4217 lines
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Entry
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- *605377 - DYSTROPHIA MYOTONICA PROTEIN KINASE; DMPK
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605377</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605377">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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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=ENSG00000104936;t=ENST00000291270" 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=1760" 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=605377" 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 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=ENSG00000104936;t=ENST00000291270" 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_001081560,NM_001081562,NM_001081563,NM_001288764,NM_001288765,NM_001288766,NM_001424162,NM_001424163,NM_001424164,NM_001424165,NM_001424166,NM_001424168,NM_001424169,NM_004409" 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_004409" 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=605377" 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=05645&isoform_id=05645_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/DMPK" 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/181603,181604,181605,181606,186756,307177,553530,633865,976143,976144,976145,976146,976147,976148,1184879,38512203,47059024,62088306,71051932,119577784,119577785,119577786,119577787,119577788,119577789,126091040,126091095,126131093,194380972,194386406,221045148,311348498,311348499,311348500,311348501,311348503,311348504,311348505,311348506,311348508,311348509,311348510,311348511,311348513,311348514,311348515,311348516,311348518,311348519,311348520,311348521,311348523,311348524,311348525,311348526,311348528,311348529,311348530,311348531,311348533,311348534,311348535,311348536,311348538,311348539,311348540,311348541,311348543,311348544,311348545,311348546,311348548,311348549,311348550,311348551,311348553,311348554,311348555,311348556,311348558,311348559,311348560,311348561,311348563,311348564,311348565,311348566,311348568,311348569,311348570,311348571,311348573,311348574,311348575,311348576,311348578,311348579,311348580,311348581,311348583,311348584,311348585,311348586,311348588,311348589,311348590,311348591,311348593,311348594,311348595,311348596,311348598,311348599,311348600,311348601,311348603,311348604,311348605,311348606,311348608,311348609,311348610,311348611,311348613,311348614,311348615,311348616,311348618,311348619,311348620,311348621,311348623,311348624,311348625,311348626,311348628,311348629,311348630,311348631,311348633,311348634,311348635,311348636,311348638,311348639,311348640,311348641,311348643,311348644,311348645,311348646,311348648,311348649,311348650,311348651,311348653,311348654,311348655,311348656,311348658,311348659,311348660,311348661,311348663,311348664,311348665,311348666,311348668,311348669,311348670,311348671,311348673,311348674,311348675,311348676,311348678,311348679,311348680,311348681,311348683,311348684,311348685,311348686,311348688,311348689,311348690,311348691,311348693,311348694,311348695,311348696,363548519,571026659,571026661,571026702,608785259,608785261,608785263,2574009614,2574210199,2574210306,2574210329,2574210408,2574210418,2574210425,2574210438,2574210466,2574210481" 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/Q09013" 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=1760" 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=ENSG00000104936;t=ENST00000291270" 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=DMPK" 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=DMPK" 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+1760" 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/DMPK" 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:1760" 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/1760" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr19&hgg_gene=ENST00000291270.9&hgg_start=45769717&hgg_end=45782490&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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|
<span class="panel-title">
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<span class="small">
|
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
|
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/dmpk" 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=605377[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=605377[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/DMPK/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/ENSG00000104936" 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=DMPK" 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=DMPK" 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=DMPK" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=DMPK&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/PA27380" 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:2933" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:94906" 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/DMPK#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:94906" 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/1760/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1760" 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>
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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">
|
|
<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:605377" 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">
|
|
<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://reactome.org/content/query?q=DMPK&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> 77956009<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>
|
|
605377
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
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DYSTROPHIA MYOTONICA PROTEIN KINASE; DMPK
|
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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>
|
|
<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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
DM KINASE; DMK<br />
|
|
DM PROTEIN KINASE<br />
|
|
MYOTONIN-PROTEIN KINASE
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=DMPK" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">DMPK</a></em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/19/833?start=-3&limit=10&highlight=833">19q13.32</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:45769717-45782490&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">19:45,769,717-45,782,490</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/833?start=-3&limit=10&highlight=833">
|
|
19q13.32
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Myotonic dystrophy 1
|
|
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<p>A CTG repeat in DMPK is transcribed and is located in the 3-prime untranslated region (UTR) of an mRNA that is expressed in tissues affected by myotonic dystrophy (DM1; <a href="/entry/160900">160900</a>). The polypeptide encoded by this mRNA is a member of the protein kinase family. Since the triplet repeat sequence is within a gene that has a sequence similar to protein kinases, <a href="#12" class="mim-tip-reference" title="Fu, Y.-H., Pizzuti, A., Fenwick, R. G., Jr., King, J., Rajnarayan, S., Dunne, P. W., Dubel, J., Nasser, G. A., Ashizawa, T., de Jong, P., Wieringa, B., Korneluk, R., Perryman, M. B., Epstein, H. F., Caskey, C. T. <strong>An unstable triplet repeat in a gene related to myotonic muscular dystrophy.</strong> Science 255: 1256-1258, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1546326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1546326</a>] [<a href="https://doi.org/10.1126/science.1546326" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1546326">Fu et al. (1992)</a> suggested that the gene be referred to as myotonin-protein kinase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1546326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Jansen, G., Mahadevan, M., Amemiya, C., Wormskamp, N., Segers, B., Hendriks, W., O'Hoy, K., Baird, S., Sabourin, L., Lennon, G., Jap, P. L., Iles, D., Coerwinkel, M., Hofker, M., Carrano, A. V., de Jong, P. J., Korneluk, R. G., Wieringa, B. <strong>Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.</strong> Nature Genet. 1: 261-266, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302022</a>] [<a href="https://doi.org/10.1038/ng0792-261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302022">Jansen et al. (1992)</a> demonstrated that the brain and heart transcripts of the DM kinase gene are subject to alternative RNA splicing in both human and mouse. The unstable (CTG)5-30 motif is found uniquely in humans, although the flanking nucleotides are also present in mouse. In both species another active gene, called DMRN9 (DMWD; <a href="/entry/609857">609857</a>), was found in close proximity to the DM kinase gene. DMRN9 transcripts, mainly expressed in brain and testis, possess a single large open reading frame. <a href="#15" class="mim-tip-reference" title="Jansen, G., Mahadevan, M., Amemiya, C., Wormskamp, N., Segers, B., Hendriks, W., O'Hoy, K., Baird, S., Sabourin, L., Lennon, G., Jap, P. L., Iles, D., Coerwinkel, M., Hofker, M., Carrano, A. V., de Jong, P. J., Korneluk, R. G., Wieringa, B. <strong>Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.</strong> Nature Genet. 1: 261-266, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302022</a>] [<a href="https://doi.org/10.1038/ng0792-261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302022">Jansen et al. (1992)</a> suggested that clinical manifestations of myotonic dystrophy may be caused by the expanded CTG repeat compromising the alternative expression of DM kinase or DMRN9 proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302022" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 involvement of a protein kinase in myotonic dystrophy is consistent with the pivotal role of such enzymes in a wide range of biochemical and cellular pathways, and was indeed predicted by <a href="#32" class="mim-tip-reference" title="Roses, A. D., Appel, S. H. <strong>Muscle membrane protein kinase in myotonic muscular dystrophy.</strong> Nature 250: 245-247, 1974.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4277586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4277586</a>] [<a href="https://doi.org/10.1038/250245a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4277586">Roses and Appel (1974)</a>. <a href="#34" class="mim-tip-reference" title="Shaw, D. J., McCurrach, M., Rundle, S. A., Harley, H. G., Crow, S. R., Sohn, R., Thirion, J.-P., Hamshere, M. G., Buckler, A. J., Harper, P. S., Housman, D. E., Brook, J. D. <strong>Genomic organization and transcriptional units at the myotonic dystrophy locus.</strong> Genomics 18: 673-679, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7905855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7905855</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80372-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7905855">Shaw et al. (1993)</a> demonstrated that the DMK gene encodes a protein of 624 amino acids with an N-terminal domain highly homologous to cAMP-dependent serine-threonine protein kinases, an intermediate domain with a high alpha-helical content and weak similarity to various filamentous proteins, and a hydrophobic C-terminal segment. They also isolated a second gene, located very close to DMK and homologous to the mouse gene Dmrn9 (<a href="#15" class="mim-tip-reference" title="Jansen, G., Mahadevan, M., Amemiya, C., Wormskamp, N., Segers, B., Hendriks, W., O'Hoy, K., Baird, S., Sabourin, L., Lennon, G., Jap, P. L., Iles, D., Coerwinkel, M., Hofker, M., Carrano, A. V., de Jong, P. J., Korneluk, R. G., Wieringa, B. <strong>Characterization of the myotonic dystrophy region predicts multiple protein isoform-encoding mRNAs.</strong> Nature Genet. 1: 261-266, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302022</a>] [<a href="https://doi.org/10.1038/ng0792-261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302022">Jansen et al., 1992</a>). Strong expression of the latter gene in brain suggested that it may play a role in mental symptoms in severe cases of myotonic dystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7905855+1302022+4277586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Mahadevan, M. S., Amemiya, C., Jansen, G., Sabourin, L., Baird, S., Neville, C. E., Wormskamp, N., Segers, B., Batzer, M., Lamerdin, J., de Jong, P., Wieringa, B., Korneluk, R. G. <strong>Structure and genomic sequence of the myotonic dystrophy (DM kinase) gene.</strong> Hum. Molec. Genet. 2: 299-304, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8499920/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8499920</a>] [<a href="https://doi.org/10.1093/hmg/2.3.299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8499920">Mahadevan et al. (1993)</a> presented the genomic sequences of the human and murine DM kinase gene. They predicted a translation initiation codon and determined the organization of the gene. Several polymorphisms were identified within the human gene, and PCR assays to detect 2 of these were described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8499920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Fu, Y.-H., Friedman, D. L., Richards, S., Pearlman, J. A., Gibbs, R. A., Pizzuti, A., Ashizawa, T., Perryman, M. B., Scarlato, G., Fenwick, R. G., Jr., Caskey, C. T. <strong>Decreased expression of myotonin-protein kinase messenger RNA and protein in adult form of myotonic dystrophy.</strong> Science 260: 235-238, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8469976/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8469976</a>] [<a href="https://doi.org/10.1126/science.8469976" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8469976">Fu et al. (1993)</a> determined the genomic sequence of the gene that they referred to as myotonin-protein kinase (Mt-PK). In a length of 11,612 bp, the Mt-PK gene contained a minimum of 14 exons. Several forms of alternatively spliced mRNA were demonstrated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8469976" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Shaw, D. J., McCurrach, M., Rundle, S. A., Harley, H. G., Crow, S. R., Sohn, R., Thirion, J.-P., Hamshere, M. G., Buckler, A. J., Harper, P. S., Housman, D. E., Brook, J. D. <strong>Genomic organization and transcriptional units at the myotonic dystrophy locus.</strong> Genomics 18: 673-679, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7905855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7905855</a>] [<a href="https://doi.org/10.1016/s0888-7543(05)80372-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7905855">Shaw et al. (1993)</a> determined that the DMK gene contains 15 exons distributed over about 13 kb of genomic DNA on chromosome 19q. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7905855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 antisera developed against synthetic DMPK peptide antigens for biochemical and histochemical studies, <a href="#37" class="mim-tip-reference" title="van der Ven, P. F. M., Jansen, G., van Kuppevelt, T. H. M. S. M., Perryman, M. B., Lupa, M., Dunne, P. W., ter Laak, H. J., Jap, P. H. K., Veerkamp, J. H., Epstein, H. F., Wieringa, B. <strong>Myotonic dystrophy kinase is a component of neuromuscular junctions.