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<title>
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Entry
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- *147265 - INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1; ITPR1
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- OMIM
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<li class="dropdown-header">
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Advanced Search
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<a href="/history"> Search History </a>
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</form>
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<p />
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</div>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*147265</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/147265">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000150995;t=ENST00000649015" 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=3708" 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=147265" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000150995;t=ENST00000649015" 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_001099952,NM_001168272,NM_001378452,NM_002222" 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_001378452" 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=147265" 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=00925&isoform_id=00925_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/ITPR1" 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/559323,4262086,46107962,62087316,119584312,119584313,119584314,119584315,119584316,119584317,119584318,119584319,194374557,194377668,194382400,219841936,269954690,269954692,269954694,519668682,1808862643" 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/Q14643" 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=3708" 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=ENSG00000150995;t=ENST00000649015" 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=ITPR1" 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=ITPR1" 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+3708" 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/ITPR1" 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:3708" 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/3708" 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=chr3&hgg_gene=ENST00000649015.2&hgg_start=4493348&hgg_end=4847506&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6180" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6180" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=147265[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=147265[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/ITPR1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000150995" 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=ITPR1" 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=ITPR1" 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=ITPR1" 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=ITPR1&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/PA29978" 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:6180" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0010051.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:96623" 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/ITPR1#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:96623" 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/3708/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002097/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=3708" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00002173;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070604-2" 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:3708" 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=ITPR1&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> 253176002, 715825009, 716724006<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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147265
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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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INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1; ITPR1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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IP3R<br />
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IP3R1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ITPR1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ITPR1</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/3/17?start=-3&limit=10&highlight=17">3p26.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:4493348-4847506&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'})">3:4,493,348-4,847,506</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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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The ITPR1 gene encodes the inositol 1,4,5-triphosphate (IP3) receptor, an intracellular IP3-gated calcium channel that modulates intracellular calcium signaling (<a href="#1" class="mim-tip-reference" title="Berridge, M. J. <strong>Inositol trisphosphate and calcium signalling.</strong> Nature 361: 315-325, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8381210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8381210</a>] [<a href="https://doi.org/10.1038/361315a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8381210">Berridge, 1993</a>; <a href="#13" class="mim-tip-reference" title="Hirota, J., Ando, H., Hamada, K., Mikoshiba, K. <strong>Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1.</strong> Biochem. J. 372: 435-441, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12611586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12611586</a>] [<a href="https://doi.org/10.1042/BJ20030110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12611586">Hirota et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8381210+12611586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#27" class="mim-tip-reference" title="Ross, C. A., Danoff, S. K., Ferris, C. D., Donath, C., Fischer, G. A., Munemitsu, S., Snyder, S. H., Ullrich, A. <strong>Inositol 1,4,5-triphosphate receptors (IP(3)R): cloning of the human cDNA and an IP(3)-related mouse cDNA indicating a family of IP(3)R-related genes. (Abstract)</strong> Soc. Neurosci. Abs. 17: 18, 1991."None>Ross et al. (1991)</a> cloned a cDNA for the human type 1 inositol 1,4,5-triphosphate receptor. <a href="#22" class="mim-tip-reference" title="Nucifora, F. C., Jr., Li, S.-H., Danoff, S., Ullrich, A., Ross, C. A. <strong>Molecular cloning of a cDNA for the human inositol 1,4,5-trisphosphate receptor type 1, and the identification of a third alternatively spliced variant.</strong> Molec. Brain Res. 32: 291-296, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7500840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7500840</a>] [<a href="https://doi.org/10.1016/0169-328x(95)00089-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7500840">Nucifora et al. (1995)</a> studied the expression of alternatively spliced forms. The long form appears to create an additional consensus protein kinase C phosphorylation site. The long form predominates in most brain regions except for the cerebellum, while the short form predominates in peripheral tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7500840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Inositol 1,4,5-triphosphate is an intracellular second messenger produced by phospholipase C through a G protein-dependent mechanism. It releases calcium from endoplasmic reticulum by binding to specific receptors that are coupled to calcium channels. These receptors are abundant in neuronal and nonneuronal tissues. The neuronal form of the receptor is abundant in the cerebellum, particularly the perikaryon of the Purkinje cells. <a href="#20" class="mim-tip-reference" title="Matsumoto, M., Nakagawa, T., Inoue, T., Nagata, E., Tanaka, K., Takano, H., Minowa, O., Kuno, J., Sakakibara, S., Yamada, M., Yoneshima, H., Miyawaki, A, Fukuichi, T., Furuichi, T., Okano, H., Mikoshiba, K., Noda, T. <strong>Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-triphosphate receptor.</strong> Nature 379: 168-171, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8538767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8538767</a>] [<a href="https://doi.org/10.1038/379168a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8538767">Matsumoto et al. (1996)</a> noted that the product of the ITPR1 gene is predominantly enriched in cerebellar Purkinje cells but is also concentrated in neurons in the hippocampal CA1 region, caudate-putamen, and cerebral cortex. The inositol triphosphate receptor shares sequence and functional homology with the ryanodine receptor (<a href="/entry/180901">180901</a>); they both trigger the release of calcium from intracellular stores. The primary structure of the inositol triphosphate receptor contains 3 domains: an inositol triphosphate binding domain near the N terminus, a coupling domain in the middle of the molecule, and a transmembrane spanning domain near the C terminus. In addition, there are at least 2 consensus protein kinase A phosphorylation sites and at least 1 consensus ATP-binding site (<a href="#22" class="mim-tip-reference" title="Nucifora, F. C., Jr., Li, S.-H., Danoff, S., Ullrich, A., Ross, C. A. <strong>Molecular cloning of a cDNA for the human inositol 1,4,5-trisphosphate receptor type 1, and the identification of a third alternatively spliced variant.</strong> Molec. Brain Res. 32: 291-296, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7500840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7500840</a>] [<a href="https://doi.org/10.1016/0169-328x(95)00089-b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7500840">Nucifora et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8538767+7500840" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Boehning, D., Patterson, R. L., Sedaghat, L., Glebova, N. O., Kurosaki, T., Snyder, S. H. <strong>Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis.</strong> Nature Cell Biol. 5: 1051-1061, 2003. Note: Erratum: Nature Cell Biol. 6 77 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14608362/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14608362</a>] [<a href="https://doi.org/10.1038/ncb1063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14608362">Boehning et al. (2003)</a> presented evidence that mammalian cytochrome c (<a href="/entry/123970">123970</a>) binds to inositol 1,4,5-trisphosphate receptors during apoptosis. The addition of 1 nanomolar cytochrome c blocked calcium-dependent inhibition of ITPR1 function in ITPR1-transfected COS cells. Early in apoptosis, cytochrome c translocated to the endoplasmic reticulum, where it selectively bound ITPR1, resulting in sustained oscillatory cytosolic calcium increases. These calcium events were linked to the coordinated release of cytochrome c from all mitochondria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14608362" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 mouse brain, <a href="#13" class="mim-tip-reference" title="Hirota, J., Ando, H., Hamada, K., Mikoshiba, K. <strong>Carbonic anhydrase-related protein is a novel binding protein for inositol 1,4,5-trisphosphate receptor type 1.</strong> Biochem. J. 372: 435-441, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12611586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12611586</a>] [<a href="https://doi.org/10.1042/BJ20030110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12611586">Hirota et al. (2003)</a> identified Carp (CA8; <a href="/entry/114815">114815</a>) as an ITPR1-binding protein. Western blot and immunohistochemical studies showed that Carp colocalized and interacted with ITPR1 predominantly in the cytoplasm of cerebellar Purkinje cells. Mutagenesis studies showed that residues 45 to 291 of Carp were essential for its association with the modulatory domain of ITPR1 (residues 1387 to 1647). Carp functioned as an inhibitor of IP3 binding to ITPR1 by reducing the affinity of the receptor for IP3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12611586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Higo, T., Hattori, M., Nakamura, T., Natsume, T., Michikawa, T., Mikoshiba, K. <strong>Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44.</strong> Cell 120: 85-98, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15652484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15652484</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15652484">Higo et al. (2005)</a> found that ERp44 (TXNDC4; <a href="/entry/609170">609170</a>), an endoplasmic reticulum (ER) luminal protein of the thioredoxin family, interacted directly with the third luminal loop of IP3R1. The interaction was dependent on pH, Ca(2+) concentration, and redox state, with the presence of free cysteine residues in the loop of IP3R1 required. Ca(2+)-imaging experiments and single-channel recording of IP3R1 activity with a planar lipid bilayer system demonstrated that IP3R1 was directly inhibited by ERp44. <a href="#12" class="mim-tip-reference" title="Higo, T., Hattori, M., Nakamura, T., Natsume, T., Michikawa, T., Mikoshiba, K. <strong>Subtype-specific and ER lumenal environment-dependent regulation of inositol 1,4,5-trisphosphate receptor type 1 by ERp44.</strong> Cell 120: 85-98, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15652484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15652484</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.048" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15652484">Higo et al. (2005)</a> concluded that ERp44 senses the environment in the ER lumen and modulates IP3R1 activity accordingly, which in turn contributes to regulating both intraluminal conditions and the complex patterns of cytosolic Ca(2+) concentrations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15652484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), <a href="#17" class="mim-tip-reference" title="Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F. <strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong> Nature 432: 1036-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616564</a>] [<a href="https://doi.org/10.1038/nature03159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616564">Kittler et al. (2004)</a> identified 37 genes required for cell division, one of which was ITPR1. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>IP3R1 localizes to dendrites and is thought to be locally translated in response to synaptic activity. <a href="#15" class="mim-tip-reference" title="Iijima, T., Imai, T., Kimura, Y., Bernstein, A., Okano, H. J., Yuzaki, M., Okano, H. <strong>Hzf protein regulates dendritic localization and BDNF-induced translation of type 1 inositol 1,4,5-triphosphate receptor mRNA.</strong> Proc. Nat. Acad. Sci. 102: 17190-17195, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16286649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16286649</a>] [<a href="https://doi.org/10.1073/pnas.0504684102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16286649">Iijima et al. (2005)</a> showed that the 3-prime UTR of mouse Ip3r1 was required as a cis element for its dendritic localization, and they identified Hzf (ZNF385A; <a href="/entry/609124">609124</a>) as a trans-acting factor. Moreover, dendritic Ip3r1 mRNA in Purkinje cells and Bdnf (<a href="/entry/113505">113505</a>)-induced protein synthesis were both reduced in Hzf-deficient mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16286649" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Inositol 1,4,5-trisphosphate receptors release calcium ions from intracellular stores. <a href="#6" class="mim-tip-reference" title="Dellis, O., Dedos, S. G., Tovey, S. C., Rahman, T.-U., Dubel, S. J., Taylor, C. W. <strong>Ca(2+) entry through plasma membrane IP(3) receptors.