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Entry
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- *609139 - RECEPTOR EXPRESSION-ENHANCING PROTEIN 1; REEP1
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- OMIM
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<p>
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<span class="h4">*609139</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/609139">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div 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 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=ENSG00000068615;t=ENST00000538924" 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=65055" 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=609139" 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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<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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<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=ENSG00000068615;t=ENST00000538924" 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_001164730,NM_001164731,NM_001164732,NM_001371279,NM_001371280,NM_001410855,NM_001410856,NM_022912,XM_005264504,XM_011533044,XM_011533045,XM_017004725,XM_017004726,XM_017004727,XM_047445536,XM_047445537" 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_001371279" 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=609139" 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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<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=07810&isoform_id=07810_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/REEP1" 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/10434977,12597657,40675688,48146719,50234926,62702206,74733929,119619863,119619864,145337859,221039928,221041692,221041722,221041768,221041776,221042656,257900514,257900516,257900518,530367986,767915077,767915079,1034615941,1034615944,1034615946,1698387366,1698401380,1832406112,2217330275,2217330277,2287254651,2287254693,2462576146,2462576148,2462576150,2462576152,2462576154,2462576156,2462576158,2462576160" 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/Q9H902" 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 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=65055" 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=ENSG00000068615;t=ENST00000538924" 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=REEP1" 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=REEP1" 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+65055" 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/REEP1" 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:65055" 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/65055" 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=chr2&hgg_gene=ENST00000538924.7&hgg_start=86213993&hgg_end=86338083&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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://medlineplus.gov/genetics/gene/reep1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=609139[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=609139[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/REEP1/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/ENSG00000068615" 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=REEP1" 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=REEP1" 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=REEP1" 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=REEP1&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/PA134906680" 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:25786" 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/FBgn0261564.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:1098827" 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/REEP1#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:1098827" 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/65055/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=65055" 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=WBGene00020562;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-110411-267" 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://reactome.org/content/query?q=REEP1&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> 763068005<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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609139
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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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RECEPTOR EXPRESSION-ENHANCING PROTEIN 1; REEP1
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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">
|
|
CHROMOSOME 2 OPEN READING FRAME 23; C2ORF23
|
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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=REEP1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">REEP1</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">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/2/441?start=-3&limit=10&highlight=441">2p11.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:86213993-86338083&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'})">2:86,213,993-86,338,083</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614751,620011,610250" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/441?start=-3&limit=10&highlight=441">
|
|
2p11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Neuronopathy, distal hereditary motor, autosomal dominant 12
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/614751"> 614751 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
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</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Neuronopathy, distal hereditary motor, autosomal recessive 6
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620011"> 620011 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spastic paraplegia 31, autosomal dominant
|
|
|
|
</span>
|
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<p>REEP1 is involved in regulation of lipid droplet (LD) formation and endoplasmic reticulum (ER) morphology (<a href="#12" class="mim-tip-reference" title="Renvoise, B., Malone, B., Falgairolle, M., Munasinghe, J., Stadler, J., Sibilla, C., Park, S. H., Blackstone, C. <strong>Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.</strong> Hum. Molec. Genet. 25: 5111-5125, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27638887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27638887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27638887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddw315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27638887">Renvoise et al., 2016</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27638887" 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>Transport of G protein-coupled receptors (GPCRs) to the cell surface membrane is critical for receptor-ligand recognition. However, mammalian GPCR odorant receptors (ORs), when heterologously expressed in cells, are poorly expressed on the cell surface. By screening for genes that induced cell surface expression of ORs expressed in human embryonic kidney cells, <a href="#13" class="mim-tip-reference" title="Saito, H., Kubota, M., Roberts, R. W., Chi, Q., Matsunami, H. <strong>RTP family members induce functional expression of mammalian odorant receptors.</strong> Cell 119: 679-691, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15550249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15550249</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15550249">Saito et al. (2004)</a> identified mouse and human REEP1. The deduced mouse Reep1 protein contains 201 amino acids. Reep1 has 2 transmembrane domains, the first of which may function as a signal peptide. Northern blot analysis of mouse tissues detected expression of Reep1 in olfactory and vomeronasal organs and in brain. In situ hybridization of mouse olfactory epithelium revealed specific expression of Reep1 in olfactory neurons. In situ hybridization of mouse brain detected Reep1 expression in a subset of brain cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15550249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A. <strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong> Am. J. Hum. Genet. 79: 365-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826527">Zuchner et al. (2006)</a> found expression of the REEP1 gene in various nonneuronal and neuronal tissues, including brain and spinal cord. REEP1 localized to the mitochondrial membrane in COS7 and MN1 cells. These authors did not detect REEP1 colocalization with the Golgi apparatus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others. <strong>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.</strong> Hum. Mutat. 