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Entry
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- *606936 - TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 4; TRPM4
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- OMIM
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<p>
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<span class="h4">*606936</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<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/606936">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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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<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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<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=ENSG00000130529;t=ENST00000252826" 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=54795" 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=606936" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000130529;t=ENST00000252826" 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_001195227,NM_001321281,NM_001321282,NM_001321283,NM_001321285,NM_017636,XM_047438992,XM_047438993" 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_017636" 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=606936" 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=09502&isoform_id=09502_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/TRPM4" 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/7019879,15593777,15617229,20269879,21314671,31335331,31335333,31335335,32487284,74715868,119572845,119572846,119572847,119572848,124376862,158259185,194381366,304766677,1007892868,1007892870,1007892872,1007892874,2217321750,2217321752,2462565994" 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/Q8TD43" 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=54795" 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=ENSG00000130529;t=ENST00000252826" 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=TRPM4" 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=TRPM4" 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+54795" 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/TRPM4" 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:54795" 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/54795" 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=ENST00000252826.10&hgg_start=49157792&hgg_end=49211836&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:17993" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/trpm4" 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=606936[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=606936[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000130529" 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=TRPM4" 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=TRPM4" 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=TRPM4" 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=TRPM4&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/PA38272" 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:17993" 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:1915917" 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/TRPM4#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:1915917" 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/54795/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=54795" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-061214-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:54795" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=TRPM4&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> 698250005<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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606936
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 4; TRPM4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TRPM4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TRPM4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/19/936?start=-3&limit=10&highlight=936">19q13.33</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:49157792-49211836&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'})">19:49,157,792-49,211,836</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
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<a href="/clinicalSynopsis/table?mimNumber=618531,604559" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
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</th>
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<th>
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Phenotype <br /> MIM number
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</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="2">
|
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<span class="mim-font">
|
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<a href="/geneMap/19/936?start=-3&limit=10&highlight=936">
|
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19q13.33
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Erythrokeratodermia variabilis et progressiva 6
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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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<a href="/entry/618531"> 618531 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
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Progressive familial heart block, type IB
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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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<a href="/entry/604559"> 604559 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606936" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606936" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<p>TRPM4 belongs to the melastatin (TRPM1; <a href="/entry/603576">603576</a>)-related transient receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N and C termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain. TRPM4 is a mediator of pressure-induced membrane depolarization and arterial constriction (review by <a href="#3" class="mim-tip-reference" title="Farooqi, A. A., Javeed, M. K., Javed, Z., Riaz, A. M., Mukhtar, S., Minhaj, S., Abbas, S., Bhatti, S. <strong>TRPM channels: same ballpark, different players, and different rules in immunogenetics.</strong> Immunogenetics 63: 773-787, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21932052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21932052</a>] [<a href="https://doi.org/10.1007/s00251-011-0570-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21932052">Farooqi et al., 2011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21932052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By searching an EST database and screening brain, testis, and placenta cDNA libraries, <a href="#17" class="mim-tip-reference" title="Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C. <strong>Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.</strong> Proc. Nat. Acad. Sci. 98: 10692-10697, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535825[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.191360198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11535825">Xu et al. (2001)</a> obtained a cDNA encoding TRPM4. The predicted TRPM4 protein has 1,040 amino acids and contains 6 putative transmembrane domains. Northern blot analysis detected TRPM4 expression in most adult tissues tested, with highest levels in heart, prostate, and colon. In fetus, TRPM4 expression was most abundant in kidney. There were at least 2 distinct bands detected (6.2 and 4.2 kb), indicating alternative splicing of TRPM4. In addition, a smaller but relatively abundant 2.4-kb transcript was detected in testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11535825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Launay, P., Fleig, A., Perraud, A.-L., Scharenberg, A. M., Penner, R., Kinet, J.-P. <strong>TRPM4 is a Ca(2+)-activated nonselective cation channel mediating cell membrane depolarization.</strong> Cell 109: 397-407, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015988</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00719-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015988">Launay et al. (2002)</a> cloned and characterized a second form of TRPM4. The predicted 1,214-amino acid protein is nearly identical to the protein reported by <a href="#17" class="mim-tip-reference" title="Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C. <strong>Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.</strong> Proc. Nat. Acad. Sci. 98: 10692-10697, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535825[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.191360198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11535825">Xu et al. (2001)</a>, except that it includes an additional 174 amino acids N-terminal to the predicted start of that protein. The shorter protein results from alternative splicing, with the third and fourth exons being spliced out and the beginning of the first exon being truncated. As a consequence, the first in-frame methionine lies in the fifth exon, resulting in the deletion of the first 174 amino acids. <a href="#9" class="mim-tip-reference" title="Launay, P., Fleig, A., Perraud, A.-L., Scharenberg, A. M., Penner, R., Kinet, J.-P. <strong>TRPM4 is a Ca(2+)-activated nonselective cation channel mediating cell membrane depolarization.</strong> Cell 109: 397-407, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015988</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00719-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015988">Launay et al. (2002)</a> proposed that the shorter protein be designated TRPM4a and the longer protein be designated TRPM4b. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11535825+12015988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Kruse, M., Schulze-Bahr, E., Corfield, V., Beckmann, A., Stallmeyer, B., Kurtbay, G., Ohmert, I., Schulze-Bahr, E., Brink, P., Pongs, O. <strong>Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.</strong> J. Clin. Invest. 119: 2737-2744, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI38292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726882">Kruse et al. (2009)</a> performed quantitative analysis of TRPM4 mRNA content in human cardiac tissue and found the highest expression level in Purkinje fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19726882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 immunohistochemistry on sections of bovine hearts, <a href="#10" class="mim-tip-reference" title="Liu, H., El Zein, L., Kruse, M., Guinamard, R., Beckmann, A., Bozio, A., Kurtbay, G., Megarbane, A., Ohmert, I., Blaysat, G., Villain, E., Pongs, O., Bouvagnet, P. <strong>Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.</strong> Circ. Cardiovasc. Genet. 3: 374-385, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562447</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.109.930867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20562447">Liu et al. (2010)</a> demonstrated that TRPM4 channel signal level is higher in atrial cardiomyocytes than in ventricular cells, but is highest in Purkinje fibers. Small bundles of highly TRPM4-positive cells were found in the subendocardium and in rare intramural bundles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20562447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 RT-PCR, <a href="#14" class="mim-tip-reference" title="Wang, H., Xu, Z., Lee, B. H., Vu, S., Hu, L., Lee, M., Bu, D., Cao, X., Hwang, S., Yang, Y., Zheng, J., Lin, Z. <strong>Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia.</strong> J. Invest. Derm. 139: 1089-1097, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30528822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30528822</a>] [<a href="https://doi.org/10.1016/j.jid.2018.10.