</strong> Science 313: 229-233, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840702</a>] [<a href="https://doi.org/10.1126/science.1125203" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840702">Dellis et al. (2006)</a> found that inositol trisphosphate stimulated opening of very few (1.9 +/- 0.2 per cell) calcium-ion permeable channels in whole-cell patch-clamp recording of DT40 chicken or mouse B cells. Activation of the B-cell receptor in perforated-patch recordings evoked the same response. Inositol trisphosphate failed to stimulate intracellular or plasma membrane channels in cells lacking IP3R. Expression of IP3R restored both responses. Mutations in the pore affected the conductances of inositol triphosphate-activated plasma membrane and intracellular channels similarly. An impermeant pore mutant abolished B cell receptor-evoked calcium ion signals, and plasma membrane IP3Rs were undetectable. After introduction of an alpha-bungarotoxin binding site near the pore, plasma membrane IP3Rs were modulated by extracellular alpha-bungarotoxin. IP3Rs are unusual among endoplasmic reticulum proteins in being also functionally expressed at the plasma membrane, where very few IP3Rs contribute substantially to the calcium ion entry evoked by the B-cell receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16840702" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="White, C., Yang, J., Monteiro, M. J., Foskett, J. K. <strong>CIB1, a ubiquitously expressed Ca(2+)-binding protein ligand of the InsP3 receptor Ca(2+) release channel.</strong> J. Biol. Chem. 281: 20825-20833, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16723353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16723353</a>] [<a href="https://doi.org/10.1074/jbc.M602175200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16723353">White et al. (2006)</a> characterized the structural determinants for binding of CABP1 (<a href="/entry/605563">605563</a>) to IP3R and found that disruption of any the 3 functional EF-hands of CABP1 reduced binding to IP3R, with EF3 and EF4 being particularly important. Examination of other ER-localized proteins with functional EF3 and EF4 showed that CIB1 (<a href="/entry/602293">602293</a>) interacted with the ligand-binding region of IP3R in a Ca(2+)-dependent manner. Recombinant CIB1 bound to IP3R and directly activated the IP3R channel for Ca(2+) release in the absence of IP3. In contrast, pre-exposure of IP3R to CIB1 reduced the number of channels available for subsequent activation by IP3, and overexpression of CIB1 decreased the amplitude of agonist-induced intracellular Ca(2+) transients and inhibited Ca(2+) release in intact cells. These findings demonstrated a paradoxical role for CIB1 on Ca(2+) release, in which binding of CIB1 as a ligand initially activates the IP3R channel, but the channel then undergoes ligand-dependent inactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16723353" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 nuclear patch-clamp recording, <a href="#30" class="mim-tip-reference" title="Taufiq-Ur-Rahman, Skupin, A., Falcke, M., Taylor, C. W. <strong>Clustering of InsP3 receptors by InsP3 retunes their regulation by InsP3 and Ca(2+).</strong> Nature 458: 655-659, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19348050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19348050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19348050[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/nature07763" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19348050">Taufiq-Ur-Rahman et al. (2009)</a> demonstrated that inositol-1,4,5-trisphosphate receptors are initially randomly distributed with an estimated separation of about 1 micron. Low concentrations of inositol-4,4,5-trisphosphate (Insp3) cause InsP3Rs to aggregate rapidly and reversibly into small clusters of about 4 closely associated InsP3Rs. At resting cytosolic calcium ion concentration, clustered InsP3Rs open independently, but with lower open probability, shorter open time, and less InsP3 sensitivity than lone InsP3Rs. Increasing cytosolic calcium ion concentration reverses the inhibition caused by clustering, InsP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes InsP3Rs to local calcium rises and increases the effects of calcium. Dynamic regulation of clustering by InsP3 retunes InsP3R sensitivity to InsP3 and calcium ion, facilitating hierarchical recruitment of the elementary events that underlie all InsP3-evoked calcium signals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19348050" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Wang, Y., Li, G., Goode, J., Paz, J. C., Ouyang, K., Screaton, R., Fischer, W. H., Chen, J., Tabas, I., Montminy, M. <strong>Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.</strong> Nature 485: 128-132, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22495310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22495310</a>] [<a href="https://doi.org/10.1038/nature10988" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22495310">Wang et al. (2012)</a> showed in mice that glucagon (GCG; <a href="/entry/138030">138030</a>) stimulates CRTC2 (<a href="/entry/608972">608972</a>) dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent PPP3CA (<a href="/entry/114105">114105</a>). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs) (ITPR1; ITPR2, <a href="/entry/600144">600144</a>; ITPR3, <a href="/entry/147267">147267</a>), which associated with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT (<a href="/entry/164730">164730</a>)-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrated how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22495310" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="Fredericks, G. J., Hoffmann, F. W., Rose, A. H., Osterheld, H. J., Hess, F. M., Mercier, F., Hoffmann, P. R. <strong>Stable expression and function of the inositol 1,4,5-triphosphate receptor requires palmitoylation by a DHHC6/selenoprotein K complex.</strong> Proc. Nat. Acad. Sci. 111: 16478-16483, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25368151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25368151</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25368151[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.1417176111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25368151">Fredericks et al. (2014)</a> found that knockout of Selk (SELENOK; <a href="/entry/607916">607916</a>) in mouse macrophages decreased Ip3r expression due to defective Ip3r palmitoylation. Immunofluorescence and coimmunoprecipitation analyses showed that the SH3 domain of Dhhc6 (ZDHHC6; <a href="/entry/618715">618715</a>) interacted with the SH3-binding domain of Selk and that Dhhc6 and Selk formed a complex in the ER membrane. Interaction between Selk and Dhhc6 was dynamic and correlated with Ip3r levels. DHHC6 knockdown reduced IP3R palmitoylation, expression, and inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) flux in HEK293 cells. Mass spectrophotometric analysis revealed that rat Ip3r was likely palmitoylated on 3 cysteines. The results demonstrated that DHHC6 and SELK palmitoylate IP3R and thereby stabilized IP3R expression, facilitating its function in the ER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25368151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Perry, R. J., Zhang, D., Guerra, M. T., Brill, A. L., Goedeke, L., Nasiri, A. R., Rabin-Court, A., Wang, Y., Peng, L., Dufour, S., Zhang, Y., Zhang, X.-M., Butrico, G. M., Toussaint, K., Nozaki, Y., Cline, G. W., Petersen, K. F., Nathanson, M. H., Ehrlich, B. E., Shulman, G. I. <strong>Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.</strong> Nature 579: 279-283, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32132708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32132708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32132708[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/s41586-020-2074-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32132708">Perry et al. (2020)</a> showed that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase (<a href="/entry/608786">608786</a>) flux, while also increasing mitochondrial fat oxidation, all of which are mediated by stimulation of the inositol triphosphate receptor-1 (INSP3R1, also known as ITPR1). In rats and mice, chronic physiologic increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment, reversing hepatic steatosis and glucose intolerance, were abrogated in Insp3r1-knockout mice. <a href="#26" class="mim-tip-reference" title="Perry, R. J., Zhang, D., Guerra, M. T., Brill, A. L., Goedeke, L., Nasiri, A. R., Rabin-Court, A., Wang, Y., Peng, L., Dufour, S., Zhang, Y., Zhang, X.-M., Butrico, G. M., Toussaint, K., Nozaki, Y., Cline, G. W., Petersen, K. F., Nathanson, M. H., Ehrlich, B. E., Shulman, G. I. <strong>Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis.</strong> Nature 579: 279-283, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32132708/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32132708</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32132708[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/s41586-020-2074-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32132708">Perry et al. (2020)</a> suggested that their results provided insights into glucagon biology and suggested that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type 2 diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32132708" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#3" class="mim-tip-reference" title="Bosanac, I., Alattia, J.-R., Mal, T. K., Chan, J., Talarico, S., Tong, F. K., Tong, K. I., Yoshikawa, F., Furuichi, T., Iwai, M., Michikawa, T., Mikoshiba, K., Ikura, M. <strong>Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand.</strong> Nature 420: 696-700, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12442173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12442173</a>] [<a href="https://doi.org/10.1038/nature01268" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12442173">Bosanac et al. (2002)</a> presented the 2.2-angstrom crystal structure of the inositol triphosphate-binding core of mouse Itpr1 in complex with inositol triphosphate. The asymmetric, boomerang-like structure consists of an N-terminal beta-trefoil domain and a C-terminal alpha-helical domain containing an 'armadillo repeat'-like fold. The cleft formed by the 2 domains exposes a cluster of arginine and lysine residues that coordinate the 3 phosphoryl groups of inositol triphosphate. Putative calcium-binding sites were identified in 2 separate locations within the inositol triphosphate-binding core. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12442173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#24" class="mim-tip-reference" title="Ozcelik, T., Suedhof, T. C., Francke, U. <strong>The genes for inositol 1,4,5-triphosphate receptors 1 (ITPR1) and 3 (ITPR3) are localized on human chromosomes 3p and 6pter-p21, respectively. (Abstract)</strong> Cytogenet. Cell Genet. 58: 1880, 1991."None>Ozcelik et al. (1991)</a> used an M13 clone for a type 1 receptor and another for a type 3 receptor as probes for assignment of their loci to human chromosomes by Southern blot analysis of DNA from human/rodent somatic cell hybrids. The ITPR1 cDNA probe was found to be associated with the presence of human chromosome 3 in all hybrids. Furthermore, it was not present in 2 hybrids that contained an isochromosome of 3q, without an intact copy of this chromosome, thus localizing ITPR1 to 3p. By isotopic in situ hybridization, <a href="#36" class="mim-tip-reference" title="Yamada, N., Makino, Y., Clark, R. A., Pearson, D. W., Mattei, M.-G., Guenet, J.-L., Ohama, E., Fujino, I., Miyawaki, A., Furuichi, T., Mikoshiba, K. <strong>Human inositol 1,4,5-triphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization.</strong> Biochem. J. 302: 781-790, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7945203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7945203</a>] [<a href="https://doi.org/10.1042/bj3020781" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7945203">Yamada et al. (1994)</a> localized the ITPR1 gene to 3p26-p25. They found that the gene is widely expressed in human tissues and thus may play critical roles in various kinds of cellular functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7945203" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#4" class="mim-tip-reference" title="Cargile, C. B., Goh, D. L.-M., Goodman, B. K., Chen, X.-N., Korenberg, J. R., Semenza, G. L., Thomas, G. H. <strong>Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome.</strong> Am. J. Med. Genet. 109: 133-138, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11977162/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11977162</a>] [<a href="https://doi.org/10.1002/ajmg.10323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11977162">Cargile et al. (2002)</a> studied a patient with clinical findings consistent with 3p- syndrome (<a href="/entry/613792">613792</a>), a rare contiguous gene disorder characterized by developmental delay, growth retardation, and dysmorphic features. They noted that all reported cases had, at a minimum, the loss of chromosomal material telomeric to 3p25.3. Their patient had an interstitial deletion involving a 4.5-Mb interval between markers D3S3630 and D3S1304. They suggested the ITPR1 gene as a candidate for the mental retardation found in this syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11977162" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Spinocerebellar Ataxia 15</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="van de Leemput, J., Chandran, J., Knight, M. A., Holtzclaw, L. A., Scholz, S., Cookson, M. R., Houlden, H., Gwinn-Hardy, K., Fung, H.-C., Lin, X., Hernandez, D., Simon-Sanchez, J., and 11 others. <strong>Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.</strong> PLoS Genet. 3: e108, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17590087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17590087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17590087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.0030108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17590087">Van de Leemput et al. (2007)</a> identified heterozygous deletions involving the ITPR1 gene in affected members of 3 unrelated families with adult-onset autosomal dominant spinocerebellar ataxia-15 (SCA15; <a href="/entry/606658">606658</a>), including the SCA15 family of Australian origin used to map the locus to 3p26-p25 (<a href="#18" class="mim-tip-reference" title="Knight, M. A., Kennerson, M. L., Anney, R. J., Matsuura, T., Nicholson, G. A., Salimi-Tari, P., Gardner, R. J. M., Storey, E., Forrest, S. M. <strong>Spinocerebellar ataxia type 15 (SCA15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant.</strong> Neurobiol. Dis. 13: 147-157, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12828938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12828938</a>] [<a href="https://doi.org/10.1016/s0969-9961(03)00029-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12828938">Knight et al., 2003</a>). Using high-density genomewide SNP genotyping, <a href="#31" class="mim-tip-reference" title="van de Leemput, J., Chandran, J., Knight, M. A., Holtzclaw, L. A., Scholz, S., Cookson, M. R., Houlden, H., Gwinn-Hardy, K., Fung, H.-C., Lin, X., Hernandez, D., Simon-Sanchez, J., and 11 others. <strong>Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.</strong> PLoS Genet. 3: e108, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17590087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17590087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17590087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.0030108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17590087">Van de Leemput et al. (2007)</a> found a large deletion removing the first 3 exons of the neighboring SUMF1 gene (<a href="/entry/607939">607939</a>) and the first 10 exons of the ITPR1 gene in the family reported by <a href="#18" class="mim-tip-reference" title="Knight, M. A., Kennerson, M. L., Anney, R. J., Matsuura, T., Nicholson, G. A., Salimi-Tari, P., Gardner, R. J. M., Storey, E., Forrest, S. M. <strong>Spinocerebellar ataxia type 15 (SCA15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant.</strong> Neurobiol. Dis. 13: 147-157, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12828938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12828938</a>] [<a href="https://doi.org/10.1016/s0969-9961(03)00029-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12828938">Knight et al. (2003)</a>. Affected members of 2 additional families were found to have even larger deletions removing the first 3 exons of SUMF1 and 44 and 40 exons of the ITPR1 gene, respectively. The deletions were not observed in a control population. As homozygous mutations in the SUMF1 gene lead to a different phenotype (MSD; <a href="/entry/272200">272200</a>) and heterozygous carriers of SUMF1 mutations do not exhibit a movement disorder, the authors concluded that deletions of the ITPR1 gene underlie the ataxia phenotype of SCA15. <a href="#31" class="mim-tip-reference" title="van de Leemput, J., Chandran, J., Knight, M. A., Holtzclaw, L. A., Scholz, S., Cookson, M. R., Houlden, H., Gwinn-Hardy, K., Fung, H.