32: 1118-27, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21618648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21618648</a>] [<a href="https://doi.org/10.1002/humu.21542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21618648">Goizet et al. (2011)</a> found expression of the REEP1 gene in human skeletal muscle cells and fibroblasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21618648" 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="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> found expression of the Reep1 gene in large motor neurons of the ventral horn of the murine spinal cord. In HeLa cells, wildtype human REEP1 localized to a cytoplasmic network consistent with the tubular portion of the peripheral ER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22703882" 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 Western blot analysis, <a href="#8" class="mim-tip-reference" title="Hurt, C. M., Bjork, S., Ho, V. K., Gilsbach, R., Hein, L., Angelotti, T. <strong>REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues.</strong> Brain Res. 1545: 12-22, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24355597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24355597</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24355597[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.brainres.2013.12.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24355597">Hurt et al. (2014)</a> detected mouse Reep1 in brain, spinal cord, and testis, but not in other tissues examined. Microarray analysis revealed Reep1 in mouse stellate ganglia and superior cervical ganglia, but not in nonneuronal supporting cells. Immunohistochemical analysis showed REEP1 colocalized with ER markers in transfected HEK293 cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24355597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Lim, Y., Cho, I.-T., Schoel, L. J., Cho, G., Golden, J. A. <strong>Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts.</strong> Ann. Neurol. 78: 679-696, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26201691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26201691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26201691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26201691">Lim et al. (2015)</a> found expression of the Reep1 gene in the brain, nerve ganglia, spinal cord, somites, and muscle of the mouse embryo. In adult mice, Reep1 was expressed in the brain, heart, skeletal muscle, and testis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26201691" 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="#13" class="mim-tip-reference" title="Saito, H., Kubota, M., Roberts, R. W., Chi, Q., Matsunami, H. <strong>RTP family members induce functional expression of mammalian odorant receptors.</strong> Cell 119: 679-691, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15550249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15550249</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15550249">Saito et al. (2004)</a> showed that mouse Reep1 promoted functional cell surface expression of ORs expressed in human embryonic kidney cells. Reep1 was associated with OR proteins and enhanced the OR responses to odorants, but its effects were much weaker than those shown by Rtp1 (<a href="/entry/609137">609137</a>) and Rtp2 (<a href="/entry/609138">609138</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15550249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By coexpression in HEK293 cells, <a href="#4" class="mim-tip-reference" title="Behrens, M., Bartelt, J., Reichling, C., Winnig, M., Kuhn, C., Meyerhof, W. <strong>Members of RTP and REEP gene families influence functional bitter taste receptor expression.</strong> J. Biol. Chem. 281: 20650-20659, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16720576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16720576</a>] [<a href="https://doi.org/10.1074/jbc.M513637200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16720576">Behrens et al. (2006)</a> found that surface expression of bitter taste receptors (see <a href="/entry/604791">604791</a>) was influenced by RTP and REEP family members, which in turn altered ligand-stimulated receptor activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16720576" 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 embryonic brain extract and HeLa cells, <a href="#10" class="mim-tip-reference" title="Lim, Y., Cho, I.-T., Schoel, L. J., Cho, G., Golden, J. A. <strong>Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts.</strong> Ann. Neurol. 78: 679-696, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26201691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26201691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26201691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26201691">Lim et al. (2015)</a> found that Reep1 was present in the ER and at mitochondria-associated ER membranes (MAMs). Studies with deletion constructs showed that the protein contains subdomains for mitochondrial as well as ER localization. A cellular luciferase-based functional assay indicated that REEP1 can facilitate ER-mitochondrial interactions, and this function was abrogated in the presence of pathogenic mutations. Expression of pathogenic REEP1 mutations in mouse primary cortical neurons resulted in defects in neurite growth and in neurite degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26201691" 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="#6" class="mim-tip-reference" title="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 8/21/2015."None>Hartz (2015)</a> mapped the REEP1 gene to chromosome 2p11.2 based on an alignment of the REEP1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AK022775" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AK022775</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>Spastic Paraplegia 31, Autosomal Dominant</em></strong></p><p>
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In affected members of 2 large unrelated multigenerational families with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#16" class="mim-tip-reference" title="Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A. <strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong> Am. J. Hum. Genet. 79: 365-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826527">Zuchner et al. (2006)</a> identified heterozygous mutations in the REEP1 gene (<a href="#0001">609139.0001</a>-<a href="#0002">609139.0002</a>). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but they were both predicted to trigger nonsense-mediated mRNA decay, resulting in a loss of function and haploinsufficiency. Direct screening of the REEP1 gene in 90 additional families with hereditary spastic paraplegia identified 4 additional mutations in 4 families. Thus, SPG31 accounted for 6.5% of patients in their overall sample. Since REEP1 is widely expressed and localized to mitochondria, the findings underscored the importance of mitochondrial function in neurodegenerative disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B. P. H., Frints, S. G. M., van Zelst-Stams, W. A. G., Byrne, P., Otto, S., Nygren, A. O. H., Baets, J., and 18 others. <strong>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.</strong> Brain 131: 1078-1086, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321925[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/awn026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321925">Beetz et al. (2008)</a> identified 16 different mutations, including 14 novel mutations, in the REEP1 gene (see, e.g., <a href="#0003">609139.0003</a>-<a href="#0004">609139.0004</a>) in 16 (3.0%) of 535 unrelated patients with familial or sporadic SPG. Small frameshift mutations were the most common type of REEP1 mutation. Most patients with confirmed SPG31 had a pure phenotype, although some also reported impaired distal vibration sense, urge incontinence, or distal amyotrophy. There was a bimodal distribution of age onset: most (71%) patients had onset in the first or second decade, whereas the rest had onset after age 30 years. Mutations were distributed throughout the gene, except for exon 3, and there were no apparent genotype/phenotype correlations. <a href="#3" class="mim-tip-reference" title="Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B. P. H., Frints, S. G. M., van Zelst-Stams, W. A. G., Byrne, P., Otto, S., Nygren, A. O. H., Baets, J., and 18 others. <strong>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.</strong> Brain 131: 1078-1086, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321925[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/awn026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321925">Beetz et al. (2008)</a> postulated haploinsufficiency as the main molecular genetic mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18321925" 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 12 multigenerational French families with SPG31, <a href="#5" class="mim-tip-reference" title="Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others. <strong>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.</strong> Hum. Mutat. 