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30528822">Wang et al. (2019)</a> detected TRPM4 mRNA expression in the epidermis from normal dorsal foot skin and in the human epidermal keratinocyte cell line HaCaT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30528822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#15" class="mim-tip-reference" title="Winkler, P. A., Huang, Y., Sun, W., Du, J., Lu, W. <strong>Electron cryo-microscopy structure of a human TRPM4 channel.</strong> Nature 552: 200-204, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29211723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29211723</a>] [<a href="https://doi.org/10.1038/nature24674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29211723">Winkler et al. (2017)</a> reported the electron cryomicroscopy structure of the most widespread human Ca2(+)-activated, nonselective (CAN) channel, TRPM4, bound to the agonist Ca(2+) and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the 'pole' and 4 helical 'ribs' spanning the N-terminal TRPM homology regions (MHRs), thus holding 4 subunits in a crown-like architecture. <a href="#15" class="mim-tip-reference" title="Winkler, P. A., Huang, Y., Sun, W., Du, J., Lu, W. <strong>Electron cryo-microscopy structure of a human TRPM4 channel.</strong> Nature 552: 200-204, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29211723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29211723</a>] [<a href="https://doi.org/10.1038/nature24674" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29211723">Winkler et al. (2017)</a> observed 2 decavanadate-binding sites, 1 in the C-terminal domain and another in the intersubunit TRPM homology region interface. A glutamine in the selectivity filter may be an important determinant of monovalent selectivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29211723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Guo, J., She, J., Zeng, W., Chen, Q., Bai, X., Jiang, Y. <strong>Structures of the calcium-activated, non-selective cation channel TRPM4.</strong> Nature 552: 205-209, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29211714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29211714</a>] [<a href="https://doi.org/10.1038/nature24997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29211714">Guo et al. (2017)</a> presented the electron cryomicroscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a 3-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is permeable only to monovalent cations; filter residue gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca(2+)- and phosphatidylinositol-4,5-bisphosphate-binding sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29211714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#1" class="mim-tip-reference" title="Autzen, H. E., Myasnikov, A. G., Campbell, M. G., Asarnow, D., Julius, D., Cheng, Y. <strong>Structure of the human TRPM4 ion channel in a lipid nanodisc.</strong> Science 359: 228-232, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29217581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29217581</a>] [<a href="https://doi.org/10.1126/science.aar4510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29217581">Autzen et al. (2018)</a> presented 2 structures of full-length human TRPM4 embedded in lipid nanodiscs at approximately 3-angstrom resolution, as determined by single-particle cryoelectron microscopy. These structures, calcium-bound and -unbound, revealed a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures corresponded to 2 distinct closed states. <a href="#1" class="mim-tip-reference" title="Autzen, H. E., Myasnikov, A. G., Campbell, M. G., Asarnow, D., Julius, D., Cheng, Y. <strong>Structure of the human TRPM4 ion channel in a lipid nanodisc.</strong> Science 359: 228-232, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29217581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29217581</a>] [<a href="https://doi.org/10.1126/science.aar4510" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29217581">Autzen et al. (2018)</a> concluded that calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29217581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#17" class="mim-tip-reference" title="Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C. <strong>Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.</strong> Proc. Nat. Acad. Sci. 98: 10692-10697, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535825[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.191360198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11535825">Xu et al. (2001)</a> mapped the TRPM4 gene to chromosome 19q13.32. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11535825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#17" class="mim-tip-reference" title="Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C. <strong>Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.</strong> Proc. Nat. Acad. Sci. 98: 10692-10697, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535825[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.191360198" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11535825">Xu et al. (2001)</a> showed that TRPM4 mediates Ca(2+) entry when expressed in HEK293 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11535825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Launay, P., Fleig, A., Perraud, A.-L., Scharenberg, A. M., Penner, R., Kinet, J.-P. <strong>TRPM4 is a Ca(2+)-activated nonselective cation channel mediating cell membrane depolarization.</strong> Cell 109: 397-407, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12015988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12015988</a>] [<a href="https://doi.org/10.1016/s0092-8674(02)00719-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12015988">Launay et al. (2002)</a> showed that TRPM4b encodes a cation channel that is directly activated by intracellular calcium concentration. They found that it conducts monovalent cations such as sodium and potassium without significant permeation of Ca(2+). TRPM4b is activated following receptor-mediated Ca(2+) mobilization, representing a regulatory mechanism that controls the magnitude of Ca(2+) influx by modulating the membrane potential and, with it, the driving force for Ca(2+) entry through other Ca(2+)-permeable pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12015988" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Launay, P., Cheng, H., Srivatsan, S., Penner, R., Fleig, A., Kinet, J.-P. <strong>TRPM4 regulates calcium oscillations after T cell activation.</strong> Science 306: 1374-1377, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15550671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15550671</a>] [<a href="https://doi.org/10.1126/science.1098845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15550671">Launay et al. (2004)</a> showed that the molecular inhibition of endogenous TRPM4 in T cells suppresses TRPM4 currents, with a profound influence on receptor-mediated calcium mobilization. Agonist-mediated oscillations in intracellular Ca(2+) concentration, which are driven by store-operated Ca(2+) influx, were transformed into a sustained elevation in intracellular Ca(2+) concentration. This increase in Ca(2+) influx enhanced interleukin-2 (<a href="/entry/147680">147680</a>) production. Thus, <a href="#8" class="mim-tip-reference" title="Launay, P., Cheng, H., Srivatsan, S., Penner, R., Fleig, A., Kinet, J.-P. <strong>TRPM4 regulates calcium oscillations after T cell activation.</strong> Science 306: 1374-1377, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15550671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15550671</a>] [<a href="https://doi.org/10.1126/science.1098845" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15550671">Launay et al. (2004)</a> concluded that TRPM4-mediated depolarization modulates calcium oscillations, with downstream effects on cytokine production in T lymphocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15550671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 rat and mouse models, <a href="#4" class="mim-tip-reference" title="Gerzanich, V., Woo, S. K., Vennekens, R., Tsymbalyuk, O., Ivanova, S., Ivanov, A., Geng, Z., Chen, Z., Nilius, B., Flockerzi, V., Freichel, M., Simard, J. M. <strong>De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury.</strong> Nature Med. 15: 185-191, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19169264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19169264</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19169264[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/nm.1899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19169264">Gerzanich et al. (2009)</a> found that Trpm4 had a pivotal role in the development of secondary hemorrhage following spinal cord injury. Trpm4 was expressed at low levels in uninjured rats. Following spinal cord injury, Trpm4 expression was upregulated in tissues surrounding the injury and extended to distant tissues, including the contralateral hemicord. In situ hybridization confirmed that Trpm4 was upregulated after injury, especially in microvessels in the penumbra. Work with cell cultures suggested that severe ATP depletion associated with spinal cord injury caused sustained Trpm4 channel opening, followed by depolarization, continuous cation influx, oncotic swelling, and oncotic cell death, resulting in capillary fragmentation and hemorrhage. Blocking Trpm4 expression in rats via treatment with antisense RNA or loss of Trpm4 expression in Trpm4 -/- mice reduced secondary hemorrhage and greatly improved lesional and behavioral outcome after spinal cord injury. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19169264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H. <strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong> Science 370: eaay3302, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33033186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33033186</a>] [<a href="https://doi.org/10.1126/science.aay3302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33033186">Yan et al. (2020)</a> found that the NMDAR subunits Grin2a (<a href="/entry/138253">138253</a>) and Grin2b (<a href="/entry/138252">138252</a>) formed a complex with Trpm4 in cultured mouse neurons and mouse brain. The interaction was mediated by a 57-amino acid intracellular domain of Trpm4, termed TwinF, that was positioned just beneath the plasma membrane. TwinF interacted with I4, an evolutionarily conserved stretch of 18 amino acids containing 4 regularly spaced isoleucines located within the intracellular, near-membrane portion of Grin2a and Grin2b. The NMDAR/Trpm4 complex could be disrupted by expression of TwinF, which competed with endogenous Trpm4 for binding to Grin2a and Grin2b, or through the use of small-molecule NMDAR/Trpm4 interaction interface inhibitors that <a href="#18" class="mim-tip-reference" title="Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H. <strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong> Science 370: eaay3302, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33033186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33033186</a>] [<a href="https://doi.org/10.1126/science.aay3302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33033186">Yan et al. (2020)</a> identified in a computational compound screen. These interface inhibitors strongly reduced NMDA-triggered toxicity and mitochondrial dysfunction, abolished CREB shutoff, boosted gene induction, and reduced neuronal loss in mouse models of stroke and retinal degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33033186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Progressive Familial Heart Block, Type IB</em></strong></p><p>