</strong> Hum. Molec. Genet. 2: 1889-1894, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8281152/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8281152</a>] [<a href="https://doi.org/10.1093/hmg/2.11.1889" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8281152">van der Ven et al. (1993)</a> found lower levels of immunoreactive DM kinase protein of 53 kD in skeletal and cardiac muscle extracts of myotonic dystrophy (DM1; <a href="/entry/160900">160900</a>) patients than in normal controls. Immunohistochemical staining revealed that DMPK is localized predominantly at sites of neuromuscular and myotendinous junctions of human and rodent skeletal muscles. The protein could also be demonstrated in the neuromuscular junctions of muscular tissues of adult and congenital cases of DM, with no gross changes in structural organization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8281152" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Because nuclear histones are known to mediate general transcriptional repression along chromosomes, <a href="#40" class="mim-tip-reference" title="Wang, Y.-H., Amirhaeri, S., Kang, S., Wells, R. D., Griffith, J. D. <strong>Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene.</strong> Science 265: 669-671, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8036515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8036515</a>] [<a href="https://doi.org/10.1126/science.8036515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8036515">Wang et al. (1994)</a> used electron microscopy to examine in vitro the nucleosome assembly of DNA containing repeating CTG triplets. The efficiency of nucleosome formation increased with expanded triplet blocks, suggesting that such blocks may repress transcription through the creation of hyperstable nucleosomes. These may alter the local chromatin structure, inhibit the passage of transcription complexes, or prevent the opening of the DNA before replication. They may also result in DNA polymerase slippage, pausing, or idling, leading to expansion of the triplet block (<a href="#40" class="mim-tip-reference" title="Wang, Y.-H., Amirhaeri, S., Kang, S., Wells, R. D., Griffith, J. D. <strong>Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene.</strong> Science 265: 669-671, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8036515/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8036515</a>] [<a href="https://doi.org/10.1126/science.8036515" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8036515">Wang et al., 1994</a>). <a href="#41" class="mim-tip-reference" title="Wang, Y.-H., Griffith, J. <strong>Expanded CTG triplet blocks from the myotonic dystrophy gene create the strongest known natural nucleosome positioning elements.</strong> Genomics 25: 570-573, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7789994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7789994</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80061-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7789994">Wang and Griffith (1995)</a> performed competitive nucleosome reconstitution to measure the energetics of nucleosome formation over CTG repeat blocks of n = 75 and n = 130. They showed that these DNA fragments are 6 and 9 times stronger in nucleosome formation, respectively, than the 5S RNA gene of Xenopus borealis, one of the strongest known natural nucleosome positioning elements. These observations give further support to the previously stated hypothesis that expanded CTG blocks may alter local chromatin structure. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8036515+7789994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Junghans, R. P., Ebralidze, A., Tiwari, B. <strong>Does (CUG)n repeat in DMPK mRNA 'paint' chromosome 19 to suppress distant genes to create the diverse phenotype of myotonic dystrophy? A new hypothesis of long-range cis autosomal inactivation.</strong> Neurogenetics 3: 59-67, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11354827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11354827</a>] [<a href="https://doi.org/10.1007/s100480000103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11354827">Junghans et al. (2001)</a> hypothesized that the diversity of phenotype in myotonic dystrophy may be due to the fact that the DM CTG repeat induces long-range cis chromosomal effects that suppress diverse genes on chromosome 19, resulting in manifest multisystem abnormalities in the clinical disorder. One of the features discussed in detail was hypercatabolism of immunoglobulin G in myotonic dystrophy and the possible significance of the FCGRT gene (<a href="/entry/601437">601437</a>) to the DM locus. A functional linkage between the FCGRT and DM genes was known long before the map location of either had been identified. <a href="#43" class="mim-tip-reference" title="Wochner, R. D., Drews, G., Strober, W., Waldmann, T. A. <strong>Accelerated breakdown of immunoglobulin G (IgG) in myotonic dystrophy: a hereditary error of immunoglobulin catabolism.</strong> J. Clin. Invest. 45: 321-329, 1966.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4159450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4159450</a>] [<a href="https://doi.org/10.1172/JCI105346" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4159450">Wochner et al. (1966)</a> found that the mean survival time of IgG in DM was 11 +/- 4 days versus 23 +/- 4 days in controls, corresponding to lower mean IgG levels. IgG synthesis rates were the same for both groups. <a href="#18" class="mim-tip-reference" title="Junghans, R. P., Ebralidze, A., Tiwari, B. <strong>Does (CUG)n repeat in DMPK mRNA 'paint' chromosome 19 to suppress distant genes to create the diverse phenotype of myotonic dystrophy? A new hypothesis of long-range cis autosomal inactivation.</strong> Neurogenetics 3: 59-67, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11354827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11354827</a>] [<a href="https://doi.org/10.1007/s100480000103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11354827">Junghans et al. (2001)</a> estimated that cis inactivation of the 1 allele of the FCGRT gene would result in an approximately 50% reduction in IgG protection, which was consistent with the observation of a 58% reduction. As reviewed by <a href="#18" class="mim-tip-reference" title="Junghans, R. P., Ebralidze, A., Tiwari, B. <strong>Does (CUG)n repeat in DMPK mRNA 'paint' chromosome 19 to suppress distant genes to create the diverse phenotype of myotonic dystrophy? A new hypothesis of long-range cis autosomal inactivation.</strong> Neurogenetics 3: 59-67, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11354827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11354827</a>] [<a href="https://doi.org/10.1007/s100480000103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11354827">Junghans et al. (2001)</a>, plasma protein catabolism occurs in vascular endothelium by endocytotic processing of plasma contents. Vascular endothelium is the most active endocytic tissue in the body and as a result the principal site for plasma protein catabolism. Plasma proteins diffusing or transported into extravascular sites are isolated from catabolism while extravascular. The so-called Brambell receptor, alternatively termed protection receptor or neonatal receptor, is located in endosomes of vascular endothelial cells and selectively recycles IgG to the cell surface, thus protecting IgG from lysosomal catabolism that is the fate of other, unprotected plasma proteins. In mice with knockout of the Fcgrt gene, the fractional catabolic rate for IgG may be accelerated up to 10-fold relative to wildtype animals in which protection is intact (<a href="#17" class="mim-tip-reference" title="Junghans, R. P., Anderson, C. L. <strong>The protection receptor for IgG catabolism is the beta-2-microglobulin-containing neonatal intestinal transport receptor.</strong> Proc. Nat. Acad. Sci. 93: 5512-5516, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8643606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8643606</a>] [<a href="https://doi.org/10.1073/pnas.93.11.5512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8643606">Junghans and Anderson, 1996</a>). This protection mechanism is directly responsible for making IgG the longest lived of all plasma proteins (<a href="#38" class="mim-tip-reference" title="Waldmann, T. A., Strober, W. <strong>Metabolism of immunoglobulins.</strong> Prog. Allergy 13: 1-110, 1969.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4186070/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4186070</a>] [<a href="https://doi.org/10.1159/000385919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4186070">Waldmann and Strober, 1969</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4186070+11354827+4159450+8643606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 several synthetic peptide substrates, <a href="#42" class="mim-tip-reference" title="Wansink, D. G., van Herpen, R. E. M. A., Coerwinkel-Driessen, M. M., Groenen, P. J. T. A., Hemmings, B. A., Wieringa, B. <strong>Alternative splicing controls myotonic dystrophy protein kinase structure, enzymatic activity, and subcellular localization.</strong> Molec. Cell. Biol. 23: 5489-5501, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12897125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12897125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12897125[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/10.1128/MCB.23.16.5489-5501.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12897125">Wansink et al. (2003)</a> characterized the substrate requirements of mouse Dmpk. Dmpk phosphorylated threonine residues more efficiently than serine, and activity increased with positively charged amino acids, preferably arginine, at positions -1 to -3. A VSGGG motif in the kinase C-terminal domain modulated both Dmpk autophosphorylation activity and protein conformation, and alternatively spliced elements in the C terminus regulated substrate specificity and intracellular localization. Proteins with a hydrophobic C terminus targeted to the endoplasmic reticulum, while those with a more hydrophilic C terminus bound to the mitochondrial outer membrane, and those with a short C-terminal tail adopted a cytosolic location. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12897125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 CTG repeats associated with DM1 are a component of a CTCF (<a href="/entry/604167">604167</a>)-dependent insulator element, and repeat expansion results in conversion of the region to heterochromatin. <a href="#6" class="mim-tip-reference" title="Cho, D. H., Thienes, C. P., Mahoney, S. E., Analau, E., Filippova, G. N., Tapscott, S. J. <strong>Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF.</strong> Molec. Cell 20: 483-489, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16285929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16285929</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.09.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16285929">Cho et al. (2005)</a> showed that the wildtype DM1 insulator is associated with bidirectional transcription, antisense transcripts that emanate from the adjacent SIX5 regulatory region and are converted into 21-nucleotide RNA fragments, H3-K9 dimethylation and H3-K4 trimethylation, and HP1-gamma (CBX3; <a href="/entry/604477">604477</a>) recruitment in the region of the CTG repeats. They found that expansion of the CTG repeat in DM1 is associated with reduced or absent CTCF binding, spread of heterochromatin, and regional CpG methylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16285929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#5" class="mim-tip-reference" title="Cavanna, J. S., Greenfield, A. J., Johnson, K. J., Marks, A. R., Nadal-Ginard, B., Brown, S. D. M. <strong>Establishment of the mouse chromosome 7 region with homology to the myotonic dystrophy region of human chromosome 19q.</strong> Genomics 7: 12-18, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1970795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1970795</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90513-t" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1970795">Cavanna et al. (1990)</a> established the region of mouse chromosome 7 homologous to the myotonic dystrophy region of human chromosome 19q. Using fluorescence in situ hybridization, <a href="#14" class="mim-tip-reference" title="Jansen, G., Bartolomei, M., Kalscheuer, V., Merkx, G., Wormskamp, N., Mariman, E., Smeets, D., Ropers, H.-H., Wieringa, B. <strong>No imprinting involved in the expression of DM-kinase mRNAs in mouse and human tissues.</strong> Hum. Molec. Genet. 2: 1221-1227, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401505/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401505</a>] [<a href="https://doi.org/10.1093/hmg/2.8.1221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401505">Jansen et al. (1993)</a> confirmed that the DM-kinase gene is proximal to the Apoe gene on mouse chromosome 7, close to an imprinted segment. No evidence of imprinting could be found in either human or mouse tissues, however. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1970795+8401505" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#27" class="mim-tip-reference" title="Mooers, B. H. M., Logue, J. S., Berglund, J. A. <strong>The structural basis of myotonic dystrophy from the crystal structure of CUG repeats.</strong> Proc. Nat. Acad. Sci. 102: 16626-16631, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16269545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16269545</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16269545[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0505873102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16269545">Mooers et al. (2005)</a> determined the crystal structure of an 18-bp RNA containing 6 CUG repeats to 1.58-angstrom resolution. The CUG repeats formed antiparallel double-stranded helices that stacked end on end in the crystal to form infinite, pseudocontinuous helices similar to the long CUG stem loops formed by the expanded CUG repeats in DM1. The CUG helix was similar in structure to A-form RNA with the exception of the unique U-U mismatches. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16269545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To determine the effect of the CTG repeat on DM expression, <a href="#4" class="mim-tip-reference" title="Carango, P., Noble, J. E., Marks, H. G., Funanage, V. L. <strong>Absence of myotonic dystrophy protein kinase (DMPK) mRNA as a result of a triplet repeat expansion in myotonic dystrophy.