32: 1118-27, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21618648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21618648</a>] [<a href="https://doi.org/10.1002/humu.21542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21618648">Goizet et al. (2011)</a> identified heterozygous mutations in the REEP1 gene (see, e.g., <a href="#0002">609139.0002</a>, <a href="#0008">609139.0008</a>, and <a href="#0009">609139.0009</a>). The mutations, which were found by direct sequencing of the REEP1 gene, segregated with the disorder in the families, although there was evidence of incomplete penetrance. The REEP1 mutation rate in their cohort of French families with spastic paraplegia was 4.5%. Skin fibroblasts derived from 1 patient showed abnormal mitochondrial morphology with elongated tubules, suggesting fission/fusion alterations. Muscle biopsy from the patient showed alteration of mitochondrial respiration with decreased oxygen consumption. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21618648" 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 4 unrelated multigenerational families with SPG31, <a href="#15" class="mim-tip-reference" title="Toft, A., Birk, S., Ballegaard, M., Duno, M., Hjermind, L. E., Nielsen, J. E., Svenstrup, K. <strong>Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.</strong> J. Neurol. 266: 735-744, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30637453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30637453</a>] [<a href="https://doi.org/10.1007/s00415-019-09196-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30637453">Toft et al. (2019)</a> identified heterozygous mutations in the REEP1 gene (see, e.g., <a href="#0001">609139.0001</a> and <a href="#0005">609139.0005</a>). Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30637453" 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>Autosomal Dominant Distal Hereditary Motor Neuronopathy 12</em></strong></p><p>
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In affected members of an Austrian family with autosomal dominant distal hereditary motor neuronopathy-12 (HMND12; <a href="/entry/614751">614751</a>), <a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> identified a heterozygous splice site mutation in the REEP1 gene (<a href="#0006">609139.0006</a>), resulting in skipping of exon 5 and a mutant protein lacking residues 102-139. The mutation was found by linkage analysis followed by exome sequencing. The patients had a purely lower motor neuron phenotype, with weakness and atrophy of the intrinsic hand muscles and milder peroneal weakness and atrophy. There were no signs of spasticity. A mutant REEP1 protein lacking exon 5 showed some localization similar to wildtype, but also accumulated in cytoplasmic compact structures of varying sizes, with the largest in the perinuclear regions. REEP1 lacking exon 5 showed colocalization with atlastin-1 (<a href="/entry/606439">606439</a>), including in the abnormal cytoplasmic structures. In contrast, the A20E mutant protein (<a href="#0004">609139.0004</a>) associated with SPG31 showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the ER. Moreover, A20E did not colocalize with atlastin. These findings suggested a different pathomechanism of these 2 mutations, which may explain the different associated phenotypes. <a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> postulated that loss-of-function REEP1 mutations (i.e., A20E) may cause upper motor neuron disease, whereas possible gain-of-function mutations (102_139del) may cause lower motor neuron disease. The findings expanded the phenotypic spectrum associated with REEP1 mutations, similar to that observed with BSCL2 (<a href="/entry/606158">606158</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22703882" 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>Autosomal Recessive Distal Hereditary Motor Neuronopathy 6</em></strong></p><p>
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In a 5-year-old boy, born of consanguineous Lebanese parents, with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; <a href="/entry/620011">620011</a>), <a href="#14" class="mim-tip-reference" title="Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., Schuelke, M. <strong>Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.</strong> Neurol. Genet. 1: e32, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27066569[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/10.1212/NXG.0000000000000032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27066569">Schottmann et al. (2015)</a> identified a homozygous splice site mutation in the REEP1 gene (<a href="#0007">609139.0007</a>). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the 1000 Genomes Project or ExAC databases. Studies of patient fibroblasts and muscle showed no full-length mRNA transcript and no REEP1 protein. Each parent was unaffected, despite being heterozygous for the mutation and haploinsufficient for REEP1, and <a href="#14" class="mim-tip-reference" title="Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., Schuelke, M. <strong>Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.</strong> Neurol. Genet. 1: e32, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27066569[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/10.1212/NXG.0000000000000032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27066569">Schottmann et al. (2015)</a> suggested that additional genetic factors may have influenced the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27066569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 14-year-old girl, born of consanguineous Iranian parents, with HMNR6, <a href="#11" class="mim-tip-reference" title="Maroofian, R., Behnam, M., Kaiyrzhanov, R., Salpietro, V., Salehi, M., Houlden, H. <strong>Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.</strong> Neurol. Genet. 5: e379, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31872057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31872057</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31872057">Maroofian et al. (2019)</a> identified a homozygous missense mutation in the REEP1 gene (W42R; <a href="#0008">609139.0008</a>). The mutation, which was found by exome sequencing, was present in the heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. The authors suggested that incomplete penetrance in the carrier parents may have resulted from modifying genes or stochastic processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31872057" 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 2.5-year-old girl, born of consanguineous Pakistani parents (family PaC6), with HMNR6, <a href="#9" class="mim-tip-reference" title="Kanwal, S., Choi, Y. J., Lim, S. O., Choi, H. J., Park, J. H., Nuzhat, R., Khan, A., Perveen, S., Choi, B.-O., Chung, K. W. <strong>Novel homozygous mutations in Pakistani families with Charcot-Marie-Tooth disease.</strong> BMC Med. Genomics 14: 174, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34193129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34193129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34193129[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/10.1186/s12920-021-01019-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34193129">Kanwal et al. (2021)</a> identified a homozygous frameshift mutation in the REEP1 gene (<a href="#0010">609139.0010</a>). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent and an unaffected sister. It was not present in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34193129" 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="#1" class="mim-tip-reference" title="Beetz, C., Koch, N., Khundadze, M., Zimmer, G., Nietzsche, S., Hertel, N., Huebner, A.-K., Mumtaz, R., Schweizer, M., Dirren, E., Karle, K. N., Irintchev, A., Alvarez, V., Redies, C., Westermann, M., Kurth, I., Deufel, T., Kessels, M. M., Qualmann, B., Hubner, C. A. <strong>A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.</strong> J. Clin. Invest. 123: 4273-82, 2013. Note: Erratum: J. Clin. Invest. 124: 2809 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24051375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24051375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24051375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI65665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24051375">Beetz et al. (2013)</a> produced a mouse line with a deletion of Reep1 exon 2 corresponding to a mutation identified in a patient with SPG31. Heterozygous mice had a gait disorder with weakness and spasticity of the hindlimbs closely resembling the human SPG31 phenotype. Homozygous knockout mice had a more severe phenotype with earlier onset and degeneration of cortical tract axons. <a href="#1" class="mim-tip-reference" title="Beetz, C., Koch, N., Khundadze, M., Zimmer, G., Nietzsche, S., Hertel, N., Huebner, A.-K., Mumtaz, R., Schweizer, M., Dirren, E., Karle, K. N., Irintchev, A., Alvarez, V., Redies, C., Westermann, M., Kurth, I., Deufel, T., Kessels, M. M., Qualmann, B., Hubner, C. A. <strong>A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.</strong> J. Clin. Invest. 123: 4273-82, 2013. Note: Erratum: J. Clin. Invest. 