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In an Afrikaner kindred with progressive heart block mapping to chromosome 19q13.3 (PFHB1B; <a href="/entry/604559">604559</a>), originally reported by <a href="#2" class="mim-tip-reference" title="Brink, A. J., Torrington, M. <strong>Progressive familial heart block--two types.</strong> S. Afr. Med. J. 52: 53-59, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/897853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">897853</a>]" pmid="897853">Brink and Torrington (1977)</a>, <a href="#7" class="mim-tip-reference" title="Kruse, M., Schulze-Bahr, E., Corfield, V., Beckmann, A., Stallmeyer, B., Kurtbay, G., Ohmert, I., Schulze-Bahr, E., Brink, P., Pongs, O. <strong>Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.</strong> J. Clin. Invest. 119: 2737-2744, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI38292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726882">Kruse et al. (2009)</a> analyzed the candidate gene TRPM4 and identified a heterozygous missense mutation (E7K; <a href="#0001">606936.0001</a>) that segregated with the disease. Cellular expression studies showed that the mutation attenuated deSUMOylation of the TRPM4 channel, resulting in impaired endocytosis and elevated TRPM4 channel density at the cell surface. <a href="#7" class="mim-tip-reference" title="Kruse, M., Schulze-Bahr, E., Corfield, V., Beckmann, A., Stallmeyer, B., Kurtbay, G., Ohmert, I., Schulze-Bahr, E., Brink, P., Pongs, O. <strong>Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.</strong> J. Clin. Invest. 119: 2737-2744, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI38292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726882">Kruse et al. (2009)</a> concluded that this type of familial heart block is thus caused by a gain-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=897853+19726882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a large Lebanese kindred and 2 French families with autosomal dominant cardiac conduction defects mapping to chromosome 19q13, <a href="#10" class="mim-tip-reference" title="Liu, H., El Zein, L., Kruse, M., Guinamard, R., Beckmann, A., Bozio, A., Kurtbay, G., Megarbane, A., Ohmert, I., Blaysat, G., Villain, E., Pongs, O., Bouvagnet, P. <strong>Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.</strong> Circ. Cardiovasc. Genet. 3: 374-385, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562447</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.109.930867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20562447">Liu et al. (2010)</a> analyzed 12 candidate genes and identified 3 heterozygous missense mutations in the TRPM4 gene (<a href="#0002">606936.0002</a>-<a href="#0004">606936.0004</a>) that were found in all affected family members. The mutations were also detected in several family members with incomplete right bundle branch block (RBBB) or no block; penetrance was calculated to be 75% for males and 54% for females. All 3 mutations resulted in gain of function due to increased channel density at the cell surface secondary to impaired endocytosis and deregulation of SUMOylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20562447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E. <strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong> Hum. Mutat. 33: 109-117, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21887725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21887725</a>] [<a href="https://doi.org/10.1002/humu.21599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21887725">Stallmeyer et al. (2012)</a> analyzed the TRPM4 gene in 160 unrelated patients with various types of inherited cardiac arrhythmias and identified 8 missense mutations in 8 patients (see, e.g., <a href="#0002">606936.0002</a> and <a href="#0004">606936.0004</a>-<a href="#0006">606936.0006</a>), including 5 (26.3%) of 19 patients with RBBB and 3 (11.5%) of 26 patients with atrioventricular (AV) block. No mutations were identified in patients with other types of cardiac arrhythmias. Noting the phenotypic variability in the mutation-positive patients, <a href="#11" class="mim-tip-reference" title="Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E. <strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong> Hum. Mutat. 33: 109-117, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21887725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21887725</a>] [<a href="https://doi.org/10.1002/humu.21599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21887725">Stallmeyer et al. (2012)</a> suggested that additional factors might modulate the disease phenotype in some patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21887725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Erythrokeratodermia Variabilis et Progressiva 6</em></strong></p><p>
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In affected members of 2 unrelated 4-generation Chinese families segregating autosomal dominant progressive symmetric erythrokeratodermia (EKVP6; <a href="/entry/618531">618531</a>), <a href="#14" class="mim-tip-reference" title="Wang, H., Xu, Z., Lee, B. H., Vu, S., Hu, L., Lee, M., Bu, D., Cao, X., Hwang, S., Yang, Y., Zheng, J., Lin, Z. <strong>Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia.</strong> J. Invest. Derm. 139: 1089-1097, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30528822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30528822</a>] [<a href="https://doi.org/10.1016/j.jid.2018.10.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30528822">Wang et al. (2019)</a> identified heterozygosity for a missense mutation in the TRPM4 gene (I1040T; <a href="#0007">606936.0007</a>). In a sporadic patient with EKVP, they identified heterozygosity for a de novo missense mutation in TRPM4 (I1033M; <a href="#0008">606936.0008</a>). None of the affected individuals reported symptoms of cardiac arrhythmias or history of cardiac disorders, and no arrhythmias were detected on repeated electrocardiograms in 3 affected individuals. Electrophysiologic analysis indicated that both mutations represented gain-of-function TRPM4 variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30528822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Janin, A., Bessiere, F., Georgescu, T., Chanavat, V., Chevalier, P., Millat, G. <strong>TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome.</strong> Europ. J. Med. Genet. 62: 103527, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30142439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30142439</a>] [<a href="https://doi.org/10.1016/j.ejmg.2018.08.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30142439">Janin et al. (2019)</a> studied a 64-year-old man with exertional dyspnea, hypertension, chronic kidney disease, coronary disease, and an electrocardiogram showing complete right bundle branch block as well as a Brugada type 1-like pattern (see <a href="/entry/601144">601144</a>) with ST segment elevation in leads V1 and V2. Analysis of a panel of 19 Brugada syndrome-associated genes revealed compound heterozygosity for a splicing mutation (c.1150+1G-A) in intron 9 and a nonsense mutation (W525X) in exon 11. The variants were present in the gnomAD database with minor allele frequencies of 0.0032% and 0.15%, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30142439" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 test the importance of calcium-activated nonselective cation channels, <a href="#13" class="mim-tip-reference" title="Vennekens, R., Olausson, J., Meissner, M., Bloch, W., Mathar, I., Philipp, S. E., Schmitz, F., Weissgerber, P., Nilius, B., Flockerzi, V., Freichel, M. <strong>Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4.</strong> Nature Immun. 8: 312-320, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17293867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17293867</a>] [<a href="https://doi.org/10.1038/ni1441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17293867">Vennekens et al. (2007)</a> generated viable and fertile Trpm4 -/- mice. Trpm4 -/- mast cells had more Ca(2+) entry after stimulation of Fcer1 (see <a href="/entry/147140">147140</a>) than did wildtype mast cells. Consequently, Trpm4 -/- mast cells had augmented degranulation and released more histamine, leukotriene, and Tnf (<a href="/entry/191160">191160</a>). Trpm4 -/- mice had more severe acute, but not late-phase, passive cutaneous anaphylaxis than wildtype mice. <a href="#13" class="mim-tip-reference" title="Vennekens, R., Olausson, J., Meissner, M., Bloch, W., Mathar, I., Philipp, S. E., Schmitz, F., Weissgerber, P., Nilius, B., Flockerzi, V., Freichel, M. <strong>Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4.</strong> Nature Immun. 8: 312-320, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17293867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17293867</a>] [<a href="https://doi.org/10.1038/ni1441" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17293867">Vennekens et al. (2007)</a> concluded that TRPM4 channels are critical regulators of Ca(2+) entry in mast cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17293867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>8 Selected Examples</a>):</strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606936[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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607142 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607142;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267607142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267607142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of an Afrikaner kindred with progressive heart block mapping to chromosome 19q13.3 (PFHB1B; <a href="/entry/604559">604559</a>), originally reported by <a href="#2" class="mim-tip-reference" title="Brink, A. J., Torrington, M. <strong>Progressive familial heart block--two types.</strong> S. Afr. Med. J. 52: 53-59, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/897853/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">897853</a>]" pmid="897853">Brink and Torrington (1977)</a>, <a href="#7" class="mim-tip-reference" title="Kruse, M., Schulze-Bahr, E., Corfield, V., Beckmann, A., Stallmeyer, B., Kurtbay, G., Ohmert, I., Schulze-Bahr, E., Brink, P., Pongs, O. <strong>Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.</strong> J. Clin. Invest. 119: 2737-2744, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19726882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19726882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19726882[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI38292" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19726882">Kruse et al. (2009)</a> identified heterozygosity for a 19G-A transition (c.19G-A, NM_017636) in exon 1 of the TRPM4 gene, predicting a glu7-to-lys (E7K) substitution at an evolutionarily conserved residue within the N terminus. The mutation was not found in unaffected family members, in 230 ancestry-matched, unrelated Afrikaner controls, or in 389 unrelated individuals of mixed European descent. The mutant channel displayed normal gating properties; however, the E7K channel was present at increased density in the plasma membrane due to attenuated channel deSUMOylation, a previously unknown mechanism in the etiology of cardiac channelopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=897853+19726882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs201907325 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201907325;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs201907325?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs201907325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs201907325" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000029159 OR RCV000208441 OR RCV000990240 OR RCV001093252 OR RCV002381261 OR RCV004700279" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029159, RCV000208441, RCV000990240, RCV001093252, RCV002381261, RCV004700279" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029159...</a>