</strong> Genomics 18: 340-348, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288237</a>] [<a href="https://doi.org/10.1006/geno.1993.1474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8288237">Carango et al. (1993)</a> separated the chromosome 19 homologs from a 36-year-old woman with DM into different cell lines by somatic cell hybridization. RT-PCR amplification of coding sequences from the DM gene showed both reduced levels of primary DM transcripts and impaired processing of these transcripts in the mutant cell line. These findings suggested that the presence of a large number of repeats in the 3-prime untranslated region of the DM gene reduces both the synthesis and the processing of DM mRNA, resulting in undetectable levels of processed DM mRNA from the mutant allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 RT-PCR, <a href="#21" class="mim-tip-reference" title="Krahe, R., Ashizawa, T., Abbruzzese, C., Roeder, E., Carango, P., Giacanelli, M., Funanage, V. L., Siciliano, M. J. <strong>Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing.</strong> Genomics 28: 1-14, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590731</a>] [<a href="https://doi.org/10.1006/geno.1995.1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590731">Krahe et al. (1995)</a> found that equal levels of unprocessed DMPK pre-mRNA were produced by the wildtype and DM alleles in skeletal muscle and cell lines of heterozygous DM patients. In contrast, processed mRNA levels from the DM allele were reduced relative to the wildtype allele as the size of the expansion increased. <a href="#21" class="mim-tip-reference" title="Krahe, R., Ashizawa, T., Abbruzzese, C., Roeder, E., Carango, P., Giacanelli, M., Funanage, V. L., Siciliano, M. J. <strong>Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing.</strong> Genomics 28: 1-14, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7590731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7590731</a>] [<a href="https://doi.org/10.1006/geno.1995.1099" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7590731">Krahe et al. (1995)</a> concluded that the unstable repeat impairs posttranscriptional processing of DM allele transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7590731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Wong, L.-J. C., Ashizawa, T., Monckton, D. G., Caskey, C. T., Richards, C. S. <strong>Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent.</strong> Am. J. Hum. Genet. 56: 114-122, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825566</a>]" pmid="7825566">Wong et al. (1995)</a> demonstrated that the expanded CTG allele, which often presents as a diffused band on Southern blot analysis, suggesting somatic mutation, shows size heterogeneity that correlates well with the age of the patients. In their study, older patients showed larger size variation. This correlation was independent of the sex of either the patient or the transmitting parent. Similar size heterogeneity was not observed in congenital cases, regardless of the size of expansion. It can be speculated that continuous expansion of the CTG repeats is related to the pathogenesis of the disease, particularly the progression of the disease with age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7825566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 dominant inheritance of myotonic dystrophy was difficult to reconcile with the fact that the expansion mutation lies outside the protein-encoding elements of the gene and should not be translated into protein. <a href="#39" class="mim-tip-reference" title="Wang, J., Pegoraro, E., Menegazzo, E., Gennarelli, M., Hoop, R. C., Angelini, C., Hoffman, E. P. <strong>Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation.</strong> Hum. Molec. Genet. 4: 599-606, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7543316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7543316</a>] [<a href="https://doi.org/10.1093/hmg/4.4.599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7543316">Wang et al. (1995)</a> used muscle biopsies from classic adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the normal and the expanded DM kinase genes and compared the results to normal and myopathic controls. They found relatively small decreases of DM kinase RNA in the total RNA pool from muscle; however, these reductions were not disease-specific. Analysis of poly(A)+ RNA showed dramatic decreases in both the mutant and the normal DM kinase RNAs, and these changes were disease-specific. <a href="#39" class="mim-tip-reference" title="Wang, J., Pegoraro, E., Menegazzo, E., Gennarelli, M., Hoop, R. C., Angelini, C., Hoffman, E. P. <strong>Myotonic dystrophy: evidence for a possible dominant-negative RNA mutation.</strong> Hum. Molec. Genet. 4: 599-606, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7543316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7543316</a>] [<a href="https://doi.org/10.1093/hmg/4.4.599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7543316">Wang et al. (1995)</a> considered these findings consistent with a novel molecular pathogenetic mechanism for myotonic dystrophy in which both the normal and expanded DM kinase genes are transcribed in patient's muscle, but the abnormal expansion-containing RNA has a dominant-negative effect on RNA metabolism by preventing the accumulation of poly(A)+ RNA. The ability of the expansion mutation to alter accumulation of poly(A)+ RNA in trans suggested that myotonic dystrophy may be the first example of a dominant-negative mutation manifested at the RNA level. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7543316" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Amack, J. D., Mahadevan, M. S. <strong>The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation.</strong> Hum. Molec. Genet. 10: 1879-1887, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555624</a>] [<a href="https://doi.org/10.1093/hmg/10.18.1879" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11555624">Amack and Mahadevan (2001)</a> showed that DMPK transcripts containing expanded CUG tracts can form both nuclear and cytoplasmic RNA foci. However, transcripts containing neither a CUG expansion alone nor a CUG expansion plus the distal region of the DMPK 3-prime untranslated region RNA affected myogenesis in C2C12 myoblasts. This implies that RNA foci formation and perturbation of any RNA binding factors involved in this process are not sufficient to block myoblast differentiation. RNA analysis of myogenic markers revealed that mutant DMPK 3-prime untranslated region mRNA significantly impeded upregulation of the differentiation factors myogenin (<a href="/entry/159980">159980</a>) and p21 (<a href="/entry/116899">116899</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 RT-PCR, <a href="#10" class="mim-tip-reference" title="Frisch, R., Singleton, K. R., Moses, P. A., Gonzalez, I. L., Carango, P., Marks, H. G., Funanage, V. L. <strong>Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy.</strong> Molec. Genet. Metab. 74: 281-291, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592825</a>] [<a href="https://doi.org/10.1006/mgme.2001.3229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592825">Frisch et al. (2001)</a> found a marked reduction of DMPK mRNA expression from chromosomes carrying expanded DMPK alleles. Most of the DMPK transcripts expressed from the expanded alleles lacked exons 13 and 14, whereas full-length transcripts were expressed predominantly from the normal alleles. <a href="#10" class="mim-tip-reference" title="Frisch, R., Singleton, K. R., Moses, P. A., Gonzalez, I. L., Carango, P., Marks, H. G., Funanage, V. L. <strong>Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy.</strong> Molec. Genet. Metab. 74: 281-291, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592825</a>] [<a href="https://doi.org/10.1006/mgme.2001.3229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592825">Frisch et al. (2001)</a> suggested that the CTG repeat expansion leads to a decrease in DMPK mRNA by affecting splicing at the 3-prime end of the DMPK pre-mRNA transcript. They also used RT-PCR to test the hypothesis that DMPK expansion alters expression of its neighboring genes, DMWD and SIX5 (<a href="/entry/600963">600963</a>). <a href="#10" class="mim-tip-reference" title="Frisch, R., Singleton, K. R., Moses, P. A., Gonzalez, I. L., Carango, P., Marks, H. G., Funanage, V. L. <strong>Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy.</strong> Molec. Genet. Metab. 74: 281-291, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11592825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11592825</a>] [<a href="https://doi.org/10.1006/mgme.2001.3229" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11592825">Frisch et al. (2001)</a> found that DMPK expansion had no effect on DMWD expression, but it did reduce SIX5 expression in congenital DM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11592825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Yang, Z., Lau, R., Marcadier, J. L., Chitayat, D., Pearson, C. E. <strong>Replication inhibitors modulate instability of an expanded trinucleotide repeat at the myotonic dystrophy type 1 disease locus in human cells.</strong> Am. J. Hum. Genet. 73: 1092-1105, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14574643[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/379523" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14574643">Yang et al. (2003)</a> studied a fibroblast cell line from the skin of a 22.5-week fetus with DM1 and demonstrated that CTG expansions occurred only in proliferating cells and that agents that affect DNA synthesis but not replication initiation can specifically modulate the instability of the expanded DM1 CTG repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14574643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Ebralidze, A., Wang, Y., Petkova, V., Ebralidse, K., Junghans, R. P. <strong>RNA leaching of transcription factors disrupts transcription in myotonic dystrophy.</strong> Science 303: 383-387, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657503</a>] [<a href="https://doi.org/10.1126/science.1088679" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14657503">Ebralidze et al. (2004)</a> showed that DMPK mutant RNA binds and sequesters transcription factors, with up to 90% depletion of selected transcription factors from active chromatin. Diverse genes are consequently reduced in expression, including the ion transporter CLC1 (<a href="/entry/118425">118425</a>), which had been implicated in myotonia. When transcription factor specificity protein-1 (SP1; <a href="/entry/189906">189906</a>) was overexpressed in DM1-affected cells, low levels of mRNA for CLC1 were restored to normal. The authors concluded that transcription factor leaching from chromatin by mutant RNA provides a potentially unifying pathomechanistic explanation for this disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14657503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#16" class="mim-tip-reference" title="Jiang, H., Mankodi, A., Swanson, M. S., Moxley, R. T., Thornton, C. A. <strong>Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons.</strong> Hum. Molec. Genet. 13: 3079-3088, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15496431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15496431</a>] [<a href="https://doi.org/10.1093/hmg/ddh327" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15496431">Jiang et al. (2004)</a> found that in postmortem DM1 brain tissue, mutant DMPK transcripts were widely expressed in cortical and subcortical neurons. The mutant transcripts accumulated in discrete foci within neuronal nuclei. Proteins in the muscleblind (see MBNL1; <a href="/entry/606516">606516</a>) family were recruited into the RNA foci and depleted elsewhere in the nucleoplasm. In parallel, a subset of neuronal pre-mRNAs showed abnormal regulation of alternative splicing. The authors suggested that CNS impairment in DM1 may result from a deleterious gain of function by mutant DMPK mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15496431" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Ranum, L. P. W., Day, J. W. <strong>Myotonic dystrophy: RNA pathogenesis comes into focus.</strong> Am. J. Hum. Genet. 74: 793-804, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15065017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15065017</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15065017[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/383590" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15065017">Ranum and Day (2004)</a> reviewed the mechanism by which the CTG expansion in the 3-prime untranslated region of the DM1 gene causes myotonic dystrophy. The discovery that type 2 myotonic dystrophy (DM2; <a href="/entry/602668">602668</a>) is caused by an untranslated CCTG expansion indicated that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15065017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Kimura, T., Nakamori, M., Lueck, J. D., Pouliquin, P., Aoike, F., Fujimura, H., Dirksen, R. T., Takahashi, M. P., Dulhunty, A. F., Sakoda, S. <strong>Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase in myotonic dystrophy type 1.</strong> Hum. Molec. Genet. 14: 2189-2200, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15972723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15972723</a>] [<a href="https://doi.org/10.1093/hmg/ddi223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15972723">Kimura et al. (2005)</a> investigated the alternative splicing of mRNAs of 2 major proteins of the sarcoplasmic reticulum, the ryanodine receptor-1 (RYR1; <a href="/entry/180901">180901</a>) and sarcoplasmic/endoplasmic reticulum Ca(2+)-transporting ATPases SERCA1 (ATP2A1; <a href="/entry/108730">108730</a>) or SERCA2 (ATP2A2; <a href="/entry/108740">108740</a>), in skeletal muscle from DM1 patients. The fetal variants, ASI(-) of RYR1, which lacks residues 3481 to 3485, and SERCA1b, which differs at the C-terminal end, were significantly increased in DM1 skeletal muscle and the transgenic mouse model of DM1 (HAS-LR). In addition, a novel variant of SERCA2 was significantly decreased in DM1 patients. The total amount of mRNA for RYR1, SERCA1, and SERCA2 in DM1 and the expression levels of their proteins in HAS-LR mice were not significantly different. However, heterologous expression of ASI(-) in cultured cells showed decreased affinity for ryanodine but similar calcium dependency, and decreased channel activity in single-channel recording when compared with wildtype RYR1. In support of this, RYR1-knockout myotubes expressing ASI(-) exhibited a decreased incidence of calcium oscillations during caffeine exposure compared with that observed for myotubes expressing wildtype RYR1. <a href="#20" class="mim-tip-reference" title="Kimura, T., Nakamori, M., Lueck, J. D., Pouliquin, P., Aoike, F., Fujimura, H., Dirksen, R. T., Takahashi, M. P., Dulhunty, A. F., Sakoda, S. <strong>Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase in myotonic dystrophy type 1.</strong> Hum. Molec. Genet. 