. Applying this to cases of classic late-onset type 2 diabetes mellitus, they found the same mutation in 1 of 50 patients. All 9 relatives of this patient who had inherited the mutation had type 2 diabetes, although 6 others without the mutation also had diabetes. MODY had not previously been considered in this family. </p>
|
|
</span>
|
|
</div>
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|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
GCK, IVS4DS, 15-BP DEL
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|
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|
|
|
<br />
|
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|
|
SNP: rs1583601110,
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|
|
|
|
|
ClinVar: RCV000992052, RCV002286425, RCV003106086
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Sun et al. (1993) analyzed the nucleotide sequence of exon 4 and its flanking intronic regions of the GCK gene in 4 hyperglycemic members of a MODY (MODY2; 125851) family and found a deletion of 15 bp, which removed the T of the GT in the donor splice site of intron 4 and the following 14 basepairs. This deletion resulted in 2 aberrant transcripts: one with exon 5 missing and the other with activation of a cryptic splice site leading to the removal of the last 8 codons of exon 4. This intronic deletion seemed to cause a more severe form of glucose intolerance than did the missense and nonsense mutations previously reported. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
GCK, SER131PRO
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<br />
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|
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SNP: rs104894010,
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|
|
ClinVar: RCV000017518, RCV002513078, RCV003147297, RCV003147298, RCV003147299, RCV004730847
|
|
|
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Stoffel et al. (1993) found heterozygosity for a ser131-to-pro mutation in the GCK gene in an obese 31-year-old Puerto Rican woman with gestational diabetes (MODY2; 125851) in her first pregnancy. She reportedly had borderline elevated blood glucose levels at age 26. Stoffel et al. (1993) showed defective enzymatic properties of the enzyme carrying the ser131-to-pro mutation. </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>.0008 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
|
|
GCK, GLU265TER
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<br />
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|
|
SNP: rs104894011,
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|
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|
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ClinVar: RCV000017519, RCV000517435
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</span>
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</div>
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|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>Stoffel et al. (1993) found a glu265-to-ter mutation in a thin 32-year-old Caucasian woman with gestational diabetes mellitus (MODY2; 125851) who was in her second pregnancy. She reportedly had elevated fasting blood glucose levels since age 16. The subject's mother and 2 sisters had diabetes mellitus treated with diet or oral hypoglycemic agents. </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>.0009 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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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GCK, VAL455MET
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<br />
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SNP: rs104894012,
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ClinVar: RCV000017520, RCV002513079
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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 31-year-old man and his 36-year-old sister from the 3-generation 'family 3' with autosomal dominant hyperinsulinemic hypoglycemia (602485) previously studied by Thornton et al. (1998), Glaser et al. (1998) identified a val455-to-met (V455M) mutation in the glucokinase gene. When expressed in vitro, the V455M mutation increased the affinity of glucokinase for glucose, resulting in higher rates of glycolysis at low glucose concentrations and therefore a higher rate of insulin secretion at any plasma glucose concentration. The finding confirmed the importance of glucokinase as a primary regulator of glucose-controlled insulin secretion in beta cells. This mutation was not found in 37 unrelated white families with hyperinsulinism, including 6 with an apparently autosomal dominant form. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 DIABETES MELLITUS, PERMANENT NEONATAL, 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2, INCLUDED
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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GCK, MET210LYS
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<br />
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SNP: rs80356654,
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gnomAD: rs80356654,
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ClinVar: RCV000017521, RCV000190348, RCV001281107, RCV003318493
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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>Njolstad et al. (2001) described an infant girl of Norwegian ancestry with neonatal diabetes mellitus (PNDM1; 606176) that persisted thereafter. The parents were first cousins, and both had glucose intolerance. At 5 years of age, the patient developed epilepsy, probably as a sequela of a neonatal brain abscess. A sister had typical type I diabetes developing at the age of 7 years. The mother had a diagnosis of gestational diabetes at the age of 25 years. The father had impaired fasting glycemia that was treated with diet. After excluding other candidate genes, Njolstad et al. (2001) found that the child was homozygous for a T-to-A transversion (ATG-AAG) at nucleotide 629 in exon 6 of the GCK gene, resulting in a met210-to-lys mutation (M210K). Her parents and sister were heterozygous for the mutation, which cosegregated with diabetes or hyperglycemia in other members of the family. Thus, in this family, heterozygosity caused GCK-related MODY (MODY2; 125851) and homozygosity caused neonatal-onset 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-text-font">
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<strong>.0011 MOVED TO 138079.0003</strong>
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</span>