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<p>In affected individuals from a large Lebanese kindred segregating autosomal dominant cardiac conduction defects (PFHB1B; <a href="/entry/604559">604559</a>), originally described by <a href="#12" class="mim-tip-reference" title="Stephan, E. <strong>Hereditary bundle branch system defect: survey of a family with four affected generations.</strong> Am. Heart J. 95: 89-95, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/619595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">619595</a>] [<a href="https://doi.org/10.1016/0002-8703(78)90401-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="619595">Stephan (1978)</a>, <a href="#10" class="mim-tip-reference" title="Liu, H., El Zein, L., Kruse, M., Guinamard, R., Beckmann, A., Bozio, A., Kurtbay, G., Megarbane, A., Ohmert, I., Blaysat, G., Villain, E., Pongs, O., Bouvagnet, P. <strong>Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.</strong> Circ. Cardiovasc. Genet. 3: 374-385, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562447</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.109.930867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20562447">Liu et al. (2010)</a> identified heterozygosity for a 1294G-A transition (c.1294G-A, ENST00000252826) (as noted in their Figure 3) in exon 11 of the TRPM4 gene, resulting in an ala432-to-thr (A432T) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete right bundle branch block (RBBB) or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=619595+20562447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 38-year-old Turkish man with first-degree atrioventricular conduction block and atypical RBBB, <a href="#11" class="mim-tip-reference" title="Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E. <strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong> Hum. Mutat. 33: 109-117, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21887725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21887725</a>] [<a href="https://doi.org/10.1002/humu.21599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21887725">Stallmeyer et al. (2012)</a> identified compound heterozygosity for the A432T mutation and a 1744G-A transition in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution (<a href="#0005">606936.0005</a>) that was not found in 670 European or 154 Turkish control samples. In addition, he carried a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del). His father and a sister had both died suddenly due to cardiac arrhythmias of unknown origin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21887725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Xian, W., Hui, X., Tian, Q., Wang, H., Moretti, A., Laugwitz, K.-L., Flockerzi, V., Ruppenthal, S., Lipp, P. <strong>Aberrant deactivation-induced gain of function in TRPM4 mutant is associated with human cardiac conduction block.</strong> Cell Rep. 24: 724-731, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30021168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30021168</a>] [<a href="https://doi.org/10.1016/j.celrep.2018.06.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30021168">Xian et al. (2018)</a> found that plasma membrane expression levels of human TRPM4 with the A432T mutation were 50% lower in HEK293 cells, but the relative membrane current was more than 2-fold larger, compared with wildtype TRPM4. Kinetic analysis showed that TRPM4-A432T had 4-fold slower calcium-dependent deactivation than wildtype. Analysis with human induced pluripotent stem cell-derived cardiac myocytes revealed that TRPM4-A432T also generated excessive membrane currents during cardiac action potentials. The authors demonstrated that altered deactivation of TRPM4-A432T was not due to alterations in glycosylation, phosphorylation, or plasma membrane phosphatidylinositol 4,5-bisphosphate levels. Instead, site-directed mutagenesis and structural modeling showed that replacement of the nonpolar, small-side-chained ala432 with a bulky threonine changed the compactness of the channel subdomain in TRPM-A432T. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30021168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387907216 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907216;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs387907216?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387907216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387907216" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000029160 OR RCV002345254" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029160, RCV002345254" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029160...</a>
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<p>In affected individuals from a French family segregating autosomal dominant cardiac conduction defects (PFHB1B; <a href="/entry/604559">604559</a>), <a href="#10" class="mim-tip-reference" title="Liu, H., El Zein, L., Kruse, M., Guinamard, R., Beckmann, A., Bozio, A., Kurtbay, G., Megarbane, A., Ohmert, I., Blaysat, G., Villain, E., Pongs, O., Bouvagnet, P. <strong>Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.</strong> Circ. Cardiovasc. Genet. 3: 374-385, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562447</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.109.930867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20562447">Liu et al. (2010)</a> identified heterozygosity for a 490C-T transition (c.490C-T, ENST00000252826) (as noted in their Figure 3) in exon 5 of the TRPM4 gene, resulting in an arg164-to-trp (R164W) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete RBBB or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20562447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>.0004 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
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TRPM4, GLY844ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200038418 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200038418;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs200038418?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs200038418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs200038418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000029161 OR RCV000249699 OR RCV000434894 OR RCV004526600 OR RCV004541017" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029161, RCV000249699, RCV000434894, RCV004526600, RCV004541017" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029161...</a>
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<p>In affected individuals from a French family segregating autosomal dominant cardiac conduction defects (PFHB1B; <a href="/entry/604559">604559</a>), <a href="#10" class="mim-tip-reference" title="Liu, H., El Zein, L., Kruse, M., Guinamard, R., Beckmann, A., Bozio, A., Kurtbay, G., Megarbane, A., Ohmert, I., Blaysat, G., Villain, E., Pongs, O., Bouvagnet, P. <strong>Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.</strong> Circ. Cardiovasc. Genet. 3: 374-385, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20562447/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20562447</a>] [<a href="https://doi.org/10.1161/CIRCGENETICS.109.930867" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20562447">Liu et al. (2010)</a> identified heterozygosity for a 2531G-A transition (c.2531G-A, ENST00000252826) (as noted in their Figure 3) in exon 17 of the TRPM4 gene, resulting in a gly844-to-asp (G844D) substitution at a conserved residue within an intracellular sequence connecting the second and third transmembrane segments. The mutation was also detected in several family members with incomplete RBBB or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20562447" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated German patients with right bundle branch block and left anterior hemiblock (LAHB), <a href="#11" class="mim-tip-reference" title="Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E. <strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong> Hum. Mutat. 33: 109-117, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21887725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21887725</a>] [<a href="https://doi.org/10.1002/humu.21599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21887725">Stallmeyer et al. (2012)</a> identified heterozygosity for the G844D mutation (c.2531G-A, NM_017636.3) in the TRPM4 gene. One patient was an asymptomatic 11-year-old German boy with RBBB and LAHB but a normal heart rate. His 45-year-old mother, who had a normal electrocardiogram (ECG), also carried the mutation. The other patient was a 17-year-old boy who was compound heterozygous for G844D and a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del); his ECG showed a 'bizarre and obvious' RBBB and LAHB. His 45-year-old father, who carried the G844D mutation, had a normal ECG, as did his 44-year-old mother, who was a heterozygous carrier of the polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21887725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0005 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
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</h4>
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TRPM4, GLY582SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs172149856 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs172149856;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs172149856?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs172149856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs172149856" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000029158 OR RCV000208117 OR RCV000990241 OR RCV001090742 OR RCV002399335 OR RCV004700278" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029158, RCV000208117, RCV000990241, RCV001090742, RCV002399335, RCV004700278" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029158...</a>
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<p>For discussion of the 1744G-A transition (c.1744G-A, NM_017636.3) in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution, that was found in compound heterozygous state in a patient with first-degree atrioventricular conduction block and atypical right bundle branch block (PFHB1B; <a href="/entry/604559">604559</a>) by <a href="#11" class="mim-tip-reference" title="Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E. <strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong> Hum. Mutat. 33: 109-117, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21887725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21887725</a>] [<a href="https://doi.org/10.1002/humu.21599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21887725">Stallmeyer et al. (2012)</a>, see <a href="#0002">606936.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21887725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<strong>.0006 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
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TRPM4, LYS914ARG
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs172151858 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs172151858;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs172151858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs172151858" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000029162" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029162" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029162</a>
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<p>In a Turkish father and son with cardiac conduction defects (PFHB1B; <a href="/entry/604559">604559</a>), <a href="#11" class="mim-tip-reference" title="Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E. <strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong> Hum. Mutat. 33: 109-117, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21887725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21887725</a>] [<a href="https://doi.org/10.1002/humu.21599" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21887725">Stallmeyer et al. (2012)</a> identified heterozygosity for a 2741A-G transition (c.2741A-G, NM_017636.3) in the TRPM4 gene, resulting in a lys914-to-arg (K914R) substitution at a highly conserved residue in the cytoplasmic TM4-TM5 linker. The son presented before 2 years of age with severe congenital third-degree atrioventricular (AV) block, requiring a cardiac pacemaker for bradycardia and follow-up of more than 30 years. His father had a less severe phenotype with asymptomatic right bundle branch block and normal AV conductance. The mutation was not found in the son's asymptomatic daughter or in 738 European or 154 Turkish control samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21887725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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<span class="mim-font">