14: 2189-2200, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15972723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15972723</a>] [<a href="https://doi.org/10.1093/hmg/ddi223" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15972723">Kimura et al. (2005)</a> suggested that aberrant splicing of RYR1 and SERCA1 mRNAs may contribute to impaired calcium homeostasis in DM1 muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15972723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 reversible transgenic mouse model of RNA toxicity in DM1, <a href="#45" class="mim-tip-reference" title="Yadava, R. S., Frenzel-McCardell, C. D., Yu, Q., Srinivasan, V., Tucker, A. L., Puymirat, J., Thornton, C. A., Prall, O. W., Harvey, R. P., Mahadevan, M. S. <strong>RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.</strong> Nature Genet. 40: 61-68, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18084293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18084293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18084293[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2007.28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18084293">Yadava et al. (2008)</a> showed that overexpression of a normal human DMPK 3-prime UTR with only (CUG)5 resulted in cardiac conduction defects, increased expression of the cardiac-specific transcription factor Nkx2.5 (NKX2E; <a href="/entry/600584">600584</a>), and profound disturbances in connexin-40 (GJA5; <a href="/entry/121013">121013</a>) and connexin-43 (GJA1; <a href="/entry/121014">121014</a>). Overexpression of the DMPK 3-prime UTR in mouse skeletal muscle also induced transcriptional activation of Nkx2.5 and its targets. Human DM1 muscle, but not normal human muscle, showed similar aberrant expression of NKX2.5 and its targets. In mice, the effects on Nkx2.5 and its targets were reversed by silencing toxic RNA expression. Furthermore, haploinsufficiency of Nkx2.5 in Nkx2.5 +/- mice had a cardioprotective effect against defects induced by DMPK 3-prime UTR. <a href="#45" class="mim-tip-reference" title="Yadava, R. S., Frenzel-McCardell, C. D., Yu, Q., Srinivasan, V., Tucker, A. L., Puymirat, J., Thornton, C. A., Prall, O. W., Harvey, R. P., Mahadevan, M. S. <strong>RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.</strong> Nature Genet. 40: 61-68, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18084293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18084293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18084293[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.2007.28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18084293">Yadava et al. (2008)</a> concluded that NKX2.5 is a modifier of DM1-associated RNA toxicity in heart. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18084293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Medica, I., Teran, N., Volk, M., Pfeifer, V., Ladavac, E., Peterlin, B. <strong>Patients with primary cataract as a genetic pool of DMPK protomutation.</strong> J. Hum. Genet. 52: 123-128, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17146587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17146587</a>] [<a href="https://doi.org/10.1007/s10038-006-0091-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17146587">Medica et al. (2007)</a> found that 4 (1.46%) of 274 unrelated patients with cataract, but no evidence or family history of DM1, carried a 'protomutation' in the DMPK gene ranging between 52 and 81 CTG repeats. The authors hypothesized that these patients with protomutations represented a source of full expansion mutation, which could be responsible for maintaining DM1 mutations in a population. Stable transmission to offspring was observed in 1 individual with a protomutation. Three of the patients were from the Croatian region of Istria, which has a high prevalence of DM1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17146587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Braida, C., Stefanatos, R. K. A., Adam, B., Mahajan, N., Smeets, H. J. M., Niel, F., Goizet, C., Arveiler, B., Koenig, M., Lagier-Tourenne, C., Mandel, J.-L., Faber, C. G., de Die-Smulders, C. E. M., Spaans, F., Monckton, D. G. <strong>Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients.</strong> Hum. Molec. Genet. 19: 1399-1412, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20080938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20080938</a>] [<a href="https://doi.org/10.1093/hmg/ddq015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20080938">Braida et al. (2010)</a> reported an unusual Dutch family cosegregating DM1, Charcot-Marie-Tooth neuropathy, encephalopathic attacks, and early hearing loss that carried a complex variant repeat at the DM1 locus. The mutation comprised an expanded CTG tract at the 5-prime end and a complex array of CTG repeats interspersed with multiple GGC and CCG repeats at the 3-prime end. The complex variant repeat tract at the 3-prime end of the array was relatively stable in both blood DNA and the maternal germline, although the 5-prime CTG tract remained genetically unstable and prone to expansion. Complex variant repeats were also identified at the 3-prime end of the CTG array of approximately 3 to 4% of unrelated DM1 patients. <a href="#3" class="mim-tip-reference" title="Braida, C., Stefanatos, R. K. A., Adam, B., Mahajan, N., Smeets, H. J. M., Niel, F., Goizet, C., Arveiler, B., Koenig, M., Lagier-Tourenne, C., Mandel, J.-L., Faber, C. G., de Die-Smulders, C. E. M., Spaans, F., Monckton, D. G. <strong>Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients.</strong> Hum. Molec. Genet. 19: 1399-1412, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20080938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20080938</a>] [<a href="https://doi.org/10.1093/hmg/ddq015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20080938">Braida et al. (2010)</a> proposed a cis-acting modifier of mutational dynamics in the 3-prime flanking DNA. The presence of such variant repeats may contribute toward the unusual symptoms in this family and additional symptomatic variation in DM1 via effects on both RNA toxicity and somatic instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20080938" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 a transgenic Dmpk-overexpressor mouse model, <a href="#13" class="mim-tip-reference" title="Groenen, P. J. T. A., Wansink, D. G., Coerwinkel, M., van den Broek, W., Jansen, G., Wieringa, B. <strong>Constitutive and regulated modes of splicing produce six major myotonic dystrophy protein kinase (DMPK) isoforms with distinct properties.</strong> Hum. Molec. Genet. 9: 605-616, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10699184/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10699184</a>] [<a href="https://doi.org/10.1093/hmg/9.4.605" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10699184">Groenen et al. (2000)</a> demonstrated that the endogenous mouse Dmpk gene and the human DMPK transgene produce 6 major alternatively spliced mRNAs which have almost identical cell type-dependent distribution frequencies and expression patterns. They generated all 6 full-length mouse cDNAs that resulted from combinations of 3 major splicing events and showed that their transfection into cultured cells produces 4 different, approximately 74-kD full-length (heart-, skeletal muscle-, or brain-specific) and 2 C-terminally truncated, approximately 68-kD (smooth muscle-specific) isoforms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10699184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Seznec, H., Agbulut, O., Sergeant, N., Savouret, C., Ghestem, A., Tabti, N., Willer, J.-C., Ourth, L., Duros, C., Brisson, E., Fouquet, C., Butler-Browne, G., Delacourte, A., Junien, C., Gourdon, G. <strong>Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities.</strong> Hum. Molec. Genet. 10: 2717-2726, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11726559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11726559</a>] [<a href="https://doi.org/10.1093/hmg/10.23.2717" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11726559">Seznec et al. (2001)</a> demonstrated that transgenic mice carrying the CTG expansion in its human DM context (more than 45 kb) and producing abnormal DMPK mRNA with at least 300 CUG repeats displayed clinical, histologic, molecular, and electrophysiologic abnormalities in skeletal muscle consistent with those observed in DM patients. Like DM patients, these transgenic mice showed abnormal tau expression in the brain. The authors concluded that these data supported an RNA transdominant effect of the CUG expansion, not only in muscle, but also in brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11726559" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#36" class="mim-tip-reference" title="van den Broek, W. J. A. A., Nelen, M. R., Wansink, D. G., Coerwinkel, M. M., te Riele, H., Groenen, P. J. T. A., Wieringa, B. <strong>Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins.</strong> Hum. Molec. Genet. 11: 191-198, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11809728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11809728</a>] [<a href="https://doi.org/10.1093/hmg/11.2.191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11809728">Van den Broek et al. (2002)</a> analyzed cis- and trans-acting parameters that determined repeat behavior in mouse models for DM1. Mice carry 'humanized' Dmpk allele(s) with either a (CTG)84 or a (CTG)11 repeat inserted at the correct position into the endogenous DM locus. Unlike in the human situation, the (CTG)84 repeat in the syntenic mouse environment was relatively stable during intergenerational segregation. However, somatic tissues showed substantial repeat expansions which were progressive upon aging and prominent in kidney, and also in stomach and small intestine, where it was cell-type restricted. Introducing the (CTG)84 allele into an Msh3 (<a href="/entry/600887">600887</a>)-deficient background completely blocked the somatic repeat instability. In contrast, Msh6 (<a href="/entry/600678">600678</a>) deficiency resulted in a significant increase in the frequency of somatic expansions. The authors hypothesized that competition of Msh3 and Msh6 for binding to Msh2 (<a href="/entry/609309">609309</a>) in functional complexes with different DNA mismatch-recognition specificity may explain why the somatic (CTG)n expansion rate is differentially affected by ablation of Msh3 and Msh6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11809728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By crossing transgenic mice with greater than 300 CTG repeat expansions in the DMPK gene with Msh3- and Msh6-deficient mice, <a href="#9" class="mim-tip-reference" title="Foiry, L., Dong, L., Savouret, C., Hubert, L., te Riele, H., Junien, C., Gourdon, G. <strong>Msh3 is a limiting factor in the formation of intergenerational CTG expansions in DM1 transgenic mice.</strong> Hum. Genet. 119: 520-526, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16552576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16552576</a>] [<a href="https://doi.org/10.1007/s00439-006-0164-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16552576">Foiry et al. (2006)</a> demonstrated that Msh3 plays a key role in the formation of expansions over successive generations. Mice with complete absence of Msh3 showed decreased frequency of intergenerational expansions and increased frequency of contractions. The absence of 1 Msh3 allele was sufficient to decrease the formation of expansions, which was more pronounced in maternal transmissions. Similar findings were observed for somatic expansions. In the absence of Msh6, the frequency of expansions decreased only in maternal transmissions, with no obvious changes in somatic instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16552576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Zhang, Y., Monckton, D. G., Siciliano, M. J., Connor, T. H., Meistrich, M. L. <strong>Age and insertion site dependence of repeat number instability of a human DM1 transgene in individual mouse sperm.</strong> Hum. Molec. Genet. 11: 791-798, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929851</a>] [<a href="https://doi.org/10.1093/hmg/11.7.791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11929851">Zhang et al. (2002)</a> used single genome-equivalent PCR of sperm DNA to measure the mutation frequencies in 2 lines of Dmt transgenic mice (Dmt-D and Dmt-E) containing an expanded CTG/CAG tract on an identical genetic background. The authors demonstrated that sperm from 8-week-old Dmt-D mice had a significantly higher mutation frequency (change of more than 1 repeat) (14.2%) than those of Dmt-E mice of the same age (5.5%), in agreement with pedigree analysis. Furthermore, the mutation frequency in sperm of Dmt-D mice increased significantly with age (28.0% at 17 weeks). The age dependence of the degree of expansion implied that mutations may accumulate with time in spermatogenic stem cells. Similar rates of expansion per spermatogenic cycle in man would yield the large expansions observed in human diseases such as myotonic dystrophy type 1. Pedigree data showed a significant age-dependent bias toward repeat contraction in female transmissions and a trend toward expansion with age in male transmissions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11929851" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 expanded (CTG)n tract in the 3-prime UTR of the DMPK gene that causes DM1 results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins, such as MBNL1 (<a href="/entry/606516">606516</a>), in nuclear inclusions. To address the question of whether therapy aimed at eliminating the toxin would be beneficial, <a href="#25" class="mim-tip-reference" title="Mahadevan, M. S., Yadava, R. S., Yu, Q., Balijepalli, S., Frenzel-McCardell, C. D., Bourne, T. D., Phillips, L. H. <strong>Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy.</strong> Nature Genet. 38: 1066-1070, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16878132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16878132</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16878132[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng1857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16878132">Mahadevan et al. (2006)</a> generated transgenic mice expressing the DMPK 3-prime UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). They found that mice overexpressing a normal DMPK 3-prime UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology, and RNA splicing defects in the absence of detectable nuclear inclusions. However, they observed increased levels of CUG-binding protein (CUGBP; <a href="/entry/601074">601074</a>) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represented the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16878132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#35" class="mim-tip-reference" title="Storbeck, C. J., Drmanic, S., Daniel, K., Waring, J. D., Jirik, F. R., Parry, D. J., Ahmed, N., Sabourin, L. A., Ikeda, J, Korneluk, R. G. <strong>Inhibition of myogenesis in transgenic mice expressing the human DMPK 3-prime-UTR.</strong> Hum. Molec. Genet. 