-C., Lin, X., Hernandez, D., Simon-Sanchez, J., and 11 others. <strong>Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.</strong> PLoS Genet. 3: e108, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17590087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17590087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17590087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.0030108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17590087">Van de Leemput et al. (2007)</a> noted that direct gene sequencing failed to identify mutations in the ITPR1 gene and that gene dosage studies were required for accurate diagnosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12828938+17590087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a large 4-generation Japanese family with SCA15, originally designated as SCA16, <a href="#16" class="mim-tip-reference" title="Iwaki, A., Kawano, Y., Miura, S., Shibata, H., Matsuse, D., Li, W., Furuya, H., Ohyagi, Y., Taniwaki, T., Kira, J., Fukumaki, Y. <strong>Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16.</strong> J. Med. Genet. 45: 32-35, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932120</a>] [<a href="https://doi.org/10.1136/jmg.2007.053942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932120">Iwaki et al. (2008)</a> identified a heterozygous deletion of exons 1 to 48 of the ITPR1 gene (<a href="#0001">147265.0001</a>). The SUMF1 gene was not affected. The findings indicated that SCA15 is due to haploinsufficiency of ITPR1. <a href="#16" class="mim-tip-reference" title="Iwaki, A., Kawano, Y., Miura, S., Shibata, H., Matsuse, D., Li, W., Furuya, H., Ohyagi, Y., Taniwaki, T., Kira, J., Fukumaki, Y. <strong>Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16.</strong> J. Med. Genet. 45: 32-35, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932120</a>] [<a href="https://doi.org/10.1136/jmg.2007.053942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932120">Iwaki et al. (2008)</a> concluded that the CNTN4 (<a href="/entry/607280">607280</a>) transition previously identified in this family was likely a rare polymorphism that was not responsible for the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17932120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a Japanese family with SCA15 originally reported by <a href="#10" class="mim-tip-reference" title="Hara, K., Fukushima, T., Suzuki, T., Shimohata, T., Oyake, M., Ishiguro, H., Hirota, K., Miyashita, A., Kuwano, R., Kurisaki, H., Yomono, H., Goto, J., Kanazawa, I., Tsuji, S. <strong>Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus.</strong> Neurology 62: 648-651, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981189</a>] [<a href="https://doi.org/10.1212/01.wnl.0000110190.08412.25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981189">Hara et al. (2004)</a>, <a href="#11" class="mim-tip-reference" title="Hara, K., Shiga, A., Nozaki, H., Mitsui, J., Takahashi, Y., Ishiguro, H., Yomono, H., Kurisaki, H., Goto, J., Ikeuchi, T., Tsuji, S., Nishizawa, M., Onodera, O. <strong>Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families.</strong> Neurology 71: 547-551, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18579805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18579805</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311277.71046.a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18579805">Hara et al. (2008)</a> identified a 414-kb deletion of chromosome 3p26 including all of the ITPR1 gene and exon 1 of the SUMF1 gene. Breakpoint analysis indicated that the deletion was mediated by nonhomologous end joining. RT-PCR showed that expression levels of both ITPR1 and SUMF1 in the patients were half of levels in normal controls. In affected members of a second unrelated Japanese family reported by <a href="#10" class="mim-tip-reference" title="Hara, K., Fukushima, T., Suzuki, T., Shimohata, T., Oyake, M., Ishiguro, H., Hirota, K., Miyashita, A., Kuwano, R., Kurisaki, H., Yomono, H., Goto, J., Kanazawa, I., Tsuji, S. <strong>Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus.</strong> Neurology 62: 648-651, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981189</a>] [<a href="https://doi.org/10.1212/01.wnl.0000110190.08412.25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981189">Hara et al. (2004)</a>, <a href="#11" class="mim-tip-reference" title="Hara, K., Shiga, A., Nozaki, H., Mitsui, J., Takahashi, Y., Ishiguro, H., Yomono, H., Kurisaki, H., Goto, J., Ikeuchi, T., Tsuji, S., Nishizawa, M., Onodera, O. <strong>Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families.</strong> Neurology 71: 547-551, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18579805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18579805</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311277.71046.a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18579805">Hara et al. (2008)</a> identified a heterozygous mutation in the ITPR1 gene (<a href="#0002">147265.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18579805+14981189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#29" class="mim-tip-reference" title="Synofzik, M., Beetz, C., Bauer, C., Bonin, M., Sanchez-Ferrero, E., Schmitz-Hubsch, T., Wullner, U., Nagele, T., Riess, O., Schols, L., Bauer, P. <strong>Spinocerebellar ataxia type 15: diagnostic assessment, frequency, and phenotypic features.</strong> J. Med. Genet. 48: 407-412, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21367767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21367767</a>] [<a href="https://doi.org/10.1136/jmg.2010.087023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21367767">Synofzik et al. (2011)</a> identified pathogenic ITPR1 deletions in 5 (8.9%) of 56 European families with autosomal dominant SCA who were negative for common SCA repeat expansions. All deletions detected by multiplex ligation-dependent probe amplification (MLPA) were confirmed by SNP array and spanned approximately 183 to 423 kb, and each family had a unique deletion. In 3 families, the deletions affected partly both the ITPR1 and SUMF1 genes, without including the 3-prime region of the ITPR1 gene. One family had a deletion preserving exons 1 and 2 in the 5-prime untranslated region of the ITPR1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21367767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Spinocerebellar Ataxia 29</em></strong></p><p>
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By exome sequencing of a member of the family with autosomal dominant spinocerebellar ataxia-29 (SCA29; <a href="/entry/117360">117360</a>) reported by <a href="#7" class="mim-tip-reference" title="Dudding, T. E., Friend, K., Schofield, P. W., Lee, S., Wilkinson, I. A., Richards, R. I. <strong>Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus.</strong> Neurology 63: 2288-2292, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15623688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15623688</a>] [<a href="https://doi.org/10.1212/01.wnl.0000147299.80872.d1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15623688">Dudding et al. (2004)</a>, <a href="#14" class="mim-tip-reference" title="Huang, L., Warman-Chardon, J., Carter, M. T., Friend, K. L., Dudding, T. E., Schwartzentruber, J., Zou, R., Schofield, P. W., Douglas, S., Bulman, D. E., Boycott, K. M. <strong>Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia.</strong> Orphanet J. Rare Dis. 7: 67, 2012. Note: Erratum: Orphanet J. Rare Dis. 17: 143, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22986007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22986007</a>] [<a href="https://doi.org/10.1186/1750-1172-7-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22986007">Huang et al. (2012)</a> identified a heterozygous mutation in the ITPR1 gene (V1553M; <a href="#0003">147265.0003</a>). The mutation was confirmed by Sanger sequencing and segregated with the disorder in this family. Direct sequencing of the ITPR1 gene in a Canadian family with a similar disorder identified a different heterozygous missense mutation (N602D; <a href="#0004">147265.0004</a>). Both mutations occurred at highly conserved residues in the coupling/regulatory domain that modulates channel function, possibly resulting in dysregulation of intracellular calcium signaling. The phenotype of SCA29 was distinguished from that of SCA15 by onset in infancy, delayed motor development, and mild cognitive impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22986007+15623688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Parolin Schnekenberg, R., Perkins, E. M., Miller, J. W., Davies, W. I. L., D'Adamo, M. C., Pessia, M., Fawcett, K. A., Sims, D., Gillard, E., Hudspith, K., Skehel, P., Williams, J., and 9 others. <strong>De novo point mutations in patients diagnosed with ataxic cerebral palsy.</strong> Brain 138: 1817-1832, 2015. Note: Erratum: Brain 139: e14, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25981959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25981959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25981959[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25981959">Parolin Schnekenberg et al. (2015)</a> reported 2 unrelated children with a clinical diagnosis of ataxic cerebral palsy who were found to carry different de novo heterozygous mutations in the ITPR1 gene (see, e.g., <a href="#0004">147265.0004</a>). Both patients showed delayed motor development, ataxic gait, and moderate intellectual disability, consistent with SCA29. Functional studies of the variants were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25981959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a mother and her 2 children with SCA29, <a href="#5" class="mim-tip-reference" title="Casey, J. P., Hirouchi, T., Hisatsune, C., Lynch, B., Murphy, R., Dunne, A. M., Miyamoto, A., Ennis, S., van der Spek, N., O'Hici, B., Mikoshiba, K., Lynch, S. A. <strong>A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca(2+) signal patterns.</strong> J. Neurol. 264: 1444-1453, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28620721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28620721</a>] [<a href="https://doi.org/10.1007/s00415-017-8545-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28620721">Casey et al. (2017)</a> identified a heterozygous missense mutation in the ITPR1 gene (R36C; <a href="#0015">147265.0015</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the mother. The mutated residue is located in the amino-terminal region of ITPR1 called the suppressor domain, a region thought to be critical for IP3 binding affinity regulation. Consistent with this, the R36C mutation showed a significantly higher affinity for IP3 binding than wildtype ITPR1 and altered the intracellular Ca(2+) signal from a transient to a sigmoidal pattern, suggesting a gain-of-function mechanism. The authors noted that previously reported ITPR1 mutations causing SCA29 have been associated with loss of function rather than gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28620721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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>Gillespie Syndrome</em></strong></p><p>
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In 3 unrelated patients with iris hypoplasia, cerebellar ataxia, and mental retardation (GLSP; <a href="/entry/206700">206700</a>), <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> identified homozygosity or compound heterozygosity for mutations in the ITPR1 gene (<a href="#0005">147265.0005</a>-<a href="#0008">147265.0008</a>). In 2 more probands with Gillespie syndrome, they identified de novo heterozygous mutations in ITPR1 (<a href="#0009">147265.0009</a> and <a href="#0010">147265.0010</a>). <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> concluded that their findings demonstrated the long-suspected coexistence of autosomal recessive and autosomal dominant patterns of inheritance of Gillespie syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 13 patients from 12 families with Gillespie syndrome, <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> identified heterozygosity for mutations in the ITPR1 gene (see, e.g., <a href="/entry/607108#0009">607108.0009</a> and <a href="/entry/607108#0011">607108.0011</a>-<a href="/entry/607108#0013">607108.0013</a>). The authors noted that the 13 patients' mutations affected only 3 residues in ITPR1, and at least 10 were shown to have occurred de novo. <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> stated that protein structure-based analysis indicated that the mutations were likely to have a dominant-negative effect, and noted that the cerebellar anomalies in these patients were similar to those seen in the SCA29 phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 6-year-old girl with a phenotype consistent with Gillespie syndrome, <a href="#32" class="mim-tip-reference" title="van Dijk, T., Barth, P., Reneman, L., Appelhof, B., Baas, F., Poll-The, B. T. <strong>A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxias</strong> Am. J. Med. Genet. 173A: 207-212, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27862915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27862915</a>] [<a href="https://doi.org/10.1002/ajmg.a.37962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27862915">van Dijk et al. (2017)</a> identified a de novo heterozygous missense mutation in the ITPR1 gene (I2550N; <a href="#0014">147265.0014</a>). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the mutation occurs within the transmembrane domain, similar to ITPR1 mutations found in other patients with Gillespie syndrome. The patient had severe pontine and cerebellar hypoplasia, although she had no ocular abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27862915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#20" class="mim-tip-reference" title="Matsumoto, M., Nakagawa, T., Inoue, T., Nagata, E., Tanaka, K., Takano, H., Minowa, O., Kuno, J., Sakakibara, S., Yamada, M., Yoneshima, H., Miyawaki, A, Fukuichi, T., Furuichi, T., Okano, H., Mikoshiba, K., Noda, T. <strong>Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-triphosphate receptor.</strong> Nature 379: 168-171, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8538767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8538767</a>] [<a href="https://doi.org/10.1038/379168a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8538767">Matsumoto et al. (1996)</a> found that most Itpr1-deficient mice generated by gene targeting die in utero, and that most animals that are born alive have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. Electroencephalograms showed that they suffer from epilepsy, indicating that ITPR1 is essential for proper brain function. However, observation by light microscope of the hematoxylin-eosin staining of the brain and peripheral tissues of deficient mice showed no abnormality and the unique electrophysiologic properties of the cerebellar Purkinje cells of deficient mice were not severely impaired. In the mouse the Intp3r locus is closely situated to the 'opisthotonos' mutant locus (opt), and Opt homozygous mutant mice exhibit phenotypes similar to those described for the knockout mice. The opt locus is on mouse chromosome 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8538767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Street, V. A., Bosma, M. M., Demas, V. P., Regan, M. R., Lin, D. D., Robinson, L. C., Agnew, W. S., Tempel, B. L. <strong>The type 1 inositol 1,4,5-triphosphate receptor gene is altered in the opisthotonos mouse.</strong> J. Neurosci. 