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<strong>.0007 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 6</strong>
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TRPM4, ILE1010THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1369949906 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1369949906;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1369949906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1369949906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000808167 OR RCV001386316 OR RCV001759549" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000808167, RCV001386316, RCV001759549" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000808167...</a>
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<p>In affected members of 2 unrelated 4-generation Chinese families (families 1 and 2) segregating autosomal dominant progressive symmetric erythrokeratodermia (EKVP6; <a href="/entry/618531">618531</a>), <a href="#14" class="mim-tip-reference" title="Wang, H., Xu, Z., Lee, B. H., Vu, S., Hu, L., Lee, M., Bu, D., Cao, X., Hwang, S., Yang, Y., Zheng, J., Lin, Z. <strong>Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia.</strong> J. Invest. Derm. 139: 1089-1097, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30528822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30528822</a>] [<a href="https://doi.org/10.1016/j.jid.2018.10.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30528822">Wang et al. (2019)</a> identified heterozygosity for a c.3119T-C transition in the TRPM4 gene, resulting in an ile1040-to-thr (I1040T) substitution at a highly conserved residue within the S6 transmembrane segment, which forms the ion permeation pore. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated fully with disease in both families; haplotype analysis indicated that c.3119T-C was a recurrent mutation that arose independently in the 2 families. Electrophysiologic studies in transfected HEK293 cells showed substantial hyperactivity with the I1040T mutant, which exhibited pronounced baseline activity, enhanced sensitivity to intracellular Ca(2+), and an elevated resting membrane potential compared to wildtype. In vitro studies demonstrated enhanced proliferation in keratinocytes overexpressing the I1033M mutant compared to wildtype. Immunochemical analysis of lesional skin from a patient in family 2 showed upregulation of markers for proliferation and differentiation of keratinocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30528822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 6</strong>
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</h4>
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TRPM4, ILE1033MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1278993777 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1278993777;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1278993777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1278993777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000808168" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000808168" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000808168</a>
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<p>In a Han Chinese girl with progressive symmetric erythrokeratodermia (EKVP6; <a href="/entry/618531">618531</a>), <a href="#14" class="mim-tip-reference" title="Wang, H., Xu, Z., Lee, B. H., Vu, S., Hu, L., Lee, M., Bu, D., Cao, X., Hwang, S., Yang, Y., Zheng, J., Lin, Z. <strong>Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia.</strong> J. Invest. Derm. 139: 1089-1097, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30528822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30528822</a>] [<a href="https://doi.org/10.1016/j.jid.2018.10.044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30528822">Wang et al. (2019)</a> identified heterozygosity for a de novo c.3099C-G transversion in the TRPM4 gene, resulting in an ile1033-to-met (I1033M) substitution at a highly conserved residue within the S6 transmembrane segment, which forms the ion permeation pore. The mutation was not found in her unaffected parents, in BGI in-house databases, or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or ExAC databases. Electrophysiologic studies in transfected HEK293 cells showed substantial hyperactivity with the I1033M mutant, which exhibited pronounced baseline activity, enhanced sensitivity to intracellular Ca(2+), and an elevated resting membrane potential compared to wildtype. In vitro studies demonstrated enhanced proliferation in keratinocytes overexpressing the I1033M mutant compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30528822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1038/nature24997" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1098845" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1161/CIRCGENETICS.109.930867" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17293867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17293867</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17293867" 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/ni1441" target="_blank">Full Text</a>]
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<div class="">
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Wang, H., Xu, Z., Lee, B. H., Vu, S., Hu, L., Lee, M., Bu, D., Cao, X., Hwang, S., Yang, Y., Zheng, J., Lin, Z.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30528822/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30528822</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30528822" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29211723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29211723</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29211723" 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/nature24674" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Xian2018" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xian, W., Hui, X., Tian, Q., Wang, H., Moretti, A., Laugwitz, K.-L., Flockerzi, V., Ruppenthal, S., Lipp, P.
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<strong>Aberrant deactivation-induced gain of function in TRPM4 mutant is associated with human cardiac conduction block.</strong>
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Cell Rep. 24: 724-731, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30021168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30021168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30021168" 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.celrep.2018.06.034" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Xu2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C.
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<strong>Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.</strong>
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Proc. Nat. Acad. Sci. 98: 10692-10697, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11535825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11535825</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11535825[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=11535825" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.191360198" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Yan2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H.
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<strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong>
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Science 370: eaay3302, 2020. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33033186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33033186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33033186" 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.aay3302" target="_blank">Full Text</a>]
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/03/2021
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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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Marla J. F. O'Neill - updated : 08/09/2019<br>Bao Lige - updated : 08/06/2019<br>Marla J. F. O'Neill - updated : 06/28/2019<br>Ada Hamosh - updated : 05/04/2018<br>Ada Hamosh - updated : 02/09/2018<br>Marla J. F. O'Neill - updated : 7/9/2012<br>Paul J. Converse - updated : 4/19/2012<br>Patricia A. Hartz - updated : 6/20/2011<br>Marla J. F. O'Neill - updated : 4/2/2010<br>Paul J. Converse - updated : 11/9/2007<br>Ada Hamosh - updated : 12/10/2004
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</span>
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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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Stylianos E. Antonarakis : 5/13/2002
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 03/03/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/12/2019<br>carol : 08/09/2019<br>mgross : 08/06/2019<br>alopez : 06/28/2019<br>joanna : 06/12/2019<br>alopez : 05/04/2018<br>alopez : 02/09/2018<br>mcolton : 06/16/2015<br>carol : 7/12/2012<br>terry : 7/9/2012<br>mgross : 4/25/2012<br>terry : 4/19/2012<br>mgross : 8/29/2011<br>terry : 6/20/2011<br>carol : 4/2/2010<br>terry : 4/2/2010<br>mgross : 11/9/2007<br>mgross : 11/9/2007<br>alopez : 12/15/2004<br>terry : 12/10/2004<br>mgross : 5/13/2002
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</span>
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</div>
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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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<strong>*</strong> 606936
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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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TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY M, MEMBER 4; TRPM4
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<div>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TRPM4</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> 698250005;
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</span>
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<strong>
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<em>
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Cytogenetic location: 19q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:49,157,792-49,211,836 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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<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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<th>
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Location
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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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<td rowspan="2">
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<span class="mim-font">
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19q13.33
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<td>
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<span class="mim-font">
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Erythrokeratodermia variabilis et progressiva 6
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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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618531
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<span class="mim-font">
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Progressive familial heart block, type IB
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<span class="mim-font">
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604559
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<td>
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<span class="mim-font">
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Autosomal dominant
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<td>
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<span class="mim-font">