13: 589-600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14734627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14734627</a>] [<a href="https://doi.org/10.1093/hmg/ddh064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14734627">Storbeck et al. (2004)</a> found that overexpression of the DMPK 3-prime UTR including either wildtype (11) or expanded (91) CTG repeats resulted in aberrant and delayed muscle development in fetal transgenic mice. Transgenic animals with either expanded or wildtype CTG repeats displayed muscle atrophy at 3 months of age. Primary myoblast cultures from both 11 and 91 repeat mice displayed reduced fusion potential, but a greater reduction was observed in the 91 repeat cultures. <a href="#35" class="mim-tip-reference" title="Storbeck, C. J., Drmanic, S., Daniel, K., Waring, J. D., Jirik, F. R., Parry, D. J., Ahmed, N., Sabourin, L. A., Ikeda, J, Korneluk, R. G. <strong>Inhibition of myogenesis in transgenic mice expressing the human DMPK 3-prime-UTR.</strong> Hum. Molec. Genet. 13: 589-600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14734627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14734627</a>] [<a href="https://doi.org/10.1093/hmg/ddh064" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14734627">Storbeck et al. (2004)</a> concluded that overexpression of the DMPK 3-prime UTR interferes with normal muscle development in mice and that this is exacerbated by inclusion of a mutant repeat. They suggested that the delayed muscle development in DM1 may involve an interplay between the expanded CTG repeat and adjacent 3-prime UTR sequences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14734627" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an aged transgenic murine line carrying approximately 25 extra copies of a complete human DMPK gene (Tg26-hDMPK), <a href="#28" class="mim-tip-reference" title="O'Cochlain, D. F., Perez-Terzic, C., Reyes, S., Kane, G. C., Behfar, A., Hodgson, D. M., Strommen, J. A., Liu, X.-K., van den Broek, W., Wansink, D. G., Wieringa, B., Terzic, A. <strong>Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy.</strong> Hum. Molec. Genet. 13: 2505-2518, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15317754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15317754</a>] [<a href="https://doi.org/10.1093/hmg/ddh266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15317754">O'Cochlain et al. (2004)</a> showed that overexpression of mRNA and protein transgene products in cardiac, skeletal, and smooth muscles resulted in deficient exercise endurance. In contrast to age-matched (11 to 15 months) wildtype controls, hearts from Tg26-hDMPK mice developed cardiomyopathic remodeling with myocardial hypertrophy, myocyte disarray, and interstitial fibrosis. Hypertrophic cardiomyopathy was associated with a propensity for dysrhythmia and characterized by overt intracellular calcium overload promoting nuclear translocation of transcription factors responsible for maladaptive gene reprogramming. Skeletal muscles in distal limbs of Tg26-hDMPK mice showed myopathy with myotonic discharges coupled with deficit in sarcolemmal chloride channels. Fiber degeneration in Tg26-hDMPK mice resulted in sarcomeric disorganization, centralization of nuclei, and tubular aggregation. Moreover, the reduced blood pressure in Tg26-hDMPK mice indicated deficient arterial smooth muscle tone. <a href="#28" class="mim-tip-reference" title="O'Cochlain, D. F., Perez-Terzic, C., Reyes, S., Kane, G. C., Behfar, A., Hodgson, D. M., Strommen, J. A., Liu, X.-K., van den Broek, W., Wansink, D. G., Wieringa, B., Terzic, A. <strong>Transgenic overexpression of human DMPK accumulates into hypertrophic cardiomyopathy, myotonic myopathy and hypotension traits of myotonic dystrophy.</strong> Hum. Molec. Genet. 13: 2505-2518, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15317754/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15317754</a>] [<a href="https://doi.org/10.1093/hmg/ddh266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15317754">O'Cochlain et al. (2004)</a> concluded that proper expression of DMPK is, therefore, mandatory in supporting the integral balance among cytoarchitectural infrastructure, ion homeostasis, and viability control in various muscle cell types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15317754" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Cooper, T. A. <strong>A reversal of misfortune for myotonic dystrophy?</strong> New Eng. J. Med. 355: 1825-1827, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17065646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17065646</a>] [<a href="https://doi.org/10.1056/NEJMcibr064708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17065646">Cooper (2006)</a> discussed the clinical implications of the study of <a href="#19" class="mim-tip-reference" title="Kanadia, R. N., Shin, J., Yuan, Y., Beattie, S. G., Wheeler, T. M., Thorton, C. A., Swanson, M. S. <strong>Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy.</strong> Proc. Nat. Acad. Sci. 103: 11748-11753, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0604970103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864772">Kanadia et al. (2006)</a>. Splicing misregulation in myotonic dystrophy results from altered functions of 2 RNA binding proteins, CUG-binding protein 1 (CUGBP1; <a href="/entry/601074">601074</a>) and muscleblind-like-1 (MBNL1; <a href="/entry/606516">606516</a>), which were identified because they bind CUG repeats in RNA. CUG-BP1 and MBNL1 are direct and antagonistic regulators of alternative splicing events that are normally regulated through development and misregulated in myotonic dystrophy. Several lines of evidence support models in which increased activity of CUG-BP1 and decreased activity of MBNL1 induce 'embryonic pattern' splicing. The fact that MBNL1 colocalizes with nuclear RNA foci in the cells of patients with myotonic dystrophy suggests that MBNL1 is sequestered by mutant RNAs (<a href="#22" class="mim-tip-reference" title="Lin, X., Miller, J. W., Mankodi, A., Kanadia, R. N., Yuan, Y., Moxley, R. T., Swanson, M. S., Thornton, C. A. <strong>Failure of MBNL1-dependent postnatal splicing transitions in myotonic dystrophy.</strong> Hum. Molec. Genet. 15: 2087-2097, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16717059/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16717059</a>] [<a href="https://doi.org/10.1093/hmg/ddl132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16717059">Lin et al., 2006</a>). It follows that splicing abnormalities and associated symptoms due to MBNL sequestration should be reversed by increased expression of MBNL. <a href="#19" class="mim-tip-reference" title="Kanadia, R. N., Shin, J., Yuan, Y., Beattie, S. G., Wheeler, T. M., Thorton, C. A., Swanson, M. S. <strong>Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy.</strong> Proc. Nat. Acad. Sci. 103: 11748-11753, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0604970103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864772">Kanadia et al. (2006)</a> tested this hypothesis by inducing the expression of exogenous MBNL1 in skeletal muscle in a mouse model of myotonic dystrophy-1. These mice, in which a human skeletal actin-alpha transgene is expressed that contains 250 CTG repeats in its 3-prime untranslated region, have myotonia, histologic abnormalities, and embryonic alternative splicing patterns that are characteristic of myotonic dystrophy. Exogenous MBNL1 not only restored ClC-1 and other splicing abnormalities to the adult patterns but also reversed the myotonia. <a href="#7" class="mim-tip-reference" title="Cooper, T. A. <strong>A reversal of misfortune for myotonic dystrophy?</strong> New Eng. J. Med. 355: 1825-1827, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17065646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17065646</a>] [<a href="https://doi.org/10.1056/NEJMcibr064708" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17065646">Cooper (2006)</a> suggested that the results of the study by <a href="#19" class="mim-tip-reference" title="Kanadia, R. N., Shin, J., Yuan, Y., Beattie, S. G., Wheeler, T. M., Thorton, C. A., Swanson, M. S. <strong>Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy.</strong> Proc. Nat. Acad. Sci. 103: 11748-11753, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16864772/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16864772</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16864772[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0604970103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16864772">Kanadia et al. (2006)</a> are relevant to other 'expansion' disorders, such as the fragile X-associated tremor-ataxia syndrome (FXTAS; <a href="/entry/300623">300623</a>), in which a pathogenic mechanism that parallels that of myotonic dystrophy has been suggested (<a href="#30" class="mim-tip-reference" title="Ranum, L. P. W., Cooper, T. A. <strong>RNA-mediated neuromuscular disorders.</strong> Ann. Rev. Neurosci. 29: 259-277, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16776586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16776586</a>] [<a href="https://doi.org/10.1146/annurev.neuro.29.051605.113014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16776586">Ranum and Cooper, 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17065646+16864772+16776586+16717059" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 Mbnl1-deficient Drosophila embryos, <a href="#23" class="mim-tip-reference" title="Machuca-Tzili, L., Thorpe, H., Robinson, T. E., Sewry, C., Brook, J. D. <strong>Flies deficient in muscleblind protein model features of myotonic dystrophy with altered splice forms of Z-band associated transcripts.</strong> Hum. Genet. 120: 487-499, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16927100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16927100</a>] [<a href="https://doi.org/10.1007/s00439-006-0228-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16927100">Machuca-Tzili et al. (2006)</a> found abnormal splicing of the Z-band associated proteins CG30084, which is the Drosophila homolog of ZASP/LDB3 (<a href="/entry/605906">605906</a>), and alpha-actinin. Studies of skeletal muscle tissue from 3 unrelated DM1 patients showed abnormal splicing of LDB3 but normal splicing of alpha-actinin-2 (ACTN2; <a href="/entry/102573">102573</a>). The findings suggested that the molecular breakdown of Z-band structures in flies and DM1 patients involves the MBNL1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16927100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Orengo, J. P., Chambon, P., Metzger, D., Mosier, D. R., Snipes, G. J., Cooper, T. A. <strong>Expanded CTG repeats within the DMPK 3-prime UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy.</strong> Proc. Nat. Acad. Sci. 105: 2646-2651, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272483</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272483[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0708519105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18272483">Orengo et al. (2008)</a> found that transgenic mice with inducible expression of 960 CTG repeats in the Dmpk gene in skeletal muscle showed severe myotonia and muscle wasting. Muscle biopsy showed intranuclear CUG RNA foci with MBNL1 colocalization, misregulation of developmentally regulated alternative splicing, and increased expression of CUGBP1. Compared to other mouse models, the findings suggested a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18272483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<strong>1 Selected Example</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605377[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 MYOTONIC DYSTROPHY 1</strong>
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DMPK, (CTG)n REPEAT EXPANSION, 3-PRIME UTR
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005352" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005352" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005352</a>
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<p>The consistent genetic defect associated with myotonic dystrophy-1 (DM1; <a href="/entry/160900">160900</a>) is an amplified trinucleotide CTG repeat in the 3-prime untranslated region of the serine-threonine kinase gene DMK on 19q. Unaffected individuals have between 5 and 37 copies. DM patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat-containing segment up to several kilobases. The largest repeat sizes are seen in patients with congenital DM. Expansion in the number of tandem repeats between generations is responsible for the phenomenon of anticipation; a reverse phenomenon of contraction or reduced length of the tandem repeats is less frequently observed. The possibility that the repeat expansion may lead to dysfunction of a number of transcription units (genes) in its vicinity, perhaps through chromatin disruption, has been raised as an explanation for the variable phenotype of myotonic dystrophy (<a href="#2" class="mim-tip-reference" title="Boucher, C. A., King, S. K., Carey, N., Krahe, R., Winchester, C. L., Rahman, S., Creavin, T., Meghji, P., Bailey, M. E. S., Chartier, F. L., Brown, S. D., Siciliano, M. J., Johnson, K. J. <strong>A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.</strong> Hum. Molec. Genet. 4: 1919-1925, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595416</a>] [<a href="https://doi.org/10.1093/hmg/4.10.1919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8595416">Boucher et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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Amack, J. D., Mahadevan, M. S.
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<strong>The myotonic dystrophy expanded CUG repeat tract is necessary but not sufficient to disrupt C2C12 myoblast differentiation.</strong>
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Hum. Molec. Genet. 10: 1879-1887, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11555624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11555624</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11555624" 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/10.1093/hmg/10.18.1879" target="_blank">Full Text</a>]
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Boucher, C. A., King, S. K., Carey, N., Krahe, R., Winchester, C. L., Rahman, S., Creavin, T., Meghji, P., Bailey, M. E. S., Chartier, F. L., Brown, S. D., Siciliano, M. J., Johnson, K. J.
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<strong>A novel homeodomain-encoding gene is associated with a large CpG island interrupted by the myotonic dystrophy unstable (CTG)n repeat.</strong>
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Hum. Molec. Genet. 4: 1919-1925, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8595416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8595416</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8595416" 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/10.1093/hmg/4.10.1919" target="_blank">Full Text</a>]
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Braida, C., Stefanatos, R. K. A., Adam, B., Mahajan, N., Smeets, H. J. M., Niel, F., Goizet, C., Arveiler, B., Koenig, M., Lagier-Tourenne, C., Mandel, J.-L., Faber, C. G., de Die-Smulders, C. E. M., Spaans, F., Monckton, D. G.