17: 635-645, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8987786/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8987786</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=8987786[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/10.1523/JNEUROSCI.17-02-00635.1997" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8987786">Street et al. (1997)</a> determined that the Opt mouse has a homozygous in-frame deletion of exons 43 and 44 of the Itpr1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8987786" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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="#23" class="mim-tip-reference" title="Ogura, H., Matsumoto, M., Mikoshiba, K. <strong>Motor discoordination in mutant mice heterozygous for the type 1 inositol 1,4,5-trisphosphate receptor.</strong> Behav. Brain Res. 122: 215-219, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11334652/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11334652</a>] [<a href="https://doi.org/10.1016/s0166-4328(01)00187-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11334652">Ogura et al. (2001)</a> found that heterozygous Itpr1 knockout mice (Itpr1 +/-) demonstrated impaired motor coordination compared to wildtype mice as shown on the rotarod test. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11334652" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="van de Leemput, J., Chandran, J., Knight, M. A., Holtzclaw, L. A., Scholz, S., Cookson, M. R., Houlden, H., Gwinn-Hardy, K., Fung, H.-C., Lin, X., Hernandez, D., Simon-Sanchez, J., and 11 others. <strong>Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans.</strong> PLoS Genet. 3: e108, 2007. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17590087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17590087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17590087[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.0030108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17590087">Van de Leemput et al. (2007)</a> identified a homozygous spontaneous 18-bp deletion in exon 18 of the Itpr1 gene that caused a recessive movement disorder in mice similar to that observed in Opt mice. The deletion mutation resulted in markedly decreased levels of Itpr1 in cerebellar Purkinje cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17590087" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> generated Itpr1 +/- mice and observed no obvious morphologic differences in early development of the iris compared to their wildtype littermates. Immunohistochemistry of wildtype mice showed no specific staining of ITPR1 in the developing iris. No change in Pax6 (<a href="/entry/607108">607108</a>) levels was detected between mutant and wildtype embryos. Examination of 2 Itpr1 +/- mice at age 76 days showed only minor defects in the iris compared to their wildtype littermates, and they exhibited no major anomalies that would be consistent with the phenotype seen in Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>). <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> suggested that the role of ITPR1 in iris development is either indirect, acting at a later stage of development, or is tolerant of 50% residual channel activity. The latter would be consistent with the lack of an iris phenotype in patients with spinocerebellar ataxia-15 (SCA15; <a href="/entry/606658">606658</a>), in whom ITPR1 haploinsufficiency is the predominant genetic mechanism (see MOLECULAR GENETICS). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a large 4-generation Japanese family with spinocerebellar ataxia-15 (SCA15; <a href="/entry/606658">606658</a>), originally designated as SCA16, <a href="#16" class="mim-tip-reference" title="Iwaki, A., Kawano, Y., Miura, S., Shibata, H., Matsuse, D., Li, W., Furuya, H., Ohyagi, Y., Taniwaki, T., Kira, J., Fukumaki, Y. <strong>Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16.</strong> J. Med. Genet. 45: 32-35, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932120</a>] [<a href="https://doi.org/10.1136/jmg.2007.053942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932120">Iwaki et al. (2008)</a> identified a heterozygous deletion of exons 1 to 48 of the ITPR1 gene. The SUMF1 gene was not affected. The findings indicated that SCA15 is due to haploinsufficiency of ITPR1. <a href="#16" class="mim-tip-reference" title="Iwaki, A., Kawano, Y., Miura, S., Shibata, H., Matsuse, D., Li, W., Furuya, H., Ohyagi, Y., Taniwaki, T., Kira, J., Fukumaki, Y. <strong>Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16.</strong> J. Med. Genet. 45: 32-35, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17932120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17932120</a>] [<a href="https://doi.org/10.1136/jmg.2007.053942" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17932120">Iwaki et al. (2008)</a> concluded that the CNTN4 (<a href="/entry/607280">607280</a>) transition previously identified in this family was likely a rare polymorphism that was not responsible for the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17932120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs121912425 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912425;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=rs121912425" 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=rs121912425" 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=RCV000015924" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000015924" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000015924</a>
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<p>In affected members of a Japanese family with spinocerebellar ataxia-15 (SCA15; <a href="/entry/606658">606658</a>) reported by <a href="#10" class="mim-tip-reference" title="Hara, K., Fukushima, T., Suzuki, T., Shimohata, T., Oyake, M., Ishiguro, H., Hirota, K., Miyashita, A., Kuwano, R., Kurisaki, H., Yomono, H., Goto, J., Kanazawa, I., Tsuji, S. <strong>Japanese SCA families with an unusual phenotype linked to a locus overlapping with SCA15 locus.</strong> Neurology 62: 648-651, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14981189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14981189</a>] [<a href="https://doi.org/10.1212/01.wnl.0000110190.08412.25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14981189">Hara et al. (2004)</a>, <a href="#11" class="mim-tip-reference" title="Hara, K., Shiga, A., Nozaki, H., Mitsui, J., Takahashi, Y., Ishiguro, H., Yomono, H., Kurisaki, H., Goto, J., Ikeuchi, T., Tsuji, S., Nishizawa, M., Onodera, O. <strong>Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families.</strong> Neurology 71: 547-551, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18579805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18579805</a>] [<a href="https://doi.org/10.1212/01.wnl.0000311277.71046.a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18579805">Hara et al. (2008)</a> identified a heterozygous 8581C-T transition in exon 25 of the ITPR1 gene, resulting in a pro1059-to-leu (P1059L) substitution in the modulatory and transducing domain. The mutation was not detected in 234 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18579805+14981189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPINOCEREBELLAR ATAXIA 29</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397514535 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514535;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=rs397514535" 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=rs397514535" 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=RCV000032771 OR RCV000624908 OR RCV001091682 OR RCV003389037 OR RCV004767027" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032771, RCV000624908, RCV001091682, RCV003389037, RCV004767027" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032771...</a>
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<p>In affected members of an Australian family with early-onset nonprogressive spinocerebellar ataxia-29 (SCA29; <a href="/entry/117360">117360</a>) who were previously reported by <a href="#7" class="mim-tip-reference" title="Dudding, T. E., Friend, K., Schofield, P. W., Lee, S., Wilkinson, I. A., Richards, R. I. <strong>Autosomal dominant congenital non-progressive ataxia overlaps with the SCA15 locus.</strong> Neurology 63: 2288-2292, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15623688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15623688</a>] [<a href="https://doi.org/10.1212/01.wnl.0000147299.80872.d1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15623688">Dudding et al. (2004)</a>, <a href="#14" class="mim-tip-reference" title="Huang, L., Warman-Chardon, J., Carter, M. T., Friend, K. L., Dudding, T. E., Schwartzentruber, J., Zou, R., Schofield, P. W., Douglas, S., Bulman, D. E., Boycott, K. M. <strong>Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia.</strong> Orphanet J. Rare Dis. 7: 67, 2012. Note: Erratum: Orphanet J. Rare Dis. 17: 143, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22986007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22986007</a>] [<a href="https://doi.org/10.1186/1750-1172-7-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22986007">Huang et al. (2012)</a> identified a heterozygous 4657G-A transition in the ITPR1 gene, resulting in a val1553-to-met (V1553M) substitution at a highly conserved residue in the coupling/regulatory domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in this family and was not found in 5,379 control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22986007+15623688" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs397514536 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514536;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=rs397514536" 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=rs397514536" 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=RCV000032772" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000032772" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000032772</a>
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<p>In affected members of a Canadian family with spinocerebellar ataxia-29 (SCA29; <a href="/entry/117360">117360</a>), <a href="#14" class="mim-tip-reference" title="Huang, L., Warman-Chardon, J., Carter, M. T., Friend, K. L., Dudding, T. E., Schwartzentruber, J., Zou, R., Schofield, P. W., Douglas, S., Bulman, D. E., Boycott, K. M. <strong>Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia.</strong> Orphanet J. Rare Dis. 7: 67, 2012. Note: Erratum: Orphanet J. Rare Dis. 17: 143, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22986007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22986007</a>] [<a href="https://doi.org/10.1186/1750-1172-7-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22986007">Huang et al. (2012)</a> identified a heterozygous 1804A-G transition in the ITPR1 gene, resulting in an asn602-to-asp (N602D) substitution at a highly conserved residue in the coupling/regulatory domain. The mutation was not found in 5,379 control exomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22986007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 4-year-old girl with SCA29, <a href="#25" class="mim-tip-reference" title="Parolin Schnekenberg, R., Perkins, E. M., Miller, J. W., Davies, W. I. L., D'Adamo, M. C., Pessia, M., Fawcett, K. A., Sims, D., Gillard, E., Hudspith, K., Skehel, P., Williams, J., and 9 others. <strong>De novo point mutations in patients diagnosed with ataxic cerebral palsy.</strong> Brain 138: 1817-1832, 2015. Note: Erratum: Brain 139: e14, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25981959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25981959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25981959[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awv117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25981959">Parolin Schnekenberg et al. (2015)</a> identified a de novo heterozygous c.1759A-G transition in the ITPR1 gene, resulting in an asn602-to-asp (N602D) substitution at a conserved residue in the IRBIT binding domain. The patient was part of a cohort of children diagnosed clinically with ataxic cerebral palsy. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25981959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 GILLESPIE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs878853171 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853171;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=rs878853171" 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=rs878853171" 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=RCV000224999" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224999" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224999</a>
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<p>In a 4.5-year-old Tunisian girl with iris hypoplasia, cerebellar ataxia, and severe mental retardation (GLSP; <a href="/entry/206700">206700</a>), <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> identified homozygosity for a c.4672C-T transition (c.4672C-T, NM_001099952.2) in the ITPR1 gene (isoform 1), resulting in a gln1558-to-ter (Q1558X) substitution within the modulatory domain. Her clinically unaffected consanguineous parents were heterozygous for the substitution; ophthalmologic examination of the parents, including gonioscopy and funduscopy, revealed no abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 GILLESPIE SYNDROME</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs878853172 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853172;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=rs878853172" 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=rs878853172" 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=RCV000224993" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224993" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224993</a>
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<p>In a 16-year-old Brazilian girl with iris hypoplasia, cerebellar ataxia, and mild mental retardation (GLSP; <a href="/entry/206700">206700</a>), originally described by <a href="#19" class="mim-tip-reference" title="Luquetti, D. V., Oliveira-Sobrinho, R. P., Gil-da-Silva-Lopes, V. L. <strong>Gillespie syndrome: additional findings and parental consanguinity.</strong> Ophthal. Genet. 28: 89-93, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17558851/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17558851</a>] [<a href="https://doi.org/10.1080/13816810701209495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17558851">Luquetti et al. (2007)</a>, <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> identified homozygosity for a c.2182C-T transition (c.2182C-T, NM_001099952.2) in the ITPR1 gene (isoform 1), resulting in an arg728-to-ter (R728X) substitution within the modulatory domain. Her clinically unaffected consanguineous parents were heterozygous for the substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17558851+27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs878853173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853173;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=rs878853173" 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=rs878853173" 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=RCV000224998" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224998" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224998</a>
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<p>In a 7.5-year-old French girl with iris hypoplasia, cerebellar ataxia, and moderate mental retardation (GLSP; <a href="/entry/206700">206700</a>), <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> identified compound heterozygosity for 2 splice site mutations in the ITPR1 gene (isoform 1): the first was a c.6366+3A-T transversion (c.6366+3A-T, NM_001099952.2) in intron 50, predicted by mRNA analysis to result in a truncated transcript (Gly2102Valfs5Ter); the second was a c.6664+5G-T transversion in intron 52 (<a href="#0006">147265.0006</a>), also predicted to result in truncation (Ala2221Valfs23Ter) within the modulatory domain. The proband's clinically unaffected parents were each heterozygous for 1 of the splice site mutations; ophthalmologic examination of the parents, including gonioscopy and funduscopy, revealed no abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs878853174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853174;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=rs878853174" 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=rs878853174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>For discussion of the c.6664+5G-T transversion (c.6664+5G-T, NM_001099952.2) in the ITPR1 gene (isoform 1), predicted by mRNA analysis to result in premature termination (Ala2221Valfs23Ter), that was found in compound heterozygous state in a patient with Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>) by <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a>, see <a href="#0007">147265.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs878853175 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853175;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=rs878853175" 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=rs878853175" 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=RCV000224994 OR RCV001265870 OR RCV002516245" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224994, RCV001265870, RCV002516245" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224994...</a>