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3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>TRPM4 belongs to the melastatin (TRPM1; 603576)-related transient receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N and C termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in some TRPM channels, an enzymatic domain. TRPM4 is a mediator of pressure-induced membrane depolarization and arterial constriction (review by Farooqi et al., 2011). </p>
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<div>
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<br />
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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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<span class="mim-text-font">
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<p>By searching an EST database and screening brain, testis, and placenta cDNA libraries, Xu et al. (2001) obtained a cDNA encoding TRPM4. The predicted TRPM4 protein has 1,040 amino acids and contains 6 putative transmembrane domains. Northern blot analysis detected TRPM4 expression in most adult tissues tested, with highest levels in heart, prostate, and colon. In fetus, TRPM4 expression was most abundant in kidney. There were at least 2 distinct bands detected (6.2 and 4.2 kb), indicating alternative splicing of TRPM4. In addition, a smaller but relatively abundant 2.4-kb transcript was detected in testis. </p><p>Launay et al. (2002) cloned and characterized a second form of TRPM4. The predicted 1,214-amino acid protein is nearly identical to the protein reported by Xu et al. (2001), except that it includes an additional 174 amino acids N-terminal to the predicted start of that protein. The shorter protein results from alternative splicing, with the third and fourth exons being spliced out and the beginning of the first exon being truncated. As a consequence, the first in-frame methionine lies in the fifth exon, resulting in the deletion of the first 174 amino acids. Launay et al. (2002) proposed that the shorter protein be designated TRPM4a and the longer protein be designated TRPM4b. </p><p>Kruse et al. (2009) performed quantitative analysis of TRPM4 mRNA content in human cardiac tissue and found the highest expression level in Purkinje fibers. </p><p>By immunohistochemistry on sections of bovine hearts, Liu et al. (2010) demonstrated that TRPM4 channel signal level is higher in atrial cardiomyocytes than in ventricular cells, but is highest in Purkinje fibers. Small bundles of highly TRPM4-positive cells were found in the subendocardium and in rare intramural bundles. </p><p>By RT-PCR, Wang et al. (2019) detected TRPM4 mRNA expression in the epidermis from normal dorsal foot skin and in the human epidermal keratinocyte cell line HaCaT. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Biochemical Features</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Winkler et al. (2017) reported the electron cryomicroscopy structure of the most widespread human Ca2(+)-activated, nonselective (CAN) channel, TRPM4, bound to the agonist Ca(2+) and the modulator decavanadate. Four cytosolic C-terminal domains form an umbrella-like structure with a coiled-coil domain for the 'pole' and 4 helical 'ribs' spanning the N-terminal TRPM homology regions (MHRs), thus holding 4 subunits in a crown-like architecture. Winkler et al. (2017) observed 2 decavanadate-binding sites, 1 in the C-terminal domain and another in the intersubunit TRPM homology region interface. A glutamine in the selectivity filter may be an important determinant of monovalent selectivity. </p><p>Guo et al. (2017) presented the electron cryomicroscopy structures of the mouse TRPM4 channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a 3-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain and inhibits channel activity. TRPM4 has an exceptionally wide filter but is permeable only to monovalent cations; filter residue gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca(2+)- and phosphatidylinositol-4,5-bisphosphate-binding sites. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
Autzen et al. (2018) presented 2 structures of full-length human TRPM4 embedded in lipid nanodiscs at approximately 3-angstrom resolution, as determined by single-particle cryoelectron microscopy. These structures, calcium-bound and -unbound, revealed a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures corresponded to 2 distinct closed states. Autzen et al. (2018) concluded that calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Xu et al. (2001) mapped the TRPM4 gene to chromosome 19q13.32. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Xu et al. (2001) showed that TRPM4 mediates Ca(2+) entry when expressed in HEK293 cells. </p><p>Launay et al. (2002) showed that TRPM4b encodes a cation channel that is directly activated by intracellular calcium concentration. They found that it conducts monovalent cations such as sodium and potassium without significant permeation of Ca(2+). TRPM4b is activated following receptor-mediated Ca(2+) mobilization, representing a regulatory mechanism that controls the magnitude of Ca(2+) influx by modulating the membrane potential and, with it, the driving force for Ca(2+) entry through other Ca(2+)-permeable pathways. </p><p>Launay et al. (2004) showed that the molecular inhibition of endogenous TRPM4 in T cells suppresses TRPM4 currents, with a profound influence on receptor-mediated calcium mobilization. Agonist-mediated oscillations in intracellular Ca(2+) concentration, which are driven by store-operated Ca(2+) influx, were transformed into a sustained elevation in intracellular Ca(2+) concentration. This increase in Ca(2+) influx enhanced interleukin-2 (147680) production. Thus, Launay et al. (2004) concluded that TRPM4-mediated depolarization modulates calcium oscillations, with downstream effects on cytokine production in T lymphocytes. </p><p>Using rat and mouse models, Gerzanich et al. (2009) found that Trpm4 had a pivotal role in the development of secondary hemorrhage following spinal cord injury. Trpm4 was expressed at low levels in uninjured rats. Following spinal cord injury, Trpm4 expression was upregulated in tissues surrounding the injury and extended to distant tissues, including the contralateral hemicord. In situ hybridization confirmed that Trpm4 was upregulated after injury, especially in microvessels in the penumbra. Work with cell cultures suggested that severe ATP depletion associated with spinal cord injury caused sustained Trpm4 channel opening, followed by depolarization, continuous cation influx, oncotic swelling, and oncotic cell death, resulting in capillary fragmentation and hemorrhage. Blocking Trpm4 expression in rats via treatment with antisense RNA or loss of Trpm4 expression in Trpm4 -/- mice reduced secondary hemorrhage and greatly improved lesional and behavioral outcome after spinal cord injury. </p><p>Yan et al. (2020) found that the NMDAR subunits Grin2a (138253) and Grin2b (138252) formed a complex with Trpm4 in cultured mouse neurons and mouse brain. The interaction was mediated by a 57-amino acid intracellular domain of Trpm4, termed TwinF, that was positioned just beneath the plasma membrane. TwinF interacted with I4, an evolutionarily conserved stretch of 18 amino acids containing 4 regularly spaced isoleucines located within the intracellular, near-membrane portion of Grin2a and Grin2b. The NMDAR/Trpm4 complex could be disrupted by expression of TwinF, which competed with endogenous Trpm4 for binding to Grin2a and Grin2b, or through the use of small-molecule NMDAR/Trpm4 interaction interface inhibitors that Yan et al. (2020) identified in a computational compound screen. These interface inhibitors strongly reduced NMDA-triggered toxicity and mitochondrial dysfunction, abolished CREB shutoff, boosted gene induction, and reduced neuronal loss in mouse models of stroke and retinal degeneration. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Progressive Familial Heart Block, Type IB</em></strong></p><p>
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In an Afrikaner kindred with progressive heart block mapping to chromosome 19q13.3 (PFHB1B; 604559), originally reported by Brink and Torrington (1977), Kruse et al. (2009) analyzed the candidate gene TRPM4 and identified a heterozygous missense mutation (E7K; 606936.0001) that segregated with the disease. Cellular expression studies showed that the mutation attenuated deSUMOylation of the TRPM4 channel, resulting in impaired endocytosis and elevated TRPM4 channel density at the cell surface. Kruse et al. (2009) concluded that this type of familial heart block is thus caused by a gain-of-function mechanism. </p><p>In a large Lebanese kindred and 2 French families with autosomal dominant cardiac conduction defects mapping to chromosome 19q13, Liu et al. (2010) analyzed 12 candidate genes and identified 3 heterozygous missense mutations in the TRPM4 gene (606936.0002-606936.0004) that were found in all affected family members. The mutations were also detected in several family members with incomplete right bundle branch block (RBBB) or no block; penetrance was calculated to be 75% for males and 54% for females. All 3 mutations resulted in gain of function due to increased channel density at the cell surface secondary to impaired endocytosis and deregulation of SUMOylation. </p><p>Stallmeyer et al. (2012) analyzed the TRPM4 gene in 160 unrelated patients with various types of inherited cardiac arrhythmias and identified 8 missense mutations in 8 patients (see, e.g., 606936.0002 and 606936.0004-606936.0006), including 5 (26.3%) of 19 patients with RBBB and 3 (11.5%) of 26 patients with atrioventricular (AV) block. No mutations were identified in patients with other types of cardiac arrhythmias. Noting the phenotypic variability in the mutation-positive patients, Stallmeyer et al. (2012) suggested that additional factors might modulate the disease phenotype in some patients. </p><p><strong><em>Erythrokeratodermia Variabilis et Progressiva 6</em></strong></p><p>
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In affected members of 2 unrelated 4-generation Chinese families segregating autosomal dominant progressive symmetric erythrokeratodermia (EKVP6; 618531), Wang et al. (2019) identified heterozygosity for a missense mutation in the TRPM4 gene (I1040T; 606936.0007). In a sporadic patient with EKVP, they identified heterozygosity for a de novo missense mutation in TRPM4 (I1033M; 606936.0008). None of the affected individuals reported symptoms of cardiac arrhythmias or history of cardiac disorders, and no arrhythmias were detected on repeated electrocardiograms in 3 affected individuals. Electrophysiologic analysis indicated that both mutations represented gain-of-function TRPM4 variants. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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Janin et al. (2019) studied a 64-year-old man with exertional dyspnea, hypertension, chronic kidney disease, coronary disease, and an electrocardiogram showing complete right bundle branch block as well as a Brugada type 1-like pattern (see 601144) with ST segment elevation in leads V1 and V2. Analysis of a panel of 19 Brugada syndrome-associated genes revealed compound heterozygosity for a splicing mutation (c.1150+1G-A) in intron 9 and a nonsense mutation (W525X) in exon 11. The variants were present in the gnomAD database with minor allele frequencies of 0.0032% and 0.15%, respectively. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To test the importance of calcium-activated nonselective cation channels, Vennekens et al. (2007) generated viable and fertile Trpm4 -/- mice. Trpm4 -/- mast cells had more Ca(2+) entry after stimulation of Fcer1 (see 147140) than did wildtype mast cells. Consequently, Trpm4 -/- mast cells had augmented degranulation and released more histamine, leukotriene, and Tnf (191160). Trpm4 -/- mice had more severe acute, but not late-phase, passive cutaneous anaphylaxis than wildtype mice. Vennekens et al. (2007) concluded that TRPM4 channels are critical regulators of Ca(2+) entry in mast cells. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TRPM4, GLU7LYS
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<br />
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SNP: rs267607142,