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<strong>Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients.</strong>
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Hum. Molec. Genet. 19: 1399-1412, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20080938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20080938</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20080938" 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/10.1093/hmg/ddq015" target="_blank">Full Text</a>]
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Carango, P., Noble, J. E., Marks, H. G., Funanage, V. L.
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<strong>Absence of myotonic dystrophy protein kinase (DMPK) mRNA as a result of a triplet repeat expansion in myotonic dystrophy.</strong>
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Genomics 18: 340-348, 1993.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8288237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8288237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8288237" 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/10.1006/geno.1993.1474" target="_blank">Full Text</a>]
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Cavanna, J. S., Greenfield, A. J., Johnson, K. J., Marks, A. R., Nadal-Ginard, B., Brown, S. D. M.
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<strong>Establishment of the mouse chromosome 7 region with homology to the myotonic dystrophy region of human chromosome 19q.</strong>
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Genomics 7: 12-18, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1970795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1970795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1970795" 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/10.1016/0888-7543(90)90513-t" target="_blank">Full Text</a>]
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Cho, D. H., Thienes, C. P., Mahoney, S. E., Analau, E., Filippova, G. N., Tapscott, S. J.
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<strong>Antisense transcription and heterochromatin at the DM1 CTG repeats are constrained by CTCF.</strong>
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Molec. Cell 20: 483-489, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16285929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16285929</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16285929" 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/j.molcel.2005.09.002" target="_blank">Full Text</a>]
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Cooper, T. A.
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<strong>A reversal of misfortune for myotonic dystrophy?</strong>
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New Eng. J. Med. 355: 1825-1827, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17065646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17065646</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17065646" 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/NEJMcibr064708" target="_blank">Full Text</a>]
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Ebralidze, A., Wang, Y., Petkova, V., Ebralidse, K., Junghans, R. P.
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<strong>RNA leaching of transcription factors disrupts transcription in myotonic dystrophy.</strong>
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Science 303: 383-387, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14657503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14657503</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14657503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1088679" target="_blank">Full Text</a>]
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Foiry, L., Dong, L., Savouret, C., Hubert, L., te Riele, H., Junien, C., Gourdon, G.
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<strong>Msh3 is a limiting factor in the formation of intergenerational CTG expansions in DM1 transgenic mice.</strong>
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Hum. Genet. 119: 520-526, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16552576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16552576</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16552576" 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/s00439-006-0164-7" target="_blank">Full Text</a>]
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Frisch, R., Singleton, K. R., Moses, P. A., Gonzalez, I. L., Carango, P., Marks, H. G., Funanage, V. L.
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<strong>Effect of triplet repeat expansion on chromatin structure and expression of DMPK and neighboring genes, SIX5 and DMWD, in myotonic dystrophy.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12897125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12897125</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12897125[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=12897125" 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/10.1128/MCB.23.16.5489-5501.2003" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="43" class="mim-anchor"></a>
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<a id="Wochner1966" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wochner, R. D., Drews, G., Strober, W., Waldmann, T. A.
|
|
<strong>Accelerated breakdown of immunoglobulin G (IgG) in myotonic dystrophy: a hereditary error of immunoglobulin catabolism.</strong>
|
|
J. Clin. Invest. 45: 321-329, 1966.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4159450/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4159450</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=4159450" 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/JCI105346" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="44" class="mim-anchor"></a>
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<a id="Wong1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wong, L.-J. C., Ashizawa, T., Monckton, D. G., Caskey, C. T., Richards, C. S.
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<strong>Somatic heterogeneity of the CTG repeat in myotonic dystrophy is age and size dependent.</strong>
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Am. J. Hum. Genet. 56: 114-122, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7825566/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7825566</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7825566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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<li>
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<a id="45" class="mim-anchor"></a>
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<a id="Yadava2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yadava, R. S., Frenzel-McCardell, C. D., Yu, Q., Srinivasan, V., Tucker, A. L., Puymirat, J., Thornton, C. A., Prall, O. W., Harvey, R. P., Mahadevan, M. S.
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<strong>RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression.</strong>
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Nature Genet. 40: 61-68, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18084293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18084293</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18084293[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=18084293" 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/ng.2007.28" 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="46" class="mim-anchor"></a>
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<a id="Yang2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, Z., Lau, R., Marcadier, J. L., Chitayat, D., Pearson, C. E.
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<strong>Replication inhibitors modulate instability of an expanded trinucleotide repeat at the myotonic dystrophy type 1 disease locus in human cells.</strong>
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Am. J. Hum. Genet. 73: 1092-1105, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574643/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574643</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14574643[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=14574643" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/379523" 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="47" class="mim-anchor"></a>
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<a id="Zhang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y., Monckton, D. G., Siciliano, M. J., Connor, T. H., Meistrich, M. L.
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<strong>Age and insertion site dependence of repeat number instability of a human DM1 transgene in individual mouse sperm.</strong>
|
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Hum. Molec. Genet. 11: 791-798, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11929851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11929851</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11929851" 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/10.1093/hmg/11.7.791" target="_blank">Full Text</a>]
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</p>
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</ol>
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<div>
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<br />
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</div>
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<div>
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<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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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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George E. Tiller - updated : 11/17/2011
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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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George E. Tiller - updated : 11/20/2008<br>Patricia A. Hartz - updated : 8/18/2008<br>Patricia A. Hartz - updated : 6/6/2008<br>Cassandra L. Kniffin - updated : 3/12/2008<br>George E. Tiller - updated : 6/21/2007<br>George E. Tiller - updated : 5/21/2007<br>Cassandra L. Kniffin - updated : 5/14/2007<br>Cassandra L. Kniffin - updated : 12/27/2006<br>Victor A. McKusick - updated : 11/30/2006<br>George E. Tiller - updated : 11/28/2006<br>Victor A. McKusick - updated : 9/27/2006<br>Cassandra L. Kniffin - updated : 7/11/2006<br>Patricia A. Hartz - updated : 2/9/2006<br>Patricia A. Hartz - updated : 1/26/2006<br>Patricia A. Hartz - updated : 1/26/2006<br>Patricia A. Hartz - updated : 12/21/2005<br>Victor A. McKusick - updated : 4/27/2004<br>Ada Hamosh - updated : 2/2/2004<br>Victor A. McKusick - updated : 12/12/2003<br>Patricia A. Hartz - updated : 10/10/2003<br>George E. Tiller - updated : 9/17/2002<br>George E. Tiller - updated : 5/23/2002<br>George E. Tiller - updated : 1/29/2002<br>Victor A. McKusick - updated : 5/11/2001
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh : 10/31/2000
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</span>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 11/08/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/31/2019<br>mcolton : 07/21/2015<br>carol : 11/22/2011<br>terry : 11/17/2011<br>carol : 3/21/2011<br>alopez : 9/4/2009<br>terry : 8/27/2009<br>wwang : 11/20/2008<br>mgross : 8/18/2008<br>mgross : 6/12/2008<br>terry : 6/6/2008<br>wwang : 4/1/2008<br>ckniffin : 3/12/2008<br>terry : 9/18/2007<br>wwang : 6/25/2007<br>terry : 6/21/2007<br>wwang : 6/4/2007<br>terry : 5/21/2007<br>wwang : 5/16/2007<br>ckniffin : 5/14/2007<br>wwang : 12/28/2006<br>ckniffin : 12/27/2006<br>alopez : 12/8/2006<br>terry : 11/30/2006<br>carol : 11/28/2006<br>carol : 11/28/2006<br>alopez : 10/5/2006<br>terry : 9/27/2006<br>carol : 7/21/2006<br>ckniffin : 7/11/2006<br>wwang : 4/26/2006<br>mgross : 2/9/2006<br>mgross : 1/27/2006<br>terry : 1/26/2006<br>terry : 1/26/2006<br>wwang : 1/24/2006<br>wwang : 12/21/2005<br>mgross : 4/14/2005<br>terry : 4/27/2004<br>alopez : 2/2/2004<br>cwells : 12/16/2003<br>terry : 12/12/2003<br>mgross : 10/10/2003<br>mgross : 10/10/2003<br>cwells : 10/29/2002<br>cwells : 9/17/2002<br>cwells : 5/30/2002<br>cwells : 5/23/2002<br>cwells : 2/5/2002<br>cwells : 1/29/2002<br>cwells : 5/31/2001<br>mcapotos : 5/23/2001<br>mcapotos : 5/17/2001<br>mcapotos : 5/17/2001<br>terry : 5/11/2001<br>carol : 11/1/2000<br>carol : 10/31/2000
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605377
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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DYSTROPHIA MYOTONICA PROTEIN KINASE; DMPK
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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DM KINASE; DMK<br />
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DM PROTEIN KINASE<br />
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MYOTONIN-PROTEIN KINASE
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: DMPK</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 77956009;
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</span>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 19q13.32
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:45,769,717-45,782,490 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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19q13.32
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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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Myotonic dystrophy 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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160900
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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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</tbody>
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</table>
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<br />
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
|