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<p>In an 18-year-old French woman with iris hypoplasia and cerebellar ataxia, who was reported to have normal intelligence (GLSP; <a href="/entry/206700">206700</a>), <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> identified heterozygosity for a de novo in-frame 3-bp deletion (c.7687_7689del, NM_001099952.2) in the ITPR1 gene (isoform 1), resulting in deletion of lys2563 (K2563del). The mutation was not present in her unaffected parents or in the ExAC, 1000 Genomes Project, dbSNP (build 132), or Imagine deja-vu databases. Coexpression of the K2563del mutant with wildtype in HEK-3KO cells resulted in altered calcium release, suggesting that the mutation exerts a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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 4 unrelated patients with Gillespie syndrome, including the French woman studied by <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a>, <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> identified heterozygosity for a de novo in-frame 3-bp deletion (c.7786_7789delAAG, NM_001168272.1) in the ITPR1 gene (isoform 3), which resulting in deletion of lys2596 (K2596del). In addition to iris hypoplasia and cerebellar ataxia, 2 of the patients had global delay, 1 had mild to moderate intellectual disability, and the French woman was listed as having 'mild' intellectual disability. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27108797+27108798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs878853176 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853176;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=rs878853176" 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=rs878853176" 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=RCV000224997" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224997" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224997</a>
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<p>In an 18-month-old girl with Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>), born of consanguineous French parents from La Guadeloupe, <a href="#9" class="mim-tip-reference" title="Gerber, S., Alzayady, K. J., Burglen, L., Bremond-Gibnac, D., Marchesin, V., Roche, O., Rio, M., Funalot, B., Calmon, R., Durr, A., Gil-da-Silva-Lopes, V. L., Ribeiro Bittar, M. F., and 18 others. <strong>Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome.</strong> Am. J. Hum. Genet. 98: 971-980, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108797/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108797</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108797[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108797">Gerber et al. (2016)</a> identified heterozygosity for a de novo c.7659T-G transversion (c.7659T-G, NM_001099952.2) in the ITPR1 gene (isoform 3), resulting in a phe2553-to-leu (F2553L) substitution. Neither of her unaffected parents carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108797" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs878853177 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878853177;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=rs878853177" 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=rs878853177" 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=RCV000224992" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224992" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224992</a>
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<p>In a mother and daughter with Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>), originally described by <a href="#33" class="mim-tip-reference" title="Verhulst, S., Smet, H., Ceulemans, B., Geerts, Y., Tassignon, M. J. <strong>Gillespie syndrome, partial aniridia, cerebellar ataxia and mental retardation in mother and daughter.</strong> Bull. Soc. Belge Ophtal. 250: 37-42, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7952360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7952360</a>]" pmid="7952360">Verhulst et al. (1993)</a>, <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> identified heterozygosity for a c.6281A-G transition (c.6281A-G, NM_001168272.1) in the ITPR1 gene (isoform 3), resulting in a glu2094-to-gly (E2094G) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7952360+27108798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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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ITPR1, GLY2539ARG, 7615G-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"><span class="text-primary">●</span> rs752281590 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs752281590;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/rs752281590?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=rs752281590" 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=rs752281590" 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=RCV000224995 OR RCV000622922 OR RCV001092121 OR RCV001200032 OR RCV001542744" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224995, RCV000622922, RCV001092121, RCV001200032, RCV001542744" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224995...</a>
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<p>In 5 unrelated patients with Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>), <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> identified heterozygosity for a de novo c.7615G-A transition (c.7615G-A, NM_001168272.1) in the ITPR1 gene (isoform 3), resulting in a gly2539-to-arg (G2539R) substitution in the transmembrane calcium ion transport domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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> rs752281590 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs752281590;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/rs752281590?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=rs752281590" 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=rs752281590" 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=RCV000224996 OR RCV001531555" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000224996, RCV001531555" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000224996...</a>
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<p>In a 7-year-old boy with Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>), <a href="#21" class="mim-tip-reference" title="McEntagart, M., Williamson, K. A., Rainger, J. K., Wheeler, A., Seawright, A., De Baere, E., Verdin, H., Bergendahl, L. T., Quigley, A., Rainger, J., Dixit, A., Sarkar, A., and 26 others. <strong>A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect.</strong> Am. J. Hum. Genet. 98: 981-992, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27108798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27108798</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27108798[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27108798">McEntagart et al. (2016)</a> identified heterozygosity for a de novo c.7615G-C transversion (c.7615G-C, NM_001168272.1) in the ITPR1 gene (isoform 3), resulting in a gly2539-to-arg (G2539R) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27108798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs1553758021 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553758021;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=rs1553758021" 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=rs1553758021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 6-year-old girl with a phenotype consistent with Gillespie syndrome (GLSP; <a href="/entry/206700">206700</a>), <a href="#32" class="mim-tip-reference" title="van Dijk, T., Barth, P., Reneman, L., Appelhof, B., Baas, F., Poll-The, B. T. <strong>A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxias</strong> Am. J. Med. Genet. 173A: 207-212, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27862915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27862915</a>] [<a href="https://doi.org/10.1002/ajmg.a.37962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27862915">van Dijk et al. (2017)</a> identified a de novo heterozygous c.7649T-A transversion (c.7649T-A, NM_001099952.2) in exon 56 the ITPR1 gene, resulting in an ile2550-to-asn (I2550N) substitution at a highly conserved residue in the transmembrane domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. The patient had severe pontine and cerebellar hypoplasia, although she had no ocular abnormalities. <a href="#32" class="mim-tip-reference" title="van Dijk, T., Barth, P., Reneman, L., Appelhof, B., Baas, F., Poll-The, B. T. <strong>A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxias</strong> Am. J. Med. Genet. 173A: 207-212, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27862915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27862915</a>] [<a href="https://doi.org/10.1002/ajmg.a.37962" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27862915">Van Dijk et al. (2017)</a> noted that ITRP1 mutations identified in other patients with Gillespie syndrome also occur within or near the transmembrane domain of the protein (see, e.g., G2539R, <a href="#0012">147265.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27862915" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon 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">rs2124927471 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2124927471;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=rs2124927471" 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=rs2124927471" 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=RCV002051254 OR RCV002471172 OR RCV002545403 OR RCV003987914" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002051254, RCV002471172, RCV002545403, RCV003987914" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002051254...</a>
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<p>In a mother and her 2 children with autosomal dominant spinocerebellar ataxia-29 (SCA29; <a href="/entry/117360">117360</a>), <a href="#5" class="mim-tip-reference" title="Casey, J. P., Hirouchi, T., Hisatsune, C., Lynch, B., Murphy, R., Dunne, A. M., Miyamoto, A., Ennis, S., van der Spek, N., O'Hici, B., Mikoshiba, K., Lynch, S. A. <strong>A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca(2+) signal patterns.</strong> J. Neurol. 264: 1444-1453, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28620721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28620721</a>] [<a href="https://doi.org/10.1007/s00415-017-8545-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28620721">Casey et al. (2017)</a> identified a heterozygous c.106C-T transition (c.106C-T, NM_001168272.1) in the ITPR1 gene, resulting in an arg36-to-cys (R36C) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the mother. The mutated residue is located in the amino-terminal region of ITPR1 called the suppressor domain, a region thought to be critical for IP3 binding affinity regulation. Consistent with this, the R36C mutation showed a significantly higher affinity for IP3 binding than wildtype ITPR1 and altered the intracellular Ca(2+) signal from a transient to a sigmoidal pattern, suggesting a gain-of-function mechanism. The authors noted that previously reported ITPR1 mutations causing SCA29 have been associated with loss of function rather than gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28620721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1002/ajmg.10323" target="_blank">Full Text</a>]
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Casey, J. P., Hirouchi, T., Hisatsune, C., Lynch, B., Murphy, R., Dunne, A. M., Miyamoto, A., Ennis, S., van der Spek, N., O'Hici, B., Mikoshiba, K., Lynch, S. A.
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<strong>A novel gain-of-function mutation in the ITPR1 suppressor domain causes spinocerebellar ataxia with altered Ca(2+) signal patterns.</strong>
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J. Neurol. 264: 1444-1453, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28620721/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28620721</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28620721" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00415-017-8545-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1125203" target="_blank">Full Text</a>]
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Dudding, T. E., Friend, K., Schofield, P. W., Lee, S., Wilkinson, I. A., Richards, R. I.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15623688/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15623688</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15623688" 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/10.1212/01.wnl.0000147299.80872.d1" target="_blank">Full Text</a>]
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Hara, K., Fukushima, T., Suzuki, T., Shimohata, T., Oyake, M., Ishiguro, H., Hirota, K., Miyashita, A., Kuwano, R., Kurisaki, H., Yomono, H., Goto, J., Kanazawa, I., Tsuji, S.
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[<a href="https://doi.org/10.1212/01.wnl.0000110190.08412.25" target="_blank">Full Text</a>]
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Hara, K., Shiga, A., Nozaki, H., Mitsui, J., Takahashi, Y., Ishiguro, H., Yomono, H., Kurisaki, H., Goto, J., Ikeuchi, T., Tsuji, S., Nishizawa, M., Onodera, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18579805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18579805</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18579805" 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/10.1212/01.wnl.0000311277.71046.a0" target="_blank">Full Text</a>]
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Higo, T., Hattori, M., Nakamura, T., Natsume, T., Michikawa, T., Mikoshiba, K.
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[<a href="https://doi.org/10.1016/j.cell.2004.11.048" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12611586/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12611586</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12611586" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Taufiq-Ur-Rahman2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Taufiq-Ur-Rahman, Skupin, A., Falcke, M., Taylor, C. W.
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<strong>Clustering of InsP3 receptors by InsP3 retunes their regulation by InsP3 and Ca(2+).</strong>
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Nature 458: 655-659, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19348050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19348050</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19348050[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=19348050" 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/nature07763" target="_blank">Full Text</a>]
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</p>
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<a id="van de Leemput2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van de Leemput, J., Chandran, J., Knight, M. A., Holtzclaw, L. A., Scholz, S., Cookson, M. R., Houlden, H., Gwinn-Hardy, K., Fung, H.-C., Lin, X., Hernandez, D., Simon-Sanchez, J., and 11 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17590087/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17590087</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17590087[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=17590087" 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/10.1371/journal.pgen.0030108" target="_blank">Full Text</a>]
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<a id="van Dijk2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van Dijk, T., Barth, P., Reneman, L., Appelhof, B., Baas, F., Poll-The, B. T.