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ClinVar: RCV000003968, RCV004532279
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of an Afrikaner kindred with progressive heart block mapping to chromosome 19q13.3 (PFHB1B; 604559), originally reported by Brink and Torrington (1977), Kruse et al. (2009) identified heterozygosity for a 19G-A transition (c.19G-A, NM_017636) in exon 1 of the TRPM4 gene, predicting a glu7-to-lys (E7K) substitution at an evolutionarily conserved residue within the N terminus. The mutation was not found in unaffected family members, in 230 ancestry-matched, unrelated Afrikaner controls, or in 389 unrelated individuals of mixed European descent. The mutant channel displayed normal gating properties; however, the E7K channel was present at increased density in the plasma membrane due to attenuated channel deSUMOylation, a previously unknown mechanism in the etiology of cardiac channelopathies. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TRPM4, ALA432THR
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<br />
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SNP: rs201907325,
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gnomAD: rs201907325,
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ClinVar: RCV000029159, RCV000208441, RCV000990240, RCV001093252, RCV002381261, RCV004700279
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected individuals from a large Lebanese kindred segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), originally described by Stephan (1978), Liu et al. (2010) identified heterozygosity for a 1294G-A transition (c.1294G-A, ENST00000252826) (as noted in their Figure 3) in exon 11 of the TRPM4 gene, resulting in an ala432-to-thr (A432T) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete right bundle branch block (RBBB) or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. </p><p>In a 38-year-old Turkish man with first-degree atrioventricular conduction block and atypical RBBB, Stallmeyer et al. (2012) identified compound heterozygosity for the A432T mutation and a 1744G-A transition in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution (606936.0005) that was not found in 670 European or 154 Turkish control samples. In addition, he carried a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del). His father and a sister had both died suddenly due to cardiac arrhythmias of unknown origin. </p><p>Xian et al. (2018) found that plasma membrane expression levels of human TRPM4 with the A432T mutation were 50% lower in HEK293 cells, but the relative membrane current was more than 2-fold larger, compared with wildtype TRPM4. Kinetic analysis showed that TRPM4-A432T had 4-fold slower calcium-dependent deactivation than wildtype. Analysis with human induced pluripotent stem cell-derived cardiac myocytes revealed that TRPM4-A432T also generated excessive membrane currents during cardiac action potentials. The authors demonstrated that altered deactivation of TRPM4-A432T was not due to alterations in glycosylation, phosphorylation, or plasma membrane phosphatidylinositol 4,5-bisphosphate levels. Instead, site-directed mutagenesis and structural modeling showed that replacement of the nonpolar, small-side-chained ala432 with a bulky threonine changed the compactness of the channel subdomain in TRPM-A432T. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TRPM4, ARG164TRP
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<br />
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SNP: rs387907216,
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gnomAD: rs387907216,
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ClinVar: RCV000029160, RCV002345254
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected individuals from a French family segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), Liu et al. (2010) identified heterozygosity for a 490C-T transition (c.490C-T, ENST00000252826) (as noted in their Figure 3) in exon 5 of the TRPM4 gene, resulting in an arg164-to-trp (R164W) substitution at a highly conserved residue in the cytoplasmic N terminus. The mutation was also detected in several family members with incomplete RBBB or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
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TRPM4, GLY844ASP
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<br />
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|
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SNP: rs200038418,
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gnomAD: rs200038418,
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ClinVar: RCV000029161, RCV000249699, RCV000434894, RCV004526600, RCV004541017
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected individuals from a French family segregating autosomal dominant cardiac conduction defects (PFHB1B; 604559), Liu et al. (2010) identified heterozygosity for a 2531G-A transition (c.2531G-A, ENST00000252826) (as noted in their Figure 3) in exon 17 of the TRPM4 gene, resulting in a gly844-to-asp (G844D) substitution at a conserved residue within an intracellular sequence connecting the second and third transmembrane segments. The mutation was also detected in several family members with incomplete RBBB or no block, consistent with incomplete penetrance, but was not found in 300 ethnically matched control chromosomes. Functional analysis in HEK293 cells demonstrated that current amplitudes were dramatically elevated for mutant versus wildtype channels, despite no increase in Ca(2+) affinity for the mutant channels compared to wildtype. Quantitative analysis of transfected COS-7 cells revealed that the gain of function was due to increased density of mutant channels at the cell surface, which was found to result from impaired endocytosis and deregulation of SUMOylation. </p><p>In 2 unrelated German patients with right bundle branch block and left anterior hemiblock (LAHB), Stallmeyer et al. (2012) identified heterozygosity for the G844D mutation (c.2531G-A, NM_017636.3) in the TRPM4 gene. One patient was an asymptomatic 11-year-old German boy with RBBB and LAHB but a normal heart rate. His 45-year-old mother, who had a normal electrocardiogram (ECG), also carried the mutation. The other patient was a 17-year-old boy who was compound heterozygous for G844D and a polymorphic in-frame deletion (2283-2294del, resulting in R762-G765del); his ECG showed a 'bizarre and obvious' RBBB and LAHB. His 45-year-old father, who carried the G844D mutation, had a normal ECG, as did his 44-year-old mother, who was a heterozygous carrier of the polymorphism. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
TRPM4, GLY582SER
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|
|
|
<br />
|
|
|
|
SNP: rs172149856,
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|
|
|
gnomAD: rs172149856,
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|
|
|
|
ClinVar: RCV000029158, RCV000208117, RCV000990241, RCV001090742, RCV002399335, RCV004700278
|
|
|
|
|
|
</span>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 1744G-A transition (c.1744G-A, NM_017636.3) in the TRPM4 gene, resulting in a gly582-to-ser (G582S) substitution, that was found in compound heterozygous state in a patient with first-degree atrioventricular conduction block and atypical right bundle branch block (PFHB1B; 604559) by Stallmeyer et al. (2012), see 606936.0002. </p>
|
|
</span>
|
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</div>
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<div>
|
|
<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PROGRESSIVE FAMILIAL HEART BLOCK, TYPE IB</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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TRPM4, LYS914ARG
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<br />
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SNP: rs172151858,
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ClinVar: RCV000029162
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a Turkish father and son with cardiac conduction defects (PFHB1B; 604559), Stallmeyer et al. (2012) identified heterozygosity for a 2741A-G transition (c.2741A-G, NM_017636.3) in the TRPM4 gene, resulting in a lys914-to-arg (K914R) substitution at a highly conserved residue in the cytoplasmic TM4-TM5 linker. The son presented before 2 years of age with severe congenital third-degree atrioventricular (AV) block, requiring a cardiac pacemaker for bradycardia and follow-up of more than 30 years. His father had a less severe phenotype with asymptomatic right bundle branch block and normal AV conductance. The mutation was not found in the son's asymptomatic daughter or in 738 European or 154 Turkish control samples. </p>
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|
</span>
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</div>
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 6</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
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TRPM4, ILE1010THR
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<br />
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SNP: rs1369949906,
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ClinVar: RCV000808167, RCV001386316, RCV001759549
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated 4-generation Chinese families (families 1 and 2) segregating autosomal dominant progressive symmetric erythrokeratodermia (EKVP6; 618531), Wang et al. (2019) identified heterozygosity for a c.3119T-C transition in the TRPM4 gene, resulting in an ile1040-to-thr (I1040T) substitution at a highly conserved residue within the S6 transmembrane segment, which forms the ion permeation pore. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated fully with disease in both families; haplotype analysis indicated that c.3119T-C was a recurrent mutation that arose independently in the 2 families. Electrophysiologic studies in transfected HEK293 cells showed substantial hyperactivity with the I1040T mutant, which exhibited pronounced baseline activity, enhanced sensitivity to intracellular Ca(2+), and an elevated resting membrane potential compared to wildtype. In vitro studies demonstrated enhanced proliferation in keratinocytes overexpressing the I1033M mutant compared to wildtype. Immunochemical analysis of lesional skin from a patient in family 2 showed upregulation of markers for proliferation and differentiation of keratinocytes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0008 ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA 6</strong>
|
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</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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TRPM4, ILE1033MET
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<br />
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SNP: rs1278993777,
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ClinVar: RCV000808168
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</span>
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<p>In a Han Chinese girl with progressive symmetric erythrokeratodermia (EKVP6; 618531), Wang et al. (2019) identified heterozygosity for a de novo c.3099C-G transversion in the TRPM4 gene, resulting in an ile1033-to-met (I1033M) substitution at a highly conserved residue within the S6 transmembrane segment, which forms the ion permeation pore. The mutation was not found in her unaffected parents, in BGI in-house databases, or in the 1000 Genomes Project, NHLBI Exome Sequencing Project, or ExAC databases. Electrophysiologic studies in transfected HEK293 cells showed substantial hyperactivity with the I1033M mutant, which exhibited pronounced baseline activity, enhanced sensitivity to intracellular Ca(2+), and an elevated resting membrane potential compared to wildtype. In vitro studies demonstrated enhanced proliferation in keratinocytes overexpressing the I1033M mutant compared to wildtype. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Gerzanich, V., Woo, S. K., Vennekens, R., Tsymbalyuk, O., Ivanova, S., Ivanov, A., Geng, Z., Chen, Z., Nilius, B., Flockerzi, V., Freichel, M., Simard, J. M.