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>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>A CTG repeat in DMPK is transcribed and is located in the 3-prime untranslated region (UTR) of an mRNA that is expressed in tissues affected by myotonic dystrophy (DM1; 160900). The polypeptide encoded by this mRNA is a member of the protein kinase family. Since the triplet repeat sequence is within a gene that has a sequence similar to protein kinases, Fu et al. (1992) suggested that the gene be referred to as myotonin-protein kinase. </p><p>Jansen et al. (1992) demonstrated that the brain and heart transcripts of the DM kinase gene are subject to alternative RNA splicing in both human and mouse. The unstable (CTG)5-30 motif is found uniquely in humans, although the flanking nucleotides are also present in mouse. In both species another active gene, called DMRN9 (DMWD; 609857), was found in close proximity to the DM kinase gene. DMRN9 transcripts, mainly expressed in brain and testis, possess a single large open reading frame. Jansen et al. (1992) suggested that clinical manifestations of myotonic dystrophy may be caused by the expanded CTG repeat compromising the alternative expression of DM kinase or DMRN9 proteins. </p><p>The involvement of a protein kinase in myotonic dystrophy is consistent with the pivotal role of such enzymes in a wide range of biochemical and cellular pathways, and was indeed predicted by Roses and Appel (1974). Shaw et al. (1993) demonstrated that the DMK gene encodes a protein of 624 amino acids with an N-terminal domain highly homologous to cAMP-dependent serine-threonine protein kinases, an intermediate domain with a high alpha-helical content and weak similarity to various filamentous proteins, and a hydrophobic C-terminal segment. They also isolated a second gene, located very close to DMK and homologous to the mouse gene Dmrn9 (Jansen et al., 1992). Strong expression of the latter gene in brain suggested that it may play a role in mental symptoms in severe cases of myotonic dystrophy. </p><p>Mahadevan et al. (1993) presented the genomic sequences of the human and murine DM kinase gene. They predicted a translation initiation codon and determined the organization of the gene. Several polymorphisms were identified within the human gene, and PCR assays to detect 2 of these were described. </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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<h4>
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<strong>Gene Structure</strong>
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<p>Fu et al. (1993) determined the genomic sequence of the gene that they referred to as myotonin-protein kinase (Mt-PK). In a length of 11,612 bp, the Mt-PK gene contained a minimum of 14 exons. Several forms of alternatively spliced mRNA were demonstrated. </p><p>Shaw et al. (1993) determined that the DMK gene contains 15 exons distributed over about 13 kb of genomic DNA on chromosome 19q. </p>
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<strong>Gene Function</strong>
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<p>Using antisera developed against synthetic DMPK peptide antigens for biochemical and histochemical studies, van der Ven et al. (1993) found lower levels of immunoreactive DM kinase protein of 53 kD in skeletal and cardiac muscle extracts of myotonic dystrophy (DM1; 160900) patients than in normal controls. Immunohistochemical staining revealed that DMPK is localized predominantly at sites of neuromuscular and myotendinous junctions of human and rodent skeletal muscles. The protein could also be demonstrated in the neuromuscular junctions of muscular tissues of adult and congenital cases of DM, with no gross changes in structural organization. </p><p>Because nuclear histones are known to mediate general transcriptional repression along chromosomes, Wang et al. (1994) used electron microscopy to examine in vitro the nucleosome assembly of DNA containing repeating CTG triplets. The efficiency of nucleosome formation increased with expanded triplet blocks, suggesting that such blocks may repress transcription through the creation of hyperstable nucleosomes. These may alter the local chromatin structure, inhibit the passage of transcription complexes, or prevent the opening of the DNA before replication. They may also result in DNA polymerase slippage, pausing, or idling, leading to expansion of the triplet block (Wang et al., 1994). Wang and Griffith (1995) performed competitive nucleosome reconstitution to measure the energetics of nucleosome formation over CTG repeat blocks of n = 75 and n = 130. They showed that these DNA fragments are 6 and 9 times stronger in nucleosome formation, respectively, than the 5S RNA gene of Xenopus borealis, one of the strongest known natural nucleosome positioning elements. These observations give further support to the previously stated hypothesis that expanded CTG blocks may alter local chromatin structure. </p><p>Junghans et al. (2001) hypothesized that the diversity of phenotype in myotonic dystrophy may be due to the fact that the DM CTG repeat induces long-range cis chromosomal effects that suppress diverse genes on chromosome 19, resulting in manifest multisystem abnormalities in the clinical disorder. One of the features discussed in detail was hypercatabolism of immunoglobulin G in myotonic dystrophy and the possible significance of the FCGRT gene (601437) to the DM locus. A functional linkage between the FCGRT and DM genes was known long before the map location of either had been identified. Wochner et al. (1966) found that the mean survival time of IgG in DM was 11 +/- 4 days versus 23 +/- 4 days in controls, corresponding to lower mean IgG levels. IgG synthesis rates were the same for both groups. Junghans et al. (2001) estimated that cis inactivation of the 1 allele of the FCGRT gene would result in an approximately 50% reduction in IgG protection, which was consistent with the observation of a 58% reduction. As reviewed by Junghans et al. (2001), plasma protein catabolism occurs in vascular endothelium by endocytotic processing of plasma contents. Vascular endothelium is the most active endocytic tissue in the body and as a result the principal site for plasma protein catabolism. Plasma proteins diffusing or transported into extravascular sites are isolated from catabolism while extravascular. The so-called Brambell receptor, alternatively termed protection receptor or neonatal receptor, is located in endosomes of vascular endothelial cells and selectively recycles IgG to the cell surface, thus protecting IgG from lysosomal catabolism that is the fate of other, unprotected plasma proteins. In mice with knockout of the Fcgrt gene, the fractional catabolic rate for IgG may be accelerated up to 10-fold relative to wildtype animals in which protection is intact (Junghans and Anderson, 1996). This protection mechanism is directly responsible for making IgG the longest lived of all plasma proteins (Waldmann and Strober, 1969). </p><p>Using several synthetic peptide substrates, Wansink et al. (2003) characterized the substrate requirements of mouse Dmpk. Dmpk phosphorylated threonine residues more efficiently than serine, and activity increased with positively charged amino acids, preferably arginine, at positions -1 to -3. A VSGGG motif in the kinase C-terminal domain modulated both Dmpk autophosphorylation activity and protein conformation, and alternatively spliced elements in the C terminus regulated substrate specificity and intracellular localization. Proteins with a hydrophobic C terminus targeted to the endoplasmic reticulum, while those with a more hydrophilic C terminus bound to the mitochondrial outer membrane, and those with a short C-terminal tail adopted a cytosolic location. </p><p>The CTG repeats associated with DM1 are a component of a CTCF (604167)-dependent insulator element, and repeat expansion results in conversion of the region to heterochromatin. Cho et al. (2005) showed that the wildtype DM1 insulator is associated with bidirectional transcription, antisense transcripts that emanate from the adjacent SIX5 regulatory region and are converted into 21-nucleotide RNA fragments, H3-K9 dimethylation and H3-K4 trimethylation, and HP1-gamma (CBX3; 604477) recruitment in the region of the CTG repeats. They found that expansion of the CTG repeat in DM1 is associated with reduced or absent CTCF binding, spread of heterochromatin, and regional CpG methylation. </p>
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<strong>Mapping</strong>
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<p>Cavanna et al. (1990) established the region of mouse chromosome 7 homologous to the myotonic dystrophy region of human chromosome 19q. Using fluorescence in situ hybridization, Jansen et al. (1993) confirmed that the DM-kinase gene is proximal to the Apoe gene on mouse chromosome 7, close to an imprinted segment. No evidence of imprinting could be found in either human or mouse tissues, however. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Mooers et al. (2005) determined the crystal structure of an 18-bp RNA containing 6 CUG repeats to 1.58-angstrom resolution. The CUG repeats formed antiparallel double-stranded helices that stacked end on end in the crystal to form infinite, pseudocontinuous helices similar to the long CUG stem loops formed by the expanded CUG repeats in DM1. The CUG helix was similar in structure to A-form RNA with the exception of the unique U-U mismatches. </p>
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<strong>Molecular Genetics</strong>
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<p>To determine the effect of the CTG repeat on DM expression, Carango et al. (1993) separated the chromosome 19 homologs from a 36-year-old woman with DM into different cell lines by somatic cell hybridization. RT-PCR amplification of coding sequences from the DM gene showed both reduced levels of primary DM transcripts and impaired processing of these transcripts in the mutant cell line. These findings suggested that the presence of a large number of repeats in the 3-prime untranslated region of the DM gene reduces both the synthesis and the processing of DM mRNA, resulting in undetectable levels of processed DM mRNA from the mutant allele. </p><p>Using RT-PCR, Krahe et al. (1995) found that equal levels of unprocessed DMPK pre-mRNA were produced by the wildtype and DM alleles in skeletal muscle and cell lines of heterozygous DM patients. In contrast, processed mRNA levels from the DM allele were reduced relative to the wildtype allele as the size of the expansion increased. Krahe et al. (1995) concluded that the unstable repeat impairs posttranscriptional processing of DM allele transcripts. </p><p>Wong et al. (1995) demonstrated that the expanded CTG allele, which often presents as a diffused band on Southern blot analysis, suggesting somatic mutation, shows size heterogeneity that correlates well with the age of the patients. In their study, older patients showed larger size variation. This correlation was independent of the sex of either the patient or the transmitting parent. Similar size heterogeneity was not observed in congenital cases, regardless of the size of expansion. It can be speculated that continuous expansion of the CTG repeats is related to the pathogenesis of the disease, particularly the progression of the disease with age. </p><p>The dominant inheritance of myotonic dystrophy was difficult to reconcile with the fact that the expansion mutation lies outside the protein-encoding elements of the gene and should not be translated into protein. Wang et al. (1995) used muscle biopsies from classic adult-onset myotonic dystrophy patients to study the accumulation of transcripts from both the normal and the expanded DM kinase genes and compared the results to normal and myopathic controls. They found relatively small decreases of DM kinase RNA in the total RNA pool from muscle; however, these reductions were not disease-specific. Analysis of poly(A)+ RNA showed dramatic decreases in both the mutant and the normal DM kinase RNAs, and these changes were disease-specific. Wang et al. (1995) considered these findings consistent with a novel molecular pathogenetic mechanism for myotonic dystrophy in which both the normal and expanded DM kinase genes are transcribed in patient's muscle, but the abnormal expansion-containing RNA has a dominant-negative effect on RNA metabolism by preventing the accumulation of poly(A)+ RNA. The ability of the expansion mutation to alter accumulation of poly(A)+ RNA in trans suggested that myotonic dystrophy may be the first example of a dominant-negative mutation manifested at the RNA level. </p><p>Amack and Mahadevan (2001) showed that DMPK transcripts containing expanded CUG tracts can form both nuclear and cytoplasmic RNA foci. However, transcripts containing neither a CUG expansion alone nor a CUG expansion plus the distal region of the DMPK 3-prime untranslated region RNA affected myogenesis in C2C12 myoblasts. This implies that RNA foci formation and perturbation of any RNA binding factors involved in this process are not sufficient to block myoblast differentiation. RNA analysis of myogenic markers revealed that mutant DMPK 3-prime untranslated region mRNA significantly impeded upregulation of the differentiation factors myogenin (159980) and p21 (116899). </p><p>Using RT-PCR, Frisch et al. (2001) found a marked reduction of DMPK mRNA expression from chromosomes carrying expanded DMPK alleles. Most of the DMPK transcripts expressed from the expanded alleles lacked exons 13 and 14, whereas full-length transcripts were expressed predominantly from the normal alleles. Frisch et al. (2001) suggested that the CTG repeat expansion leads to a decrease in DMPK mRNA by affecting splicing at the 3-prime end of the DMPK pre-mRNA transcript. They also used RT-PCR to test the hypothesis that DMPK expansion alters expression of its neighboring genes, DMWD and SIX5 (600963). Frisch et al. (2001) found that DMPK expansion had no effect on DMWD expression, but it did reduce SIX5 expression in congenital DM. </p><p>Yang et al. (2003) studied a fibroblast cell line from the skin of a 22.5-week fetus with DM1 and demonstrated that CTG expansions occurred only in proliferating cells and that agents that affect DNA synthesis but not replication initiation can specifically modulate the instability of the expanded DM1 CTG repeat. </p><p>Ebralidze et al. (2004) showed that DMPK mutant RNA binds and sequesters transcription factors, with up to 90% depletion of selected transcription factors from active chromatin. Diverse genes are consequently reduced in expression, including the ion transporter CLC1 (118425), which had been implicated in myotonia. When transcription factor specificity protein-1 (SP1; 189906) was overexpressed in DM1-affected cells, low levels of mRNA for CLC1 were restored to normal. The authors concluded that transcription factor leaching from chromatin by mutant RNA provides a potentially unifying pathomechanistic explanation for this disease. </p><p>Jiang et al. (2004) found that in postmortem DM1 brain tissue, mutant DMPK transcripts were widely expressed in cortical and subcortical neurons. The mutant transcripts accumulated in discrete foci within neuronal nuclei. Proteins in the muscleblind (see MBNL1; 606516) family were recruited into the RNA foci and depleted elsewhere in the nucleoplasm. In parallel, a subset of neuronal pre-mRNAs showed abnormal regulation of alternative splicing. The authors suggested that CNS impairment in DM1 may result from a deleterious gain of function by mutant DMPK mRNA. </p><p>Ranum and Day (2004) reviewed the mechanism by which the CTG expansion in the 3-prime untranslated region of the DM1 gene causes myotonic dystrophy. The discovery that type 2 myotonic dystrophy (DM2; 602668) is caused by an untranslated CCTG expansion indicated that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. </p><p>Kimura et al. (2005) investigated the alternative splicing of mRNAs of 2 major proteins of the sarcoplasmic