124: 2809 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24051375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24051375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24051375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1172/JCI65665" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24051375">Beetz et al. (2013)</a> showed that the Reep1 protein was found in cellular membranes and enriched in endoplasmic reticulum where its binding to liposomes was proposed to normally increase membrane curvature. Whether the reduced complexity of ER structure in Reep1 knockout mice was causative remained uncertain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24051375" 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="Renvoise, B., Malone, B., Falgairolle, M., Munasinghe, J., Stadler, J., Sibilla, C., Park, S. H., Blackstone, C. <strong>Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.</strong> Hum. Molec. Genet. 25: 5111-5125, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27638887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27638887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27638887[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddw315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27638887">Renvoise et al. (2016)</a> found that Reep1 -/- mice bred normally. Reep1 -/- offspring appeared normal at birth, but they soon developed age-dependent spasticity and impaired motor function. Motoneurons of Reep1 -/- mice exhibited increased activity, and loss of Reep1 led to reduced neuronal axon length and decreased branching in the central nervous system (CNS). Reep1 -/- and wildtype mice had similar body weight, but Reep1 -/- mice appeared thinner and had a significant reduction in fat tissue, as Reep1 acted during adipocyte differentiation to regulate adipogenesis. Reep1 was also involved in CNS lipid metabolism, particularly in cerebral cortex, as lipid profiles in Reep1 -/- brain were changed. Reep1-/- mouse embryonic fibroblasts displayed altered ER morphology and LD defects with increased phosphorylation of perilipin A (PLIN1; <a href="/entry/170290">170290</a>), which coats LDs and is involved in regulating lipid stores. Further analysis showed that Reep1 was important for LD formation and ER morphology and mechanistically linked atlastin-1 (ATL1; <a href="/entry/606439">606439</a>) and Reep1. Immunoprecipitation analysis revealed that Reep1 also bound seipin (BSCL2; <a href="/entry/606158">606158</a>), an ER protein involved in regulating LD formation and morphology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27638887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=609139[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs387906263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906263;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/rs387906263?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=rs387906263" 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=rs387906263" 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=RCV000001936 OR RCV001847562" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001936, RCV001847562" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001936...</a>
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<p>In 14 affected members of a large 3-generational family (DUK2299) with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#16" class="mim-tip-reference" title="Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A. <strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong> Am. J. Hum. Genet. 79: 365-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826527">Zuchner et al. (2006)</a> identified a heterozygous 1-bp deletion (c.507delC, NM_022912) in the REEP1 gene, predicted to result in a frameshift and premature termination (Pro170fs). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to trigger nonsense-mediated mRNA decay, resulting in a loss of function and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Toft, A., Birk, S., Ballegaard, M., Duno, M., Hjermind, L. E., Nielsen, J. E., Svenstrup, K. <strong>Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.</strong> J. Neurol. 266: 735-744, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30637453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30637453</a>] [<a href="https://doi.org/10.1007/s00415-019-09196-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30637453">Toft et al. (2019)</a> identified this heterozygous 1-bp deletion in the REEP1 gene in a father and son (family B) with SPG31; these authors referred to the mutation as c.512delC (c.512delC, NM_022912.2), predicted to result in a frameshift and premature termination (Pro171HisfsTer52). Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30637453" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000001937" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001937" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001937</a>
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<p>In 5 affected members of a 3-generational family (DUK2036) with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#16" class="mim-tip-reference" title="Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A. <strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong> Am. J. Hum. Genet. 79: 365-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826527">Zuchner et al. (2006)</a> identified a heterozygous A-to-G transition in intron 3 of the REEP1 gene (c.182-2A-G, NM_022912), predicted to result in a splicing alteration, a frameshift, and premature termination (Trp61fs). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to trigger nonsense-mediated mRNA decay, resulting in a loss of function and haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others. <strong>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.</strong> Hum. Mutat. 32: 1118-27, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21618648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21618648</a>] [<a href="https://doi.org/10.1002/humu.21542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21618648">Goizet et al. (2011)</a> identified this heterozygous mutation, which they referred to as c.183-2A-G, in a 74-year-old French man (FSP-731) with onset of SPG31 at 2 years of age. He had a family history of the disorder, but family members were not available for segregation studies. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a splicing defect. The phenotype was a pure form of SPG31. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21618648" 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> rs377637314 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs377637314;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/rs377637314?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=rs377637314" 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=rs377637314" 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=RCV000001938 OR RCV001333150 OR RCV001703411 OR RCV001847563 OR RCV003258655 OR RCV003904794" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001938, RCV001333150, RCV001703411, RCV001847563, RCV003258655, RCV003904794" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001938...</a>
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<p>In a male patient (family DUK2354) with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#16" class="mim-tip-reference" title="Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A. <strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong> Am. J. Hum. Genet. 79: 365-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826527">Zuchner et al. (2006)</a> identified a heterozygous G-to-T transversion (c.606+43G-T, NM_022912) in a highly conserved domain of the 3-prime untranslated region of the REEP1 gene. The mutation occurred in a microRNA-binding site (MIRN140; <a href="/entry/611894">611894</a>), and was predicted to foster suppressive miRNA-mediated effects on translation, leading to less available REEP1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B. P. H., Frints, S. G. M., van Zelst-Stams, W. A. G., Byrne, P., Otto, S., Nygren, A. O. H., Baets, J., and 18 others. <strong>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.</strong> Brain 131: 1078-1086, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321925[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/awn026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321925">Beetz et al. (2008)</a> identified the c.606+43G-T mutation in 2 unrelated probands with SPG31. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18321925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Hewamadduma, C., McDermott, C., Kirby, J., Grierson, A., Panayi, M., Dalton, A., Rajabally, Y., Shaw, P. <strong>New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP).</strong> Neurogenetics 10: 105-110, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19034539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19034539</a>] [<a href="https://doi.org/10.1007/s10048-008-0163-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19034539">Hewamadduma et al. (2009)</a> identified a heterozygous c.606+43G-T mutation in affected members of 2 unrelated British families with SPG31. The proband of the first family developed unsteady gait and increased tone and hyperreflexia in the upper and lower limbs at age 25 years. The disease progressed, and she became wheelchair-bound. She also had mild distal sensory loss. The proband of the second family had difficulties in running and walking since age 9. At age 27, she had severe spastic tetraparesis with spastic dysarthria and dysphagia, indicating bulbar involvement. The findings indicated an expanded phenotypic spectrum associated with REEP1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19034539" 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> rs121918262 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918262;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/rs121918262?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=rs121918262" 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=rs121918262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 8 affected members of a family (DUK2189) with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#16" class="mim-tip-reference" title="Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A. <strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong> Am. J. Hum. Genet. 79: 365-369, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/505361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16826527">Zuchner et al. (2006)</a> identified a heterozygous c.59C-A transversion (c.59C-A, NM_022912) in the REEP1 gene, resulting in an ala20-to-glu (A20E) substitution. The variant was not present in 730 control chromosomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated probands with SPG31, <a href="#3" class="mim-tip-reference" title="Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B. P. H., Frints, S. G. M., van Zelst-Stams, W. A. G., Byrne, P., Otto, S., Nygren, A. O. H., Baets, J., and 18 others. <strong>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.</strong> Brain 131: 1078-1086, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321925[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/awn026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18321925">Beetz et al. (2008)</a> identified a heterozygous c.59C-A transversion in exon 2 of the REEP1 gene, resulting in an ala20-to-glu (A20E) substitution in the first transmembrane domain. One of the patients had a family history of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18321925" 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>Variant Function</em></strong></p><p>
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In HeLa cells, <a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> found that the A20E mutant protein showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the ER, as was found with wildtype REEP1. The mutant A20E REEP1 protein showed no interaction with atlastin-1 (<a href="/entry/606439">606439</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22703882" 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 in vitro functional expression studies, <a href="#10" class="mim-tip-reference" title="Lim, Y., Cho, I.-T., Schoel, L. J., Cho, G., Golden, J. A. <strong>Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts.</strong> Ann. Neurol. 78: 679-696, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26201691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26201691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26201691[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.24488" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26201691">Lim et al. (2015)</a> found that the A20E mutation interfered with the ability of REEP1 to facilitate ER-mitochondria interactions when coexpressed with the wildtype gene, consistent with a dominant-negative effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26201691" 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 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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">rs121918263 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918263;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=rs121918263" 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=rs121918263" 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=RCV000001940 OR RCV001847565 OR RCV002243614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000001940, RCV001847565, RCV002243614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000001940...</a>
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<p>In 3 affected members of a British family with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#7" class="mim-tip-reference" title="Hewamadduma, C., McDermott, C., Kirby, J., Grierson, A., Panayi, M., Dalton, A., Rajabally, Y., Shaw, P. <strong>New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP).</strong> Neurogenetics 10: 105-110, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19034539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19034539</a>] [<a href="https://doi.org/10.1007/s10048-008-0163-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19034539">Hewamadduma et al. (2009)</a> identified a heterozygous c.337C-T transition (c.337C-T, NM_022912.1) in exon 5 of the REEP1 gene, resulting in an arg113-to-ter (R113X) substitution. The mutation was not identified in 132 British control individuals. The age at onset ranged between 15 and 30 years. The proband had increased tone and hyperreflexia of all 4 limbs. Both he and his affected father also had profound lower limb wasting. All 3 had pes cavus and severe gait disturbances, necessitating wheelchair use by the early thirties. Neurophysiologic studies of the proband showed chronic denervation in the peroneal and quadriceps muscles, consistent with a motor neuropathy. The amyotrophy and neuropathy in this family were reminiscent of distal motor neuronopathy type VB (<a href="/entry/614751">614751</a>) (<a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al., 2012</a>). <a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> suggested that the R113X mutation may partially escape nonsense-mediated mRNA decay and thus also have a toxic gain-of-function effect causing lower motor neuron disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22703882+19034539" 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 9 affected individuals from 2 unrelated multigenerational families (families A and C) with SPG31, <a href="#15" class="mim-tip-reference" title="Toft, A., Birk, S., Ballegaard, M., Duno, M., Hjermind, L. E., Nielsen, J. E., Svenstrup, K. <strong>Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.</strong> J. Neurol. 266: 735-744, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30637453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30637453</a>] [<a href="https://doi.org/10.1007/s00415-019-09196-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30637453">Toft et al. (2019)</a> identified a heterozygous R113X substitution in the REEP1 gene. One additional family member with the mutation was asymptomatic at age 85 years, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30637453" 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">rs387907242 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907242;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=rs387907242" 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=rs387907242" 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=RCV000029244 OR RCV000789557" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000029244, RCV000789557" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000029244...</a>