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<strong>De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury.</strong>
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Nature Med. 15: 185-191, 2009.
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<p class="mim-text-font">
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Guo, J., She, J., Zeng, W., Chen, Q., Bai, X., Jiang, Y.
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<strong>Structures of the calcium-activated, non-selective cation channel TRPM4.</strong>
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Nature 552: 205-209, 2017.
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[PubMed: 29211714]
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[Full Text: https://doi.org/10.1038/nature24997]
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<p class="mim-text-font">
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Janin, A., Bessiere, F., Georgescu, T., Chanavat, V., Chevalier, P., Millat, G.
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<strong>TRPM4 mutations to cause autosomal recessive and not autosomal dominant Brugada type 1 syndrome.</strong>
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Europ. J. Med. Genet. 62: 103527, 2019. Note: Electronic Article.
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[PubMed: 30142439]
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[Full Text: https://doi.org/10.1016/j.ejmg.2018.08.008]
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<p class="mim-text-font">
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Kruse, M., Schulze-Bahr, E., Corfield, V., Beckmann, A., Stallmeyer, B., Kurtbay, G., Ohmert, I., Schulze-Bahr, E., Brink, P., Pongs, O.
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<strong>Impaired endocytosis of the ion channel TRPM4 is associated with human progressive familial heart block type I.</strong>
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J. Clin. Invest. 119: 2737-2744, 2009.
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[PubMed: 19726882]
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[Full Text: https://doi.org/10.1172/JCI38292]
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<p class="mim-text-font">
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Launay, P., Cheng, H., Srivatsan, S., Penner, R., Fleig, A., Kinet, J.-P.
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<strong>TRPM4 regulates calcium oscillations after T cell activation.</strong>
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Science 306: 1374-1377, 2004.
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[PubMed: 15550671]
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[Full Text: https://doi.org/10.1126/science.1098845]
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Launay, P., Fleig, A., Perraud, A.-L., Scharenberg, A. M., Penner, R., Kinet, J.-P.
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<strong>TRPM4 is a Ca(2+)-activated nonselective cation channel mediating cell membrane depolarization.</strong>
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Cell 109: 397-407, 2002.
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[PubMed: 12015988]
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[Full Text: https://doi.org/10.1016/s0092-8674(02)00719-5]
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<p class="mim-text-font">
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Liu, H., El Zein, L., Kruse, M., Guinamard, R., Beckmann, A., Bozio, A., Kurtbay, G., Megarbane, A., Ohmert, I., Blaysat, G., Villain, E., Pongs, O., Bouvagnet, P.
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<strong>Gain-of-function mutations in TRPM4 cause autosomal dominant isolated cardiac conduction disease.</strong>
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Circ. Cardiovasc. Genet. 3: 374-385, 2010.
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[PubMed: 20562447]
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[Full Text: https://doi.org/10.1161/CIRCGENETICS.109.930867]
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Stallmeyer, B., Zumhagen, S., Denjoy, I., Duthoit, G., Hebert, J.-L., Ferrer, X., Maugenre, S., Schmitz, W., Kirchhefer, U., Schulze-Bahr, E., Guicheney, P., Schulze-Bahr, E.
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<strong>Mutational spectrum in the Ca(2+)-activated cation channel gene TRPM4 in patients with cardiac conductance disturbances.</strong>
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Hum. Mutat. 33: 109-117, 2012.
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[PubMed: 21887725]
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[Full Text: https://doi.org/10.1002/humu.21599]
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<p class="mim-text-font">
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Stephan, E.
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<strong>Hereditary bundle branch system defect: survey of a family with four affected generations.</strong>
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Am. Heart J. 95: 89-95, 1978.
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[PubMed: 619595]
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[Full Text: https://doi.org/10.1016/0002-8703(78)90401-5]
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Vennekens, R., Olausson, J., Meissner, M., Bloch, W., Mathar, I., Philipp, S. E., Schmitz, F., Weissgerber, P., Nilius, B., Flockerzi, V., Freichel, M.
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<strong>Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4.</strong>
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Nature Immun. 8: 312-320, 2007.
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[PubMed: 17293867]
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[Full Text: https://doi.org/10.1038/ni1441]
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Wang, H., Xu, Z., Lee, B. H., Vu, S., Hu, L., Lee, M., Bu, D., Cao, X., Hwang, S., Yang, Y., Zheng, J., Lin, Z.
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<strong>Gain-of-function mutations in TRPM4 activation gate cause progressive symmetric erythrokeratodermia.</strong>
|
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J. Invest. Derm. 139: 1089-1097, 2019.
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[PubMed: 30528822]
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[Full Text: https://doi.org/10.1016/j.jid.2018.10.044]
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Winkler, P. A., Huang, Y., Sun, W., Du, J., Lu, W.
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<strong>Electron cryo-microscopy structure of a human TRPM4 channel.</strong>
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Nature 552: 200-204, 2017.
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[PubMed: 29211723]
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[Full Text: https://doi.org/10.1038/nature24674]
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<p class="mim-text-font">
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Xian, W., Hui, X., Tian, Q., Wang, H., Moretti, A., Laugwitz, K.-L., Flockerzi, V., Ruppenthal, S., Lipp, P.
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<strong>Aberrant deactivation-induced gain of function in TRPM4 mutant is associated with human cardiac conduction block.</strong>
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Cell Rep. 24: 724-731, 2018.
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[PubMed: 30021168]
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[Full Text: https://doi.org/10.1016/j.celrep.2018.06.034]
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Xu, X.-Z. S., Moebius, F., Gill, D. L., Montell, C.
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<strong>Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform.</strong>
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Proc. Nat. Acad. Sci. 98: 10692-10697, 2001.
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[PubMed: 11535825]
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Yan, J., Bengtson, C. P., Buchthal, B., Hagenston, A. M., Bading, H.
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<strong>Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants.</strong>
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Science 370: eaay3302, 2020. Note: Electronic Article.
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[PubMed: 33033186]
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[Full Text: https://doi.org/10.1126/science.aay3302]
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