reticulum, the ryanodine receptor-1 (RYR1; 180901) and sarcoplasmic/endoplasmic reticulum Ca(2+)-transporting ATPases SERCA1 (ATP2A1; 108730) or SERCA2 (ATP2A2; 108740), in skeletal muscle from DM1 patients. The fetal variants, ASI(-) of RYR1, which lacks residues 3481 to 3485, and SERCA1b, which differs at the C-terminal end, were significantly increased in DM1 skeletal muscle and the transgenic mouse model of DM1 (HAS-LR). In addition, a novel variant of SERCA2 was significantly decreased in DM1 patients. The total amount of mRNA for RYR1, SERCA1, and SERCA2 in DM1 and the expression levels of their proteins in HAS-LR mice were not significantly different. However, heterologous expression of ASI(-) in cultured cells showed decreased affinity for ryanodine but similar calcium dependency, and decreased channel activity in single-channel recording when compared with wildtype RYR1. In support of this, RYR1-knockout myotubes expressing ASI(-) exhibited a decreased incidence of calcium oscillations during caffeine exposure compared with that observed for myotubes expressing wildtype RYR1. Kimura et al. (2005) suggested that aberrant splicing of RYR1 and SERCA1 mRNAs may contribute to impaired calcium homeostasis in DM1 muscle. </p><p>Using a reversible transgenic mouse model of RNA toxicity in DM1, Yadava et al. (2008) showed that overexpression of a normal human DMPK 3-prime UTR with only (CUG)5 resulted in cardiac conduction defects, increased expression of the cardiac-specific transcription factor Nkx2.5 (NKX2E; 600584), and profound disturbances in connexin-40 (GJA5; 121013) and connexin-43 (GJA1; 121014). Overexpression of the DMPK 3-prime UTR in mouse skeletal muscle also induced transcriptional activation of Nkx2.5 and its targets. Human DM1 muscle, but not normal human muscle, showed similar aberrant expression of NKX2.5 and its targets. In mice, the effects on Nkx2.5 and its targets were reversed by silencing toxic RNA expression. Furthermore, haploinsufficiency of Nkx2.5 in Nkx2.5 +/- mice had a cardioprotective effect against defects induced by DMPK 3-prime UTR. Yadava et al. (2008) concluded that NKX2.5 is a modifier of DM1-associated RNA toxicity in heart. </p><p>Medica et al. (2007) found that 4 (1.46%) of 274 unrelated patients with cataract, but no evidence or family history of DM1, carried a 'protomutation' in the DMPK gene ranging between 52 and 81 CTG repeats. The authors hypothesized that these patients with protomutations represented a source of full expansion mutation, which could be responsible for maintaining DM1 mutations in a population. Stable transmission to offspring was observed in 1 individual with a protomutation. Three of the patients were from the Croatian region of Istria, which has a high prevalence of DM1. </p><p>Braida et al. (2010) reported an unusual Dutch family cosegregating DM1, Charcot-Marie-Tooth neuropathy, encephalopathic attacks, and early hearing loss that carried a complex variant repeat at the DM1 locus. The mutation comprised an expanded CTG tract at the 5-prime end and a complex array of CTG repeats interspersed with multiple GGC and CCG repeats at the 3-prime end. The complex variant repeat tract at the 3-prime end of the array was relatively stable in both blood DNA and the maternal germline, although the 5-prime CTG tract remained genetically unstable and prone to expansion. Complex variant repeats were also identified at the 3-prime end of the CTG array of approximately 3 to 4% of unrelated DM1 patients. Braida et al. (2010) proposed a cis-acting modifier of mutational dynamics in the 3-prime flanking DNA. The presence of such variant repeats may contribute toward the unusual symptoms in this family and additional symptomatic variation in DM1 via effects on both RNA toxicity and somatic instability. </p>
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<strong>Animal Model</strong>
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<p>Using a transgenic Dmpk-overexpressor mouse model, Groenen et al. (2000) demonstrated that the endogenous mouse Dmpk gene and the human DMPK transgene produce 6 major alternatively spliced mRNAs which have almost identical cell type-dependent distribution frequencies and expression patterns. They generated all 6 full-length mouse cDNAs that resulted from combinations of 3 major splicing events and showed that their transfection into cultured cells produces 4 different, approximately 74-kD full-length (heart-, skeletal muscle-, or brain-specific) and 2 C-terminally truncated, approximately 68-kD (smooth muscle-specific) isoforms. </p><p>Seznec et al. (2001) demonstrated that transgenic mice carrying the CTG expansion in its human DM context (more than 45 kb) and producing abnormal DMPK mRNA with at least 300 CUG repeats displayed clinical, histologic, molecular, and electrophysiologic abnormalities in skeletal muscle consistent with those observed in DM patients. Like DM patients, these transgenic mice showed abnormal tau expression in the brain. The authors concluded that these data supported an RNA transdominant effect of the CUG expansion, not only in muscle, but also in brain. </p><p>Van den Broek et al. (2002) analyzed cis- and trans-acting parameters that determined repeat behavior in mouse models for DM1. Mice carry 'humanized' Dmpk allele(s) with either a (CTG)84 or a (CTG)11 repeat inserted at the correct position into the endogenous DM locus. Unlike in the human situation, the (CTG)84 repeat in the syntenic mouse environment was relatively stable during intergenerational segregation. However, somatic tissues showed substantial repeat expansions which were progressive upon aging and prominent in kidney, and also in stomach and small intestine, where it was cell-type restricted. Introducing the (CTG)84 allele into an Msh3 (600887)-deficient background completely blocked the somatic repeat instability. In contrast, Msh6 (600678) deficiency resulted in a significant increase in the frequency of somatic expansions. The authors hypothesized that competition of Msh3 and Msh6 for binding to Msh2 (609309) in functional complexes with different DNA mismatch-recognition specificity may explain why the somatic (CTG)n expansion rate is differentially affected by ablation of Msh3 and Msh6. </p><p>By crossing transgenic mice with greater than 300 CTG repeat expansions in the DMPK gene with Msh3- and Msh6-deficient mice, Foiry et al. (2006) demonstrated that Msh3 plays a key role in the formation of expansions over successive generations. Mice with complete absence of Msh3 showed decreased frequency of intergenerational expansions and increased frequency of contractions. The absence of 1 Msh3 allele was sufficient to decrease the formation of expansions, which was more pronounced in maternal transmissions. Similar findings were observed for somatic expansions. In the absence of Msh6, the frequency of expansions decreased only in maternal transmissions, with no obvious changes in somatic instability. </p><p>Zhang et al. (2002) used single genome-equivalent PCR of sperm DNA to measure the mutation frequencies in 2 lines of Dmt transgenic mice (Dmt-D and Dmt-E) containing an expanded CTG/CAG tract on an identical genetic background. The authors demonstrated that sperm from 8-week-old Dmt-D mice had a significantly higher mutation frequency (change of more than 1 repeat) (14.2%) than those of Dmt-E mice of the same age (5.5%), in agreement with pedigree analysis. Furthermore, the mutation frequency in sperm of Dmt-D mice increased significantly with age (28.0% at 17 weeks). The age dependence of the degree of expansion implied that mutations may accumulate with time in spermatogenic stem cells. Similar rates of expansion per spermatogenic cycle in man would yield the large expansions observed in human diseases such as myotonic dystrophy type 1. Pedigree data showed a significant age-dependent bias toward repeat contraction in female transmissions and a trend toward expansion with age in male transmissions. </p><p>The expanded (CTG)n tract in the 3-prime UTR of the DMPK gene that causes DM1 results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNA-binding proteins, such as MBNL1 (606516), in nuclear inclusions. To address the question of whether therapy aimed at eliminating the toxin would be beneficial, Mahadevan et al. (2006) generated transgenic mice expressing the DMPK 3-prime UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). They found that mice overexpressing a normal DMPK 3-prime UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology, and RNA splicing defects in the absence of detectable nuclear inclusions. However, they observed increased levels of CUG-binding protein (CUGBP; 601074) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represented the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules. </p><p>Storbeck et al. (2004) found that overexpression of the DMPK 3-prime UTR including either wildtype (11) or expanded (91) CTG repeats resulted in aberrant and delayed muscle development in fetal transgenic mice. Transgenic animals with either expanded or wildtype CTG repeats displayed muscle atrophy at 3 months of age. Primary myoblast cultures from both 11 and 91 repeat mice displayed reduced fusion potential, but a greater reduction was observed in the 91 repeat cultures. Storbeck et al. (2004) concluded that overexpression of the DMPK 3-prime UTR interferes with normal muscle development in mice and that this is exacerbated by inclusion of a mutant repeat. They suggested that the delayed muscle development in DM1 may involve an interplay between the expanded CTG repeat and adjacent 3-prime UTR sequences. </p><p>In an aged transgenic murine line carrying approximately 25 extra copies of a complete human DMPK gene (Tg26-hDMPK), O'Cochlain et al. (2004) showed that overexpression of mRNA and protein transgene products in cardiac, skeletal, and smooth muscles resulted in deficient exercise endurance. In contrast to age-matched (11 to 15 months) wildtype controls, hearts from Tg26-hDMPK mice developed cardiomyopathic remodeling with myocardial hypertrophy, myocyte disarray, and interstitial fibrosis. Hypertrophic cardiomyopathy was associated with a propensity for dysrhythmia and characterized by overt intracellular calcium overload promoting nuclear translocation of transcription factors responsible for maladaptive gene reprogramming. Skeletal muscles in distal limbs of Tg26-hDMPK mice showed myopathy with myotonic discharges coupled with deficit in sarcolemmal chloride channels. Fiber degeneration in Tg26-hDMPK mice resulted in sarcomeric disorganization, centralization of nuclei, and tubular aggregation. Moreover, the reduced blood pressure in Tg26-hDMPK mice indicated deficient arterial smooth muscle tone. O'Cochlain et al. (2004) concluded that proper expression of DMPK is, therefore, mandatory in supporting the integral balance among cytoarchitectural infrastructure, ion homeostasis, and viability control in various muscle cell types. </p><p>Cooper (2006) discussed the clinical implications of the study of Kanadia et al. (2006). Splicing misregulation in myotonic dystrophy results from altered functions of 2 RNA binding proteins, CUG-binding protein 1 (CUGBP1; 601074) and muscleblind-like-1 (MBNL1; 606516), which were identified because they bind CUG repeats in RNA. CUG-BP1 and MBNL1 are direct and antagonistic regulators of alternative splicing events that are normally regulated through development and misregulated in myotonic dystrophy. Several lines of evidence support models in which increased activity of CUG-BP1 and decreased activity of MBNL1 induce 'embryonic pattern' splicing. The fact that MBNL1 colocalizes with nuclear RNA foci in the cells of patients with myotonic dystrophy suggests that MBNL1 is sequestered by mutant RNAs (Lin et al., 2006). It follows that splicing abnormalities and associated symptoms due to MBNL sequestration should be reversed by increased expression of MBNL. Kanadia et al. (2006) tested this hypothesis by inducing the expression of exogenous MBNL1 in skeletal muscle in a mouse model of myotonic dystrophy-1. These mice, in which a human skeletal actin-alpha transgene is expressed that contains 250 CTG repeats in its 3-prime untranslated region, have myotonia, histologic abnormalities, and embryonic alternative splicing patterns that are characteristic of myotonic dystrophy. Exogenous MBNL1 not only restored ClC-1 and other splicing abnormalities to the adult patterns but also reversed the myotonia. Cooper (2006) suggested that the results of the study by Kanadia et al. (2006) are relevant to other 'expansion' disorders, such as the fragile X-associated tremor-ataxia syndrome (FXTAS; 300623), in which a pathogenic mechanism that parallels that of myotonic dystrophy has been suggested (Ranum and Cooper, 2006). </p><p>In Mbnl1-deficient Drosophila embryos, Machuca-Tzili et al. (2006) found abnormal splicing of the Z-band associated proteins CG30084, which is the Drosophila homolog of ZASP/LDB3 (605906), and alpha-actinin. Studies of skeletal muscle tissue from 3 unrelated DM1 patients showed abnormal splicing of LDB3 but normal splicing of alpha-actinin-2 (ACTN2; 102573). The findings suggested that the molecular breakdown of Z-band structures in flies and DM1 patients involves the MBNL1 gene. </p><p>Orengo et al. (2008) found that transgenic mice with inducible expression of 960 CTG repeats in the Dmpk gene in skeletal muscle showed severe myotonia and muscle wasting. Muscle biopsy showed intranuclear CUG RNA foci with MBNL1 colocalization, misregulation of developmentally regulated alternative splicing, and increased expression of CUGBP1. Compared to other mouse models, the findings suggested a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>1 Selected Example):</strong>
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<strong>.0001 MYOTONIC DYSTROPHY 1</strong>
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DMPK, (CTG)n REPEAT EXPANSION, 3-PRIME UTR
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ClinVar: RCV000005352
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<p>The consistent genetic defect associated with myotonic dystrophy-1 (DM1; 160900) is an amplified trinucleotide CTG repeat in the 3-prime untranslated region of the serine-threonine kinase gene DMK on 19q. Unaffected individuals have between 5 and 37 copies. DM patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat-containing segment up to several kilobases. The largest repeat sizes are seen in patients with congenital DM. Expansion in the number of tandem repeats between generations is responsible for the phenomenon of anticipation; a reverse phenomenon of contraction or reduced length of the tandem repeats is less frequently observed. The possibility that the repeat expansion may lead to dysfunction of a number of transcription units (genes) in its vicinity, perhaps through chromatin disruption, has been raised as an explanation for the variable phenotype of myotonic dystrophy (Boucher et al., 1995). </p>
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