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<strong>A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxias</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27862915/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27862915</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27862915" 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/10.1002/ajmg.a.37962" target="_blank">Full Text</a>]
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<a id="33" class="mim-anchor"></a>
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<a id="Verhulst1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Verhulst, S., Smet, H., Ceulemans, B., Geerts, Y., Tassignon, M. J.
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<strong>Gillespie syndrome, partial aniridia, cerebellar ataxia and mental retardation in mother and daughter.</strong>
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<a id="34" class="mim-anchor"></a>
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<a id="Wang2012" class="mim-anchor"></a>
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<p class="mim-text-font">
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Wang, Y., Li, G., Goode, J., Paz, J. C., Ouyang, K., Screaton, R., Fischer, W. H., Chen, J., Tabas, I., Montminy, M.
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<strong>Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.</strong>
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Nature 485: 128-132, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22495310/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22495310</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22495310" 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/nature10988" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="White2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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White, C., Yang, J., Monteiro, M. J., Foskett, J. K.
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<strong>CIB1, a ubiquitously expressed Ca(2+)-binding protein ligand of the InsP3 receptor Ca(2+) release channel.</strong>
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J. Biol. Chem. 281: 20825-20833, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16723353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16723353</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16723353" 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/10.1074/jbc.M602175200" target="_blank">Full Text</a>]
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<a id="36" class="mim-anchor"></a>
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<a id="Yamada1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamada, N., Makino, Y., Clark, R. A., Pearson, D. W., Mattei, M.-G., Guenet, J.-L., Ohama, E., Fujino, I., Miyawaki, A., Furuichi, T., Mikoshiba, K.
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<strong>Human inositol 1,4,5-triphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7945203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7945203</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7945203" 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/10.1042/bj3020781" target="_blank">Full Text</a>]
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 12/20/2022
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 06/30/2020<br>Bao Lige - updated : 12/20/2019<br>Bao Lige - updated : 12/07/2018<br>Cassandra L. Kniffin - updated : 04/16/2018<br>Cassandra L. Kniffin - updated : 07/19/2016<br>Marla J. F. O'Neill - updated : 6/10/2016<br>Cassandra L. Kniffin - updated : 2/4/2013<br>Ada Hamosh - updated : 9/20/2012<br>Cassandra L. Kniffin - updated : 7/8/2011<br>Marla J. F. O'Neill - updated : 3/3/2011<br>Cassandra L. Kniffin - updated : 1/21/2010<br>Ada Hamosh - updated : 4/16/2009<br>Cassandra L. Kniffin - updated : 9/29/2008<br>Cassandra L. Kniffin - updated : 2/29/2008<br>Cassandra L. Kniffin - updated : 7/16/2007<br>Patricia A. Hartz - updated : 3/2/2007<br>Ada Hamosh - updated : 8/7/2006<br>Ada Hamosh - updated : 3/8/2005<br>Stylianos E. Antonarakis - updated : 1/24/2005<br>Patricia A. Hartz - updated : 2/9/2004<br>Ada Hamosh - updated : 11/18/2002<br>Orest Hurko - updated : 2/5/1996
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</span>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 8/21/1991
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/11/2023
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/10/2023<br>carol : 01/09/2023<br>carol : 12/21/2022<br>carol : 12/20/2022<br>carol : 06/17/2022<br>alopez : 06/30/2020<br>mgross : 12/20/2019<br>mgross : 12/07/2018<br>carol : 04/18/2018<br>ckniffin : 04/16/2018<br>carol : 10/18/2017<br>carol : 07/31/2017<br>carol : 07/18/2017<br>alopez : 07/20/2016<br>ckniffin : 07/19/2016<br>joanna : 06/13/2016<br>carol : 6/13/2016<br>carol : 6/10/2016<br>carol : 2/5/2013<br>ckniffin : 2/4/2013<br>alopez : 11/26/2012<br>alopez : 9/25/2012<br>terry : 9/20/2012<br>wwang : 7/18/2011<br>ckniffin : 7/8/2011<br>carol : 3/3/2011<br>terry : 3/3/2011<br>carol : 2/4/2010<br>ckniffin : 1/21/2010<br>alopez : 5/4/2009<br>alopez : 4/22/2009<br>alopez : 4/21/2009<br>terry : 4/16/2009<br>wwang : 10/10/2008<br>wwang : 10/6/2008<br>ckniffin : 9/29/2008<br>wwang : 6/10/2008<br>wwang : 5/13/2008<br>wwang : 5/13/2008<br>ckniffin : 2/29/2008<br>wwang : 7/20/2007<br>ckniffin : 7/16/2007<br>mgross : 3/12/2007<br>terry : 3/2/2007<br>alopez : 8/9/2006<br>terry : 8/7/2006<br>terry : 7/26/2006<br>carol : 8/30/2005<br>alopez : 3/8/2005<br>mgross : 1/24/2005<br>mgross : 2/9/2004<br>mgross : 2/9/2004<br>alopez : 12/19/2002<br>tkritzer : 11/22/2002<br>terry : 11/19/2002<br>alopez : 11/18/2002<br>alopez : 11/18/2002<br>terry : 11/18/2002<br>carol : 4/19/2000<br>carol : 4/18/2000<br>terry : 4/15/1996<br>mark : 2/5/1996<br>terry : 1/30/1996<br>mark : 1/30/1996<br>terry : 1/30/1996<br>mark : 1/11/1996<br>terry : 1/11/1996<br>carol : 12/30/1994<br>terry : 12/22/1994<br>supermim : 3/16/1992<br>carol : 2/22/1992<br>carol : 9/4/1991<br>carol : 8/21/1991
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 147265
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<div>
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<h3>
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<span class="mim-font">
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INOSITOL 1,4,5-TRIPHOSPHATE RECEPTOR, TYPE 1; ITPR1
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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IP3R<br />
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IP3R1
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ITPR1</em></strong>
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</span>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 253176002, 715825009, 716724006;
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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: 3p26.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:4,493,348-4,847,506 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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3p26.1
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</span>
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</td>
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<td>
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<span class="mim-font">
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Gillespie syndrome
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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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206700
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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<tr>
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<td>
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<span class="mim-font">
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Spinocerebellar ataxia 15
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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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606658
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Spinocerebellar ataxia 29, congenital nonprogressive
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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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117360
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ITPR1 gene encodes the inositol 1,4,5-triphosphate (IP3) receptor, an intracellular IP3-gated calcium channel that modulates intracellular calcium signaling (Berridge, 1993; Hirota et al., 2003). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ross et al. (1991) cloned a cDNA for the human type 1 inositol 1,4,5-triphosphate receptor. Nucifora et al. (1995) studied the expression of alternatively spliced forms. The long form appears to create an additional consensus protein kinase C phosphorylation site. The long form predominates in most brain regions except for the cerebellum, while the short form predominates in peripheral tissues. </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>Inositol 1,4,5-triphosphate is an intracellular second messenger produced by phospholipase C through a G protein-dependent mechanism. It releases calcium from endoplasmic reticulum by binding to specific receptors that are coupled to calcium channels. These receptors are abundant in neuronal and nonneuronal tissues. The neuronal form of the receptor is abundant in the cerebellum, particularly the perikaryon of the Purkinje cells. Matsumoto et al. (1996) noted that the product of the ITPR1 gene is predominantly enriched in cerebellar Purkinje cells but is also concentrated in neurons in the hippocampal CA1 region, caudate-putamen, and cerebral cortex. The inositol triphosphate receptor shares sequence and functional homology with the ryanodine receptor (180901); they both trigger the release of calcium from intracellular stores. The primary structure of the inositol triphosphate receptor contains 3 domains: an inositol triphosphate binding domain near the N terminus, a coupling domain in the middle of the molecule, and a transmembrane spanning domain near the C terminus. In addition, there are at least 2 consensus protein kinase A phosphorylation sites and at least 1 consensus ATP-binding site (Nucifora et al., 1995). </p><p>Boehning et al. (2003) presented evidence that mammalian cytochrome c (123970) binds to inositol 1,4,5-trisphosphate receptors during apoptosis. The addition of 1 nanomolar cytochrome c blocked calcium-dependent inhibition of ITPR1 function in ITPR1-transfected COS cells. Early in apoptosis, cytochrome c translocated to the endoplasmic reticulum, where it selectively bound ITPR1, resulting in sustained oscillatory cytosolic calcium increases. These calcium events were linked to the coordinated release of cytochrome c from all mitochondria. </p><p>In mouse brain, Hirota et al. (2003) identified Carp (CA8; 114815) as an ITPR1-binding protein. Western blot and immunohistochemical studies showed that Carp colocalized and interacted with ITPR1 predominantly in the cytoplasm of cerebellar Purkinje cells. Mutagenesis studies showed that residues 45 to 291 of Carp were essential for its association with the modulatory domain of ITPR1 (residues 1387 to 1647). Carp functioned as an inhibitor of IP3 binding to ITPR1 by reducing the affinity of the receptor for IP3. </p><p>Higo et al. (2005) found that ERp44 (TXNDC4; 609170), an endoplasmic reticulum (ER) luminal protein of the thioredoxin family, interacted directly with the third luminal loop of IP3R1. The interaction was dependent on pH, Ca(2+) concentration, and redox state, with the presence of free cysteine residues in the loop of IP3R1 required. Ca(2+)-imaging experiments and single-channel recording of IP3R1 activity with a planar lipid bilayer system demonstrated that IP3R1 was directly inhibited by ERp44. Higo et al. (2005) concluded that ERp44 senses the environment in the ER lumen and modulates IP3R1 activity accordingly, which in turn contributes to regulating both intraluminal conditions and the complex patterns of cytosolic Ca(2+) concentrations. </p><p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was ITPR1. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. </p><p>IP3R1 localizes to dendrites and is thought to be locally translated in response to synaptic activity. Iijima et al. (2005) showed that the 3-prime UTR of mouse Ip3r1 was required as a cis element for its dendritic localization, and they identified Hzf (ZNF385A; 609124) as a trans-acting factor. Moreover, dendritic Ip3r1 mRNA in Purkinje cells and Bdnf (113505)-induced protein synthesis were both reduced in Hzf-deficient mice. </p><p>Inositol 1,4,5-trisphosphate receptors release calcium ions from intracellular stores. Dellis et al. (2006) found that inositol trisphosphate stimulated opening of very few (1.9 +/- 0.2 per cell) calcium-ion permeable channels in whole-cell patch-clamp recording of DT40 chicken or mouse B cells. Activation of the B-cell receptor in perforated-patch recordings evoked the same response. Inositol trisphosphate failed to stimulate intracellular or plasma membrane channels in cells lacking IP3R. Expression of IP3R restored both responses. Mutations in the pore affected the conductances of inositol triphosphate-activated plasma membrane and intracellular channels similarly. An impermeant pore mutant abolished B cell receptor-evoked calcium ion signals, and plasma membrane IP3Rs were undetectable. After introduction of an alpha-bungarotoxin binding site near the pore, plasma membrane IP3Rs were modulated by extracellular alpha-bungarotoxin. IP3Rs are unusual among endoplasmic reticulum proteins in being also functionally expressed at the plasma membrane, where very few IP3Rs contribute substantially to the calcium ion entry evoked by the B-cell receptor. </p><p>White et al. (2006) characterized the structural determinants for binding of CABP1 (605563) to IP3R and found that disruption of any the 3 functional EF-hands of CABP1 reduced binding to IP3R, with EF3 and EF4 being particularly important. Examination of other ER-localized proteins with functional EF3 and EF4 showed that CIB1 (602293) interacted with the ligand-binding region of IP3R in a Ca(2+)-dependent manner. Recombinant CIB1 bound to IP3R and directly activated the IP3R channel for Ca(2+) release in the absence of IP3. In contrast, pre-exposure of IP3R to CIB1 reduced the number of channels available for subsequent activation by IP3, and overexpression of CIB1 decreased the amplitude of agonist-induced intracellular Ca(2+) transients and inhibited Ca(2+) release in intact cells. These findings demonstrated a paradoxical role for CIB1 on Ca(2+) release, in which binding of CIB1 as a ligand initially activates the IP3R channel, but the channel then undergoes ligand-dependent inactivation. </p><p>Using nuclear patch-clamp recording, Taufiq-Ur-Rahman et al. (2009) demonstrated that inositol-1,4,5-trisphosphate receptors are initially randomly distributed with an estimated separation of about 1 micron. Low concentrations of inositol-4,4,5-trisphosphate (Insp3) cause InsP3Rs to aggregate rapidly and reversibly into small clusters of about 4 closely associated InsP3Rs. At resting cytosolic calcium ion concentration, clustered InsP3Rs open independently, but with lower open probability, shorter open time, and less InsP3 sensitivity than lone InsP3Rs. Increasing cytosolic calcium ion concentration reverses the inhibition caused by clustering, InsP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes InsP3Rs to local calcium rises and increases the effects of calcium. Dynamic regulation of clustering by InsP3 retunes InsP3R sensitivity to InsP3 and calcium ion, facilitating hierarchical recruitment of the elementary events that underlie all InsP3-evoked calcium signals. </p><p>Wang et al. (2012) showed in mice that glucagon (GCG; 138030) stimulates CRTC2 (608972) dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent PPP3CA (114105). Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs) (ITPR1; ITPR2, 600144; ITPR3, 147267), which associated with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT (164730)-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrated how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes. </p><p>Fredericks et al. (2014) found that knockout of Selk (SELENOK; 607916) in mouse macrophages decreased Ip3r expression due to defective Ip3r palmitoylation. Immunofluorescence and coimmunoprecipitation analyses showed that the SH3 domain of Dhhc6 (ZDHHC6; 618715) interacted with the SH3-binding domain of Selk and that Dhhc6 and Selk formed a complex in the ER membrane. Interaction between Selk and Dhhc6 was dynamic and correlated with Ip3r levels. DHHC6 knockdown reduced IP3R palmitoylation, expression, and inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) flux in HEK293 cells. Mass spectrophotometric analysis revealed that rat Ip3r was likely palmitoylated on 3 cysteines. The results demonstrated that DHHC6 and SELK palmitoylate IP3R and thereby stabilized IP3R expression, facilitating its function in the ER. </p><p>Perry et al. (2020) showed that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase (608786) flux, while also increasing mitochondrial fat oxidation, all of which are mediated by stimulation of the inositol triphosphate receptor-1 (INSP3R1, also known as ITPR1). In rats and mice, chronic physiologic increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment, reversing hepatic steatosis and glucose intolerance, were abrogated in Insp3r1-knockout mice. Perry et al. (2020) suggested that their results provided insights into glucagon biology and suggested that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type 2 diabetes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Bosanac et al. (2002) presented the 2.2-angstrom crystal structure of the inositol triphosphate-binding core of mouse Itpr1 in complex with inositol triphosphate. The asymmetric, boomerang-like structure consists of an N-terminal beta-trefoil domain and a C-terminal alpha-helical domain containing an 'armadillo repeat'-like fold. The cleft formed by the 2 domains exposes a cluster of arginine and lysine residues that coordinate the 3 phosphoryl groups of inositol triphosphate. Putative calcium-binding sites were identified in 2 separate locations within the inositol triphosphate-binding core. </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>Ozcelik et al. (1991) used an M13 clone for a type 1 receptor and another for a type 3 receptor as probes for assignment of their loci to human chromosomes by Southern blot analysis of DNA from human/rodent somatic cell hybrids. The ITPR1 cDNA probe was found to be associated with the presence of human chromosome 3 in all hybrids. Furthermore, it was not present in 2 hybrids that contained an isochromosome of 3q, without an intact copy of this chromosome, thus localizing ITPR1 to 3p. By isotopic in situ hybridization, Yamada et al. (1994) localized the ITPR1 gene to 3p26-p25. They found that the gene is widely expressed in human tissues and thus may play critical roles in various kinds of cellular functions. </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>Cytogenetics</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>Cargile et al. (2002) studied a patient with clinical findings consistent with 3p- syndrome (613792), a rare contiguous gene disorder characterized by developmental delay, growth retardation, and dysmorphic features. They noted that all reported cases had, at a minimum, the loss of chromosomal material telomeric to 3p25.3. Their patient had an interstitial deletion involving a 4.5-Mb interval between markers D3S3630 and D3S1304. They suggested the ITPR1 gene as a candidate for the mental retardation found in this syndrome. </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>Spinocerebellar Ataxia 15</em></strong></p><p>
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Van de Leemput et al. (2007) identified heterozygous deletions involving the ITPR1 gene in affected members of 3 unrelated families with adult-onset autosomal dominant spinocerebellar ataxia-15 (SCA15; 606658), including the SCA15 family of Australian origin used to map the locus to 3p26-p25 (Knight et al., 2003). Using high-density genomewide SNP genotyping, Van de Leemput et al. (2007) found a large deletion removing the first 3 exons of the neighboring SUMF1 gene (607939) and the first 10 exons of the ITPR1 gene in the family reported by Knight et al. (2003). Affected members of 2 additional families were found to have even larger deletions removing the first 3 exons of SUMF1 and 44 and 40 exons of the ITPR1 gene, respectively. The deletions were not observed in a control population. As homozygous mutations in the SUMF1 gene lead to a different phenotype (MSD; 272200) and heterozygous carriers of SUMF1 mutations do not exhibit a movement disorder, the authors concluded that deletions of the ITPR1 gene underlie the ataxia phenotype of SCA15. Van de Leemput et al. (2007) noted that direct gene sequencing failed to identify mutations in the ITPR1 gene and that gene dosage studies were required for accurate diagnosis. </p><p>In affected members of a large 4-generation Japanese family with SCA15, originally designated as SCA16, Iwaki et al. (2008) identified a heterozygous deletion of exons 1 to 48 of the ITPR1 gene (147265.0001). The SUMF1 gene was not affected. The findings indicated that SCA15 is due to haploinsufficiency of ITPR1. Iwaki et al. (2008) concluded that the CNTN4 (607280) transition previously identified in this family was likely a rare polymorphism that was not responsible for the disease. </p><p>In affected members of a Japanese family with SCA15 originally reported by Hara et al. (2004), Hara et al. (2008) identified a 414-kb deletion of chromosome 3p26 including all of the ITPR1 gene and exon 1 of the SUMF1 gene. Breakpoint analysis indicated that the deletion was mediated by nonhomologous end joining. RT-PCR showed that expression levels of both ITPR1 and SUMF1 in the patients were half of levels in normal controls. In affected members of a second unrelated Japanese family reported by Hara et al. (2004), Hara et al. (2008) identified a heterozygous mutation in the ITPR1 gene (147265.0002). </p><p>Synofzik et al. (2011) identified pathogenic ITPR1 deletions in 5 (8.9%) of 56 European families with autosomal dominant SCA who were negative for common SCA repeat expansions. All deletions detected by multiplex ligation-dependent probe amplification (MLPA) were confirmed by SNP array and spanned approximately 183 to 423 kb, and each family had a unique deletion. In 3 families, the deletions affected partly both the ITPR1 and SUMF1 genes, without including the 3-prime region of the ITPR1 gene. One family had a deletion preserving exons 1 and 2 in the 5-prime untranslated region of the ITPR1 gene. </p><p><strong><em>Spinocerebellar Ataxia 29</em></strong></p><p>
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By exome sequencing of a member of the family with autosomal dominant spinocerebellar ataxia-29 (SCA29; 117360) reported by Dudding et al. (2004), Huang et al. (2012) identified a heterozygous mutation in the ITPR1 gene (V1553M; 147265.0003). The mutation was confirmed by Sanger sequencing and segregated with the disorder in this family. Direct sequencing of the ITPR1 gene in a Canadian family with a similar disorder identified a different heterozygous missense mutation (N602D; 147265.0004). Both mutations occurred at highly conserved residues in the coupling/regulatory domain that modulates channel function, possibly resulting in dysregulation of intracellular calcium signaling. The phenotype of SCA29 was distinguished from that of SCA15 by onset in infancy, delayed motor development, and mild cognitive impairment. </p><p>Parolin Schnekenberg et al. (2015) reported 2 unrelated children with a clinical diagnosis of ataxic cerebral palsy who were found to carry different de novo heterozygous mutations in the ITPR1 gene (see, e.g., 147265.0004). Both patients showed delayed motor development, ataxic gait, and moderate intellectual disability, consistent with SCA29. Functional studies of the variants were not performed. </p><p>In a mother and her 2 children with SCA29, Casey et al. (2017) identified a heterozygous missense mutation in the ITPR1 gene (R36C; 147265.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the mother. The mutated residue is located in the amino-terminal region of ITPR1 called the suppressor domain, a region thought to be critical for IP3 binding affinity regulation. Consistent with this, the R36C mutation showed a significantly higher affinity for IP3 binding than wildtype ITPR1 and altered the intracellular Ca(2+) signal from a transient to a sigmoidal pattern, suggesting a gain-of-function mechanism. The authors noted that previously reported ITPR1 mutations causing SCA29 have been associated with loss of function rather than gain of function. </p><p><strong><em>Gillespie Syndrome</em></strong></p><p>
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In 3 unrelated patients with iris hypoplasia, cerebellar ataxia, and mental retardation (GLSP; 206700), Gerber et al. (2016) identified homozygosity or compound heterozygosity for mutations in the ITPR1 gene (147265.0005-147265.0008). In 2 more probands with Gillespie syndrome, they identified de novo heterozygous mutations in ITPR1 (147265.0009 and 147265.0010). Gerber et al. (2016) concluded that their findings demonstrated the long-suspected coexistence of autosomal recessive and autosomal dominant patterns of inheritance of Gillespie syndrome. </p><p>In 13 patients from 12 families with Gillespie syndrome, McEntagart et al. (2016) identified heterozygosity for mutations in the ITPR1 gene (see, e.g., 607108.0009 and 607108.0011-607108.0013). The authors noted that the 13 patients' mutations affected only 3 residues in ITPR1, and at least 10 were shown to have occurred de novo. McEntagart et al. (2016) stated that protein structure-based analysis indicated that the mutations were likely to have a dominant-negative effect, and noted that the cerebellar anomalies in these patients were similar to those seen in the SCA29 phenotype. </p><p>In a 6-year-old girl with a phenotype consistent with Gillespie syndrome, van Dijk et al. (2017) identified a de novo heterozygous missense mutation in the ITPR1 gene (I2550N; 147265.0014). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that the mutation occurs within the transmembrane domain, similar to ITPR1 mutations found in other patients with Gillespie syndrome. The patient had severe pontine and cerebellar hypoplasia, although she had no ocular abnormalities. </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>Matsumoto et al. (1996) found that most Itpr1-deficient mice generated by gene targeting die in utero, and that most animals that are born alive have severe ataxia and tonic or tonic-clonic seizures and die by the weaning period. Electroencephalograms showed that they suffer from epilepsy, indicating that ITPR1 is essential for proper brain function. However, observation by light microscope of the hematoxylin-eosin staining of the brain and peripheral tissues of deficient mice showed no abnormality and the unique electrophysiologic properties of the cerebellar Purkinje cells of deficient mice were not severely impaired. In the mouse the Intp3r locus is closely situated to the 'opisthotonos' mutant locus (opt), and Opt homozygous mutant mice exhibit phenotypes similar to those described for the knockout mice. The opt locus is on mouse chromosome 6. </p><p>Street et al. (1997) determined that the Opt mouse has a homozygous in-frame deletion of exons 43 and 44 of the Itpr1 gene. </p><p>Ogura et al. (2001) found that heterozygous Itpr1 knockout mice (Itpr1 +/-) demonstrated impaired motor coordination compared to wildtype mice as shown on the rotarod test. </p><p>Van de Leemput et al. (2007) identified a homozygous spontaneous 18-bp deletion in exon 18 of the Itpr1 gene that caused a recessive movement disorder in mice similar to that observed in Opt mice. The deletion mutation resulted in markedly decreased levels of Itpr1 in cerebellar Purkinje cells. </p><p>McEntagart et al. (2016) generated Itpr1 +/- mice and observed no obvious morphologic differences in early development of the iris compared to their wildtype littermates. Immunohistochemistry of wildtype mice showed no specific staining of ITPR1 in the developing iris. No change in Pax6 (607108) levels was detected between mutant and wildtype embryos. Examination of 2 Itpr1 +/- mice at age 76 days showed only minor defects in the iris compared to their wildtype littermates, and they exhibited no major anomalies that would be consistent with the phenotype seen in Gillespie syndrome (GLSP; 206700). McEntagart et al. (2016) suggested that the role of ITPR1 in iris development is either indirect, acting at a later stage of development, or is tolerant of 50% residual channel activity. The latter would be consistent with the lack of an iris phenotype in patients with spinocerebellar ataxia-15 (SCA15; 606658), in whom ITPR1 haploinsufficiency is the predominant genetic mechanism (see MOLECULAR GENETICS). </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>15 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 SPINOCEREBELLAR ATAXIA 15</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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ITPR1, EX1-48DEL