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<p>In affected members of an Austrian family with autosomal dominant distal hereditary motor neuronopathy-12 (HMND12; <a href="/entry/614751">614751</a>), <a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> identified a heterozygous A-to-G transition in intron 4 of the REEP1 gene (c.305-2A-G), resulting in the skipping of exon 5. The mutant transcript was translated into a protein with internal deletion of a highly conserved portion of the protein (102_139del). The variant was not detected in over 10,000 available control chromosomes or in 88 local control individuals. The patients had a purely lower motor neuron phenotype, with weakness and atrophy of the intrinsic hand muscles and milder peroneal weakness and atrophy. There were no signs of spasticity. In HeLa cells, human wildtype REEP1 localized to a cytoplasmic network consistent with the tubular portion of the peripheral endoplasmic reticulum. Mutant REEP1 lacking exon 5 showed some localization similar to wildtype, but also accumulated in cytoplasmic compact structures of varying sizes, with the largest in the perinuclear regions. REEP1 lacking exon 5 showed colocalization with atlastin-1 (<a href="/entry/606439">606439</a>), including in the abnormal cytoplasmic structures. The A20E mutant protein (<a href="#0004">609139.0004</a>) showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the ER. Moreover, A20E did not colocalize with atlastin. These findings suggested a different pathomechanism of these 2 mutations, which may explain the different associated phenotypes. <a href="#2" class="mim-tip-reference" title="Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M. <strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong> Am. J. Hum. Genet. 91: 139-145, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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.2012.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22703882">Beetz et al. (2012)</a> postulated that loss-of-function REEP1 mutations (i.e., A20E) may cause upper motor neuron disease, whereas possible gain-of-function mutations (102_139del) may cause lower motor neuron disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22703882" 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">rs869320621 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320621;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=rs869320621" 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=rs869320621" 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 5-year-old boy, born of consanguineous Lebanese parents, with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; <a href="/entry/620011">620011</a>), <a href="#14" class="mim-tip-reference" title="Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., Schuelke, M. <strong>Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.</strong> Neurol. Genet. 1: e32, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27066569[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/10.1212/NXG.0000000000000032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27066569">Schottmann et al. (2015)</a> identified a homozygous splice site mutation at the donor splice site of exon 4 of the REEP1 gene (c.303+1-7GTAATAT-AC, NM_022912), resulting in a frameshift and premature termination (Phe62Lysfs23Ter). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the 1000 Genomes Project or ExAC databases. Studies of patient fibroblasts and muscle showed no full-length mRNA transcript and no REEP1 protein. The patient presented at birth with equinovarus foot deformity, contractures of the distal phalanges, and a high-arched palate. He later developed progressive distal muscle weakness and hypotonia, hyperreflexia, and respiratory distress. Nerve conduction studies of sensory nerves showed reduced amplitudes and normal nerve conduction velocities, consistent with an axonal neuropathy. There were no motor nerve responses. Each parent was unaffected, despite being heterozygous for the mutation and haploinsufficient for REEP1, and <a href="#14" class="mim-tip-reference" title="Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., Schuelke, M. <strong>Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.</strong> Neurol. Genet. 1: e32, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27066569[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/10.1212/NXG.0000000000000032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27066569">Schottmann et al. (2015)</a> suggested that additional genetic factors may have influenced the phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27066569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</strong>
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In 4 affected members of a 3-generation French family (FSP-418) with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#5" class="mim-tip-reference" title="Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others. <strong>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.</strong> Hum. Mutat. 32: 1118-27, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21618648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21618648</a>] [<a href="https://doi.org/10.1002/humu.21542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21618648">Goizet et al. (2011)</a> identified a heterozygous c.124T-C transition (c.124T-C, NM_022912.2) in exon 3 of the REEP1 gene, resulting in a trp42-to-arg (W42R) substitution at a highly conserved residue. The mutation, which was found by direct sequencing of the REEP1 gene, segregated with the disorder in the family, although there was evidence of incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed. The patients had a complex form of SPG31 with an axonal sensorimotor peripheral neuropathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21618648" 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>Autosomal Recessive Distal Hereditary Motor Neuronopathy 6</em></strong></p><p>
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In a 14-year-old girl, born of consanguineous Iranian parents, with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; <a href="/entry/620011">620011</a>), <a href="#11" class="mim-tip-reference" title="Maroofian, R., Behnam, M., Kaiyrzhanov, R., Salpietro, V., Salehi, M., Houlden, H. <strong>Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.</strong> Neurol. Genet. 5: e379, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31872057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31872057</a>] [<a href="https://doi.org/10.1212/NXG.0000000000000379" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31872057">Maroofian et al. (2019)</a> identified a homozygous c.124T-C transition in the REEP1 gene, resulting in a trp42-to-arg (W42R) substitution. The mutation, which was found by exome sequencing, was present in the heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. The authors suggested that incomplete penetrance in the carrier parents may have resulted from modifying genes or stochastic processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31872057" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 48-year-old French man (family N08-1658) with autosomal dominant spastic paraplegia-31 (SPG31; <a href="/entry/610250">610250</a>), <a href="#5" class="mim-tip-reference" title="Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others. <strong>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.</strong> Hum. Mutat. 32: 1118-27, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21618648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21618648</a>] [<a href="https://doi.org/10.1002/humu.21542" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21618648">Goizet et al. (2011)</a> identified a heterozygous 1-bp deletion (c.106delG, NM_022912.2) in exon 3 of the REEP1 gene, predicted to result in a frameshift and premature termination (Val36SerfsTer4). The patient had a similarly affected father and brother, but both were deceased and unavailable for study. Patient-derived skin fibroblasts showed abnormal mitochondrial morphology with elongated tubules, suggesting fission/fusion alterations. Muscle biopsy from the patient showed alteration mitochondrial respiration with decreased oxygen consumption. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21618648" 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">rs2104244539 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2104244539;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=rs2104244539" 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=rs2104244539" 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 2.5-year-old girl, born of consanguineous Pakistani parents (family PaC6), with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; <a href="/entry/620011">620011</a>), <a href="#9" class="mim-tip-reference" title="Kanwal, S., Choi, Y. J., Lim, S. O., Choi, H. J., Park, J. H., Nuzhat, R., Khan, A., Perveen, S., Choi, B.-O., Chung, K. W. <strong>Novel homozygous mutations in Pakistani families with Charcot-Marie-Tooth disease.</strong> BMC Med. Genomics 14: 174, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34193129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34193129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34193129[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/10.1186/s12920-021-01019-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34193129">Kanwal et al. (2021)</a> identified a homozygous 1-bp deletion (c.247delG, NM_022912.3) in the REEP1 gene, predicted to result in a frameshift and premature termination (Gly83AlafsTer44). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. It was not present in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34193129" 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/10.1172/JCI65665" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22703882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22703882</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22703882[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=22703882" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2012.05.007" target="_blank">Full Text</a>]
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Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B. P. H., Frints, S. G. M., van Zelst-Stams, W. A. G., Byrne, P., Otto, S., Nygren, A. O. H., Baets, J., and 18 others.