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</h4>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0012 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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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GCK, ALA456VAL
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<br />
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SNP: rs104894014,
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ClinVar: RCV000017525, RCV001818166
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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 14-year-old obese boy with a history of neonatal hypoglycemia treated with diazoxide, who was experiencing hypoglycemic episodes associated with seizures and unconsciousness (see HHF3, 602485), Christesen et al. (2002) identified heterozygosity for an ala456-to-val (A456V) substitution in exon 10 of the GCK gene. Kinetic analysis showed this to be an activating mutation. The boy's normal-weight mother, who had asymptomatic fasting hypoglycemia, carried the same mutation; the mutation was not found in his normoglycemic brother nor in 80 controls. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0013 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 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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GCK, TYR214CYS
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<br />
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SNP: rs104894015,
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ClinVar: RCV000017526, RCV005089266
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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 Finnish woman with severe hyperinsulinemic hypoglycemia from birth (602485), who had severe mental retardation and was still having hypoglycemic seizures when she died at age 29, Cuesta-Munoz et al. (2004) identified heterozygosity for a de novo tyr214-to-cys (Y214C) substitution in exon 6 of the GCK gene. Although paternity was confirmed, the mutation was not found in her parents or her 2 healthy sisters. Kinetic analysis revealed that this mutation had the highest activity index (130-fold over wildtype) of all naturally occurring activating GCK mutations described. Cuesta-Munoz et al. (2004) noted that this phenotype was considerably more severe than that of previously reported patients (see 138079.0009 and 138079.0012). </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 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
|
|
</span>
|
|
</h4>
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</div>
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<div>
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<span class="mim-text-font">
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GCK, ALA378THR
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<br />
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SNP: rs104894016,
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gnomAD: rs104894016,
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ClinVar: RCV000017527, RCV002513080, RCV003325941
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members from 5 Belgian families with MODY2 (125851), Vits et al. (2006) identified a 1132G-A transition in exon 9 of the GCK gene, resulting in an ala378-to-thr (A378T) substitution. All the probands originated from the Belgian province of West Flanders, suggesting a founder mutation; this was confirmed in 3 families by haplotype analysis. </p>
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|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0015 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 3</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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GCK, VAL91LEU
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<br />
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ClinVar: RCV000017528
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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>Kassem et al. (2010) studied a young girl with severe neonatal hypoglycemia-3 (602485) due to a val91-to-leu (V91L) missense mutation in the GCK gene. Her father had a similar clinical course but neither his DNA nor pancreatic tissue was available for study. Quantitative histologic examination after subtotal pancreatectomy due to refractory disease revealed abnormally large islets, with some beta cells containing a large nucleus, and mean islet cell areas in both the head and the tail of the pancreas were significantly larger than those of 5 age-matched controls and those of 2 age-matched HHF1 (256450) patients. </p>
|
|
</span>
|
|
</div>
|
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<div>
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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GCK, GLU339LYS
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<br />
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|
|
|
SNP: rs397514580,
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|
|
|
|
ClinVar: RCV000032978, RCV003883126, RCV005089333
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members over 3 generations of a mainland Chinese family with type 2 maturity-onset diabetes of the young (MODY2; 125851), Shen et al. (2011) identified heterozygosity for a G-A transition in exon 8 of the GCK gene, resulting in a glu339-to-lys (E339K) substitution. The mutation was not found in unaffected family members or in 200 controls. SDS-PAGE analysis of a bacterial expression system demonstrated that the protein yield of mutant GCK was significantly lower than wildtype; kinetic analysis showed that the E339K mutant had 1.4-fold and 9.9-fold lower affinity for glucose and ATP, respectively, compared to wildtype. The mutant GCK also exhibited thermal instability, with a dramatic decrease in activity at 45 degrees centigrade compared to 55 degrees centigrade for wildtype; in addition, wildtype GCK maintained 50% activity at 55 degrees centigrade for 30 minutes, whereas wildtype lost 97% of activity within 30 minutes. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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|
|
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<div>
|
|
<ol>
|
|
|
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<li>
|
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<p class="mim-text-font">
|
|
Aizawa, T., Asanuma, N., Terauchi, Y., Suzuki, N., Komatsu, M., Itoh, N., Nakabayashi, T., Hidaka, H., Ohnota, H., Yamauchi, K., Yasuda, K., Yazaki, Y., Kadowaki, T., Hashizume, K.
|
|
<strong>Analysis of the pancreatic beta cell in the mouse with targeted disruption of the pancreatic beta cell-specific glucokinase gene.</strong>
|
|
Biochem. Biophys. Res. Commun. 229: 460-465, 1996.