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<br />
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ClinVar: RCV000015923
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large 4-generation Japanese family with spinocerebellar ataxia-15 (SCA15; 606658), originally designated as SCA16, Iwaki et al. (2008) identified a heterozygous deletion of exons 1 to 48 of the ITPR1 gene. The SUMF1 gene was not affected. The findings indicated that SCA15 is due to haploinsufficiency of ITPR1. Iwaki et al. (2008) concluded that the CNTN4 (607280) transition previously identified in this family was likely a rare polymorphism that was not responsible for the disease. </p>
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</span>
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|
</div>
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<div>
|
|
<br />
|
|
</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>.0002 SPINOCEREBELLAR ATAXIA 15</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
<div>
|
|
<span class="mim-text-font">
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|
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|
ITPR1, PRO1059LEU
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|
<br />
|
|
|
|
SNP: rs121912425,
|
|
|
|
|
|
|
|
ClinVar: RCV000015924
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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|
|
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<div>
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<span class="mim-text-font">
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|
<p>In affected members of a Japanese family with spinocerebellar ataxia-15 (SCA15; 606658) reported by Hara et al. (2004), Hara et al. (2008) identified a heterozygous 8581C-T transition in exon 25 of the ITPR1 gene, resulting in a pro1059-to-leu (P1059L) substitution in the modulatory and transducing domain. The mutation was not detected in 234 control chromosomes. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
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</div>
|
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 SPINOCEREBELLAR ATAXIA 29</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
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|
ITPR1, VAL1553MET
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|
<br />
|
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|
|
SNP: rs397514535,
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|
|
ClinVar: RCV000032771, RCV000624908, RCV001091682, RCV003389037, RCV004767027
|
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|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
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<span class="mim-text-font">
|
|
<p>In affected members of an Australian family with early-onset nonprogressive spinocerebellar ataxia-29 (SCA29; 117360) who were previously reported by Dudding et al. (2004), Huang et al. (2012) identified a heterozygous 4657G-A transition in the ITPR1 gene, resulting in a val1553-to-met (V1553M) substitution at a highly conserved residue in the coupling/regulatory domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in this family and was not found in 5,379 control exomes. </p>
|
|
</span>
|
|
</div>
|
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|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 SPINOCEREBELLAR ATAXIA 29</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
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|
ITPR1, ASN602ASP
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs397514536,
|
|
|
|
|
|
|
|
ClinVar: RCV000032772
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Canadian family with spinocerebellar ataxia-29 (SCA29; 117360), Huang et al. (2012) identified a heterozygous 1804A-G transition in the ITPR1 gene, resulting in an asn602-to-asp (N602D) substitution at a highly conserved residue in the coupling/regulatory domain. The mutation was not found in 5,379 control exomes. </p><p>In a 4-year-old girl with SCA29, Parolin Schnekenberg et al. (2015) identified a de novo heterozygous c.1759A-G transition in the ITPR1 gene, resulting in an asn602-to-asp (N602D) substitution at a conserved residue in the IRBIT binding domain. The patient was part of a cohort of children diagnosed clinically with ataxic cerebral palsy. Functional studies of the variant were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
TPR1, GLN1558TER
|
|
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|
|
|
<br />
|
|
|
|
SNP: rs878853171,
|
|
|
|
|
|
|
|
ClinVar: RCV000224999
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4.5-year-old Tunisian girl with iris hypoplasia, cerebellar ataxia, and severe mental retardation (GLSP; 206700), Gerber et al. (2016) identified homozygosity for a c.4672C-T transition (c.4672C-T, NM_001099952.2) in the ITPR1 gene (isoform 1), resulting in a gln1558-to-ter (Q1558X) substitution within the modulatory domain. Her clinically unaffected consanguineous parents were heterozygous for the substitution; ophthalmologic examination of the parents, including gonioscopy and funduscopy, revealed no abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, ARG728TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs878853172,
|
|
|
|
|
|
|
|
ClinVar: RCV000224993
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 16-year-old Brazilian girl with iris hypoplasia, cerebellar ataxia, and mild mental retardation (GLSP; 206700), originally described by Luquetti et al. (2007), Gerber et al. (2016) identified homozygosity for a c.2182C-T transition (c.2182C-T, NM_001099952.2) in the ITPR1 gene (isoform 1), resulting in an arg728-to-ter (R728X) substitution within the modulatory domain. Her clinically unaffected consanguineous parents were heterozygous for the substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, IVS50DS, A-T, +3
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs878853173,
|
|
|
|
|
|
|
|
ClinVar: RCV000224998
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7.5-year-old French girl with iris hypoplasia, cerebellar ataxia, and moderate mental retardation (GLSP; 206700), Gerber et al. (2016) identified compound heterozygosity for 2 splice site mutations in the ITPR1 gene (isoform 1): the first was a c.6366+3A-T transversion (c.6366+3A-T, NM_001099952.2) in intron 50, predicted by mRNA analysis to result in a truncated transcript (Gly2102Valfs5Ter); the second was a c.6664+5G-T transversion in intron 52 (147265.0006), also predicted to result in truncation (Ala2221Valfs23Ter) within the modulatory domain. The proband's clinically unaffected parents were each heterozygous for 1 of the splice site mutations; ophthalmologic examination of the parents, including gonioscopy and funduscopy, revealed no abnormalities. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, IVS52DS, G-T, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs878853174,
|
|
|
|
|
|
|
|
ClinVar: RCV000225000
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.6664+5G-T transversion (c.6664+5G-T, NM_001099952.2) in the ITPR1 gene (isoform 1), predicted by mRNA analysis to result in premature termination (Ala2221Valfs23Ter), that was found in compound heterozygous state in a patient with Gillespie syndrome (GLSP; 206700) by Gerber et al. (2016), see 147265.0007. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, 3-BP DEL, NT7687
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs878853175,
|
|
|
|
|
|
|
|
ClinVar: RCV000224994, RCV001265870, RCV002516245
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-year-old French woman with iris hypoplasia and cerebellar ataxia, who was reported to have normal intelligence (GLSP; 206700), Gerber et al. (2016) identified heterozygosity for a de novo in-frame 3-bp deletion (c.7687_7689del, NM_001099952.2) in the ITPR1 gene (isoform 1), resulting in deletion of lys2563 (K2563del). The mutation was not present in her unaffected parents or in the ExAC, 1000 Genomes Project, dbSNP (build 132), or Imagine deja-vu databases. Coexpression of the K2563del mutant with wildtype in HEK-3KO cells resulted in altered calcium release, suggesting that the mutation exerts a dominant-negative effect. </p><p>In 4 unrelated patients with Gillespie syndrome, including the French woman studied by Gerber et al. (2016), McEntagart et al. (2016) identified heterozygosity for a de novo in-frame 3-bp deletion (c.7786_7789delAAG, NM_001168272.1) in the ITPR1 gene (isoform 3), which resulting in deletion of lys2596 (K2596del). In addition to iris hypoplasia and cerebellar ataxia, 2 of the patients had global delay, 1 had mild to moderate intellectual disability, and the French woman was listed as having 'mild' intellectual disability. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, PHE2553LEU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs878853176,
|
|
|
|
|
|
|
|
ClinVar: RCV000224997
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 18-month-old girl with Gillespie syndrome (GLSP; 206700), born of consanguineous French parents from La Guadeloupe, Gerber et al. (2016) identified heterozygosity for a de novo c.7659T-G transversion (c.7659T-G, NM_001099952.2) in the ITPR1 gene (isoform 3), resulting in a phe2553-to-leu (F2553L) substitution. Neither of her unaffected parents carried the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, GLU2094GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs878853177,
|
|
|
|
|
|
|
|
ClinVar: RCV000224992
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and daughter with Gillespie syndrome (GLSP; 206700), originally described by Verhulst et al. (1993), McEntagart et al. (2016) identified heterozygosity for a c.6281A-G transition (c.6281A-G, NM_001168272.1) in the ITPR1 gene (isoform 3), resulting in a glu2094-to-gly (E2094G) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, GLY2539ARG, 7615G-A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs752281590,
|
|
|
|
|
|
gnomAD: rs752281590,
|
|
|
|
|
|
ClinVar: RCV000224995, RCV000622922, RCV001092121, RCV001200032, RCV001542744
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 unrelated patients with Gillespie syndrome (GLSP; 206700), McEntagart et al. (2016) identified heterozygosity for a de novo c.7615G-A transition (c.7615G-A, NM_001168272.1) in the ITPR1 gene (isoform 3), resulting in a gly2539-to-arg (G2539R) substitution in the transmembrane calcium ion transport domain. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, GLY2539ARG, 7615G-C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs752281590,
|
|
|
|
|
|
gnomAD: rs752281590,
|
|
|
|
|
|
ClinVar: RCV000224996, RCV001531555
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-year-old boy with Gillespie syndrome (GLSP; 206700), McEntagart et al. (2016) identified heterozygosity for a de novo c.7615G-C transversion (c.7615G-C, NM_001168272.1) in the ITPR1 gene (isoform 3), resulting in a gly2539-to-arg (G2539R) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 GILLESPIE SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ITPR1, ILE2550ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1553758021,
|
|
|
|
|
|
|
|
ClinVar: RCV000625707
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-year-old girl with a phenotype consistent with Gillespie syndrome (GLSP; 206700), van Dijk et al. (2017) identified a de novo heterozygous c.7649T-A transversion (c.7649T-A, NM_001099952.2) in exon 56 the ITPR1 gene, resulting in an ile2550-to-asn (I2550N) substitution at a highly conserved residue in the transmembrane domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP or ExAC databases. Functional studies of the variant and studies of patient cells were not performed. The patient had severe pontine and cerebellar hypoplasia, although she had no ocular abnormalities. Van Dijk et al. (2017) noted that ITRP1 mutations identified in other patients with Gillespie syndrome also occur within or near the transmembrane domain of the protein (see, e.g., G2539R, 147265.0012). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0015 SPINOCEREBELLAR ATAXIA 29</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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ITPR1, ARG36CYS
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<br />
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SNP: rs2124927471,
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ClinVar: RCV002051254, RCV002471172, RCV002545403, RCV003987914
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a mother and her 2 children with autosomal dominant spinocerebellar ataxia-29 (SCA29; 117360), Casey et al. (2017) identified a heterozygous c.106C-T transition (c.106C-T, NM_001168272.1) in the ITPR1 gene, resulting in an arg36-to-cys (R36C) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, occurred de novo in the mother. The mutated residue is located in the amino-terminal region of ITPR1 called the suppressor domain, a region thought to be critical for IP3 binding affinity regulation. Consistent with this, the R36C mutation showed a significantly higher affinity for IP3 binding than wildtype ITPR1 and altered the intracellular Ca(2+) signal from a transient to a sigmoidal pattern, suggesting a gain-of-function mechanism. The authors noted that previously reported ITPR1 mutations causing SCA29 have been associated with loss of function rather than gain of function. </p>
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</span>
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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>REFERENCES</strong>
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</span>
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