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<strong>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.</strong>
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Brain 131: 1078-1086, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18321925/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18321925</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18321925[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=18321925" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awn026" target="_blank">Full Text</a>]
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Behrens, M., Bartelt, J., Reichling, C., Winnig, M., Kuhn, C., Meyerhof, W.
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<strong>Members of RTP and REEP gene families influence functional bitter taste receptor expression.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16720576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16720576</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16720576" 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.M513637200" target="_blank">Full Text</a>]
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Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others.
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Hum. Mutat. 32: 1118-27, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21618648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21618648</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21618648" 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/humu.21542" target="_blank">Full Text</a>]
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Baltimore, Md. 8/21/2015.
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Hewamadduma, C., McDermott, C., Kirby, J., Grierson, A., Panayi, M., Dalton, A., Rajabally, Y., Shaw, P.
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<strong>New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP).</strong>
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Neurogenetics 10: 105-110, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19034539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19034539</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19034539" 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/s10048-008-0163-z" target="_blank">Full Text</a>]
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Hurt, C. M., Bjork, S., Ho, V. K., Gilsbach, R., Hein, L., Angelotti, T.
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<strong>REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues.</strong>
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Brain Res. 1545: 12-22, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24355597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24355597</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24355597[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=24355597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.brainres.2013.12.008" target="_blank">Full Text</a>]
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<a id="Kanwal2021" class="mim-anchor"></a>
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Kanwal, S., Choi, Y. J., Lim, S. O., Choi, H. J., Park, J. H., Nuzhat, R., Khan, A., Perveen, S., Choi, B.-O., Chung, K. W.
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<strong>Novel homozygous mutations in Pakistani families with Charcot-Marie-Tooth disease.</strong>
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BMC Med. Genomics 14: 174, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34193129/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34193129</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34193129[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=34193129" 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/10.1186/s12920-021-01019-5" target="_blank">Full Text</a>]
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<a id="Lim2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Lim, Y., Cho, I.-T., Schoel, L. J., Cho, G., Golden, J. A.
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<strong>Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts.</strong>
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Ann. Neurol. 78: 679-696, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26201691/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26201691</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26201691[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=26201691" 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/ana.24488" target="_blank">Full Text</a>]
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<a id="Maroofian2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Maroofian, R., Behnam, M., Kaiyrzhanov, R., Salpietro, V., Salehi, M., Houlden, H.
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<strong>Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.</strong>
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Neurol. Genet. 5: e379, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31872057/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31872057</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31872057" 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/NXG.0000000000000379" target="_blank">Full Text</a>]
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<a id="Renvoise2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Renvoise, B., Malone, B., Falgairolle, M., Munasinghe, J., Stadler, J., Sibilla, C., Park, S. H., Blackstone, C.
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<strong>Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.</strong>
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Hum. Molec. Genet. 25: 5111-5125, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27638887/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27638887</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27638887[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=27638887" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddw315" target="_blank">Full Text</a>]
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<a id="Saito2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saito, H., Kubota, M., Roberts, R. W., Chi, Q., Matsunami, H.
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<strong>RTP family members induce functional expression of mammalian odorant receptors.</strong>
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Cell 119: 679-691, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15550249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15550249</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15550249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2004.11.021" target="_blank">Full Text</a>]
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<a id="Schottmann2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., Schuelke, M.
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<strong>Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.</strong>
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Neurol. Genet. 1: e32, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27066569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27066569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27066569[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=27066569" 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/NXG.0000000000000032" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Toft2019" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Toft, A., Birk, S., Ballegaard, M., Duno, M., Hjermind, L. E., Nielsen, J. E., Svenstrup, K.
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<strong>Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.</strong>
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J. Neurol. 266: 735-744, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30637453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30637453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30637453" 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/s00415-019-09196-1" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Zuchner2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A.