|
|
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|
|
[PubMed: 8954920]
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|
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[Full Text: https://doi.org/10.1006/bbrc.1996.1826]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bali, D., Svetlanov, A., Lee, H.-W., Fusco-DeMane, D., Leiser, M., Li, B., Barzilai, N., Surana, M., Hou, H., Fleischer, N., DePinho, R., Rossetti, L., Efrat, S.
|
|
<strong>Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene.</strong>
|
|
J. Biol. Chem. 270: 21464-21467, 1995.
|
|
|
|
|
|
[PubMed: 7665557]
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[Full Text: https://doi.org/10.1074/jbc.270.37.21464]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Byrne, M. M., Sturis, J., Clement, K., Vionnet, N., Pueyo, M. E., Stoffel, M., Takeda, J., Passa, P., Cohen, D., Bell, G. I., Velho, G., Froguel, P., Polonsky, K. S.
|
|
<strong>Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.</strong>
|
|
J. Clin. Invest. 93: 1120-1130, 1994.
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|
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|
|
[PubMed: 8132752]
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[Full Text: https://doi.org/10.1172/JCI117064]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Chiu, K. C., Tanizawa, Y., Permutt, M. A.
|
|
<strong>Non-sense mutation of glucokinase gene. (Letter)</strong>
|
|
Lancet 341: 385-386, 1993.
|
|
|
|
|
|
[PubMed: 8094164]
|
|
|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Christesen, H. B. T., Jacobsen, B. B., Odili, S., Buettger, C., Cuesta-Munoz, A., Hansen, T., Brusgaard, K., Massa, O., Magnuson, M. A., Shiota, C., Matschinsky, F., Barbetti, F.
|
|
<strong>The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy.</strong>
|
|
Diabetes 51: 1240-1246, 2002.
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|
|
[PubMed: 11916951]
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|
|
[Full Text: https://doi.org/10.2337/diabetes.51.4.1240]
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</p>
|
|
</li>
|
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|
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<li>
|
|
<p class="mim-text-font">
|
|
Concannon, P.
|
|
<strong>Personal Communication.</strong>
|
|
Seattle, Wash. 7/26/1995.
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|
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Cuesta-Munoz, A. L., Huopio, H., Otonkoski, T., Gomez-Zumaquero, J. M., Nanto-Salonen, K., Rahier, J., Lopez-Enriquez, S., Garcia-Gimeno, M. A., Sanz, P., Soriguer, F. C., Laakso, M.
|
|
<strong>Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.</strong>
|
|
Diabetes 53: 2164-2168, 2004.
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|
|
|
|
|
[PubMed: 15277402]
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|
|
[Full Text: https://doi.org/10.2337/diabetes.53.8.2164]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Danial, N. N., Gramm, C. F., Scorrano, L., Zhang, C.-Y., Krauss, S., Ranger, A. M., Datta, S. R., Greenberg, M. E., Licklider, L. J., Lowell, B. B., Gygi, S. P., Korsmeyer, S. J.
|
|
<strong>BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis.</strong>
|
|
Nature 424: 952-956, 2003.
|
|
|
|
|
|
[PubMed: 12931191]
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|
|
[Full Text: https://doi.org/10.1038/nature01825]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Datta, S. R., Ranger, A. M., Lin, M. Z., Sturgill, J. F., Ma, Y.-C., Cowan, C. W., Dikkes, P., Korsmeyer, S. J., Greenberg, M. E.
|
|
<strong>Survival factor-mediated BAD phosphorylation raises the mitochondrial threshold for apoptosis.</strong>
|
|
Dev. Cell 3: 631-643, 2002.
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|
|
[PubMed: 12431371]
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|
|
[Full Text: https://doi.org/10.1016/s1534-5807(02)00326-x]
|
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Dunger, D. B., Ong, K. K. L., Huxtable, S. J., Sherriff, A., Woods, K. A., Ahmed, M. L., Golding, J., Pembrey, M. E., Ring, S., ALSPAC Study Team, Bennett, S. T., Todd, J. A.
|
|
<strong>Association of the INS VNTR with size at birth.</strong>
|
|
Nature Genet. 19: 98-100, 1998.
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|
|
|
|
|
[PubMed: 9590300]
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|
[Full Text: https://doi.org/10.1038/ng0598-98]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M. O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F., Tanizawa, Y., Weissenbach, J., Beckmann, J. S., Lathrop, G. M., Passa, P., Permutt, M. A., Cohen, D.
|
|
<strong>Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus.</strong>
|
|
Nature 356: 162-164, 1992. Note: Erratum: Nature 357: 607 only, 1992.
|
|
|
|
|
|
[PubMed: 1545870]
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|
|
[Full Text: https://doi.org/10.1038/356162a0]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Froguel, P., Velho, G.
|
|
<strong>Non-sense mutation of glucokinase gene. (Letter)</strong>
|
|
Lancet 341: 385 only, 1993.
|
|
|
|
|
|
[PubMed: 8094163]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Froguel, P., Zouali, H., Vionnet, N., Velho, G., Vaxillaire, M., Sun, F., Lesage, S., Stoffel, M., Takeda, J., Passa, P., Permutt, M. A., Beckmann, J. S., Bell, G. I., Cohen, D.
|
|
<strong>Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus.</strong>
|
|
New Eng. J. Med. 328: 697-702, 1993.
|
|
|
|
|
|
[PubMed: 8433729]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199303113281005]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Glaser, B., Kesavan, P., Heyman, M., Davis, E., Cuesta, A., Buchs, A., Stanley, C. A., Thornton, P. S., Permutt, M. A., Matschinsky, F. M., Herold, K. C.
|
|
<strong>Familial hyperinsulinism caused by an activating glucokinase mutation.</strong>
|
|
New Eng. J. Med. 338: 226-230, 1998.
|
|
|
|
|
|
[PubMed: 9435328]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1056/NEJM199801223380404]
|
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|
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</p>
|
|
</li>
|
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Gloyn, A. L., Noordam, K., Willemsen, M. A. A. P., Ellard, S., Lam, W. W. K., Campbell, I. W., Midgley, P., Shiota, C., Buettger, C., Magnuson, M. A., Matschinsky, F. M., Hattersley, A. T.
|
|
<strong>Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations.</strong>
|
|
Diabetes 52: 2433-2440, 2003.
|
|
|
|
|
|
[PubMed: 12941786]
|
|
|
|
|
|
[Full Text: https://doi.org/10.2337/diabetes.52.9.2433]
|
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</p>
|
|
</li>
|
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Gloyn, A. L.
|
|
<strong>Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy.</strong>
|
|
Hum. Mutat. 22: 353-362, 2003.
|
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Thornton, P. S., Satin-Smith, M. S., Herold, K., Glaser, B., Chiu, K. C., Nestorowicz, A., Permutt, M. A., Baker, L., Stanley, C. A.
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<strong>Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus.</strong>
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Vits, L., Beckers, D., Craen, M., de Beaufort, C., Vanfleteren, E., Dahan, K., Nollet, A., Vanhaverbeke, G., Imschoot, S. V., Bourguignon, J.-P., Beauloye, V., Storm, K., Massa, G., Giri, M., Nobels, F., De Schepper, J., Rooman, R., Van den Bruel, A., Mathieu, C., Wuyts, W.
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Ada Hamosh - updated : 01/17/2023<br>Patricia A. Hartz - updated : 02/14/2018<br>Patricia A. Hartz - updated : 6/24/2014<br>Marla J. F. O'Neill - updated : 11/2/2012<br>Patricia A. Hartz - updated : 4/15/2010<br>Marla J. F. O'Neill - reorganized : 4/14/2010<br>Marla J. F. O'Neill - updated : 4/14/2010<br>Ada Hamosh - updated : 1/15/2010<br>Victor A. McKusick - updated : 5/23/2007<br>Marla J. F. O'Neill - updated : 4/17/2007<br>Marla J. F. O'Neill - updated : 3/9/2007<br>Victor A. McKusick - updated : 11/28/2006<br>Cassandra L. Kniffin - updated : 11/2/2006<br>John A. Phillips, III - updated : 10/19/2006<br>George E. Tiller - updated : 8/31/2006<br>Marla J. F. O'Neill - updated : 3/17/2006<br>Marla J. F. O'Neill - updated : 1/25/2006<br>Victor A. McKusick - updated : 11/19/2003<br>Ada Hamosh - updated : 9/16/2003<br>Ada Hamosh - updated : 8/5/2003<br>Ada Hamosh - updated : 10/18/2001<br>Ada Hamosh - updated : 8/23/2001<br>Victor A. McKusick - updated : 6/25/2001<br>Victor A. McKusick - updated : 2/2/1999<br>Victor A. McKusick - updated : 6/25/1998<br>Victor A. McKusick - updated : 4/15/1998<br>Jennifer P. Macke - updated : 9/2/1997
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