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<strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong>
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Am. J. Hum. Genet. 79: 365-369, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16826527/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16826527</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16826527[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=16826527" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/505361" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<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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Bao Lige - updated : 10/06/2022
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Alan F. Scott - updated : 08/30/2022<br>Cassandra L. Kniffin - updated : 08/24/2022<br>Cassandra L. Kniffin - updated : 11/10/2015<br>Patricia A. Hartz - updated : 8/21/2015<br>Cassandra L. Kniffin - updated : 7/31/2012<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Victor A. McKusick - updated : 7/7/2006
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</span>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 1/5/2005
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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="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/17/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="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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mgross : 10/06/2022<br>alopez : 08/30/2022<br>carol : 08/30/2022<br>carol : 08/30/2022<br>ckniffin : 08/24/2022<br>alopez : 10/04/2016<br>alopez : 11/13/2015<br>ckniffin : 11/10/2015<br>mgross : 8/24/2015<br>mcolton : 8/21/2015<br>carol : 1/21/2015<br>carol : 8/1/2012<br>carol : 8/1/2012<br>ckniffin : 7/31/2012<br>wwang : 2/21/2011<br>wwang : 5/21/2009<br>ckniffin : 5/14/2009<br>alopez : 7/12/2006<br>terry : 7/7/2006<br>mgross : 1/5/2005
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</span>
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</div>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 609139
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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RECEPTOR EXPRESSION-ENHANCING PROTEIN 1; REEP1
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</span>
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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CHROMOSOME 2 OPEN READING FRAME 23; C2ORF23
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: REEP1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 763068005;
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</span>
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</p>
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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: 2p11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:86,213,993-86,338,083 </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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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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2p11.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Neuronopathy, distal hereditary motor, autosomal dominant 12
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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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614751
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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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<td>
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<span class="mim-font">
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Neuronopathy, distal hereditary motor, autosomal recessive 6
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</span>
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</td>
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<td>
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<span class="mim-font">
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620011
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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<tr>
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<td>
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<span class="mim-font">
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Spastic paraplegia 31, 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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610250
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tbody>
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</table>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>REEP1 is involved in regulation of lipid droplet (LD) formation and endoplasmic reticulum (ER) morphology (Renvoise et al., 2016). </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>Transport of G protein-coupled receptors (GPCRs) to the cell surface membrane is critical for receptor-ligand recognition. However, mammalian GPCR odorant receptors (ORs), when heterologously expressed in cells, are poorly expressed on the cell surface. By screening for genes that induced cell surface expression of ORs expressed in human embryonic kidney cells, Saito et al. (2004) identified mouse and human REEP1. The deduced mouse Reep1 protein contains 201 amino acids. Reep1 has 2 transmembrane domains, the first of which may function as a signal peptide. Northern blot analysis of mouse tissues detected expression of Reep1 in olfactory and vomeronasal organs and in brain. In situ hybridization of mouse olfactory epithelium revealed specific expression of Reep1 in olfactory neurons. In situ hybridization of mouse brain detected Reep1 expression in a subset of brain cells. </p><p>Zuchner et al. (2006) found expression of the REEP1 gene in various nonneuronal and neuronal tissues, including brain and spinal cord. REEP1 localized to the mitochondrial membrane in COS7 and MN1 cells. These authors did not detect REEP1 colocalization with the Golgi apparatus. </p><p>Goizet et al. (2011) found expression of the REEP1 gene in human skeletal muscle cells and fibroblasts. </p><p>Beetz et al. (2012) found expression of the Reep1 gene in large motor neurons of the ventral horn of the murine spinal cord. In HeLa cells, wildtype human REEP1 localized to a cytoplasmic network consistent with the tubular portion of the peripheral ER. </p><p>Using Western blot analysis, Hurt et al. (2014) detected mouse Reep1 in brain, spinal cord, and testis, but not in other tissues examined. Microarray analysis revealed Reep1 in mouse stellate ganglia and superior cervical ganglia, but not in nonneuronal supporting cells. Immunohistochemical analysis showed REEP1 colocalized with ER markers in transfected HEK293 cells. </p><p>Lim et al. (2015) found expression of the Reep1 gene in the brain, nerve ganglia, spinal cord, somites, and muscle of the mouse embryo. In adult mice, Reep1 was expressed in the brain, heart, skeletal muscle, and testis. </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">
|
|
<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>Saito et al. (2004) showed that mouse Reep1 promoted functional cell surface expression of ORs expressed in human embryonic kidney cells. Reep1 was associated with OR proteins and enhanced the OR responses to odorants, but its effects were much weaker than those shown by Rtp1 (609137) and Rtp2 (609138). </p><p>By coexpression in HEK293 cells, Behrens et al. (2006) found that surface expression of bitter taste receptors (see 604791) was influenced by RTP and REEP family members, which in turn altered ligand-stimulated receptor activation. </p><p>In mouse embryonic brain extract and HeLa cells, Lim et al. (2015) found that Reep1 was present in the ER and at mitochondria-associated ER membranes (MAMs). Studies with deletion constructs showed that the protein contains subdomains for mitochondrial as well as ER localization. A cellular luciferase-based functional assay indicated that REEP1 can facilitate ER-mitochondrial interactions, and this function was abrogated in the presence of pathogenic mutations. Expression of pathogenic REEP1 mutations in mouse primary cortical neurons resulted in defects in neurite growth and in neurite degeneration. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>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>Hartz (2015) mapped the REEP1 gene to chromosome 2p11.2 based on an alignment of the REEP1 sequence (GenBank AK022775) with the genomic sequence (GRCh38).</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>
|
|
<span class="mim-font">
|
|
<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>Spastic Paraplegia 31, Autosomal Dominant</em></strong></p><p>
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In affected members of 2 large unrelated multigenerational families with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Zuchner et al. (2006) identified heterozygous mutations in the REEP1 gene (609139.0001-609139.0002). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but they were both predicted to trigger nonsense-mediated mRNA decay, resulting in a loss of function and haploinsufficiency. Direct screening of the REEP1 gene in 90 additional families with hereditary spastic paraplegia identified 4 additional mutations in 4 families. Thus, SPG31 accounted for 6.5% of patients in their overall sample. Since REEP1 is widely expressed and localized to mitochondria, the findings underscored the importance of mitochondrial function in neurodegenerative disease. </p><p>Beetz et al. (2008) identified 16 different mutations, including 14 novel mutations, in the REEP1 gene (see, e.g., 609139.0003-609139.0004) in 16 (3.0%) of 535 unrelated patients with familial or sporadic SPG. Small frameshift mutations were the most common type of REEP1 mutation. Most patients with confirmed SPG31 had a pure phenotype, although some also reported impaired distal vibration sense, urge incontinence, or distal amyotrophy. There was a bimodal distribution of age onset: most (71%) patients had onset in the first or second decade, whereas the rest had onset after age 30 years. Mutations were distributed throughout the gene, except for exon 3, and there were no apparent genotype/phenotype correlations. Beetz et al. (2008) postulated haploinsufficiency as the main molecular genetic mechanism. </p><p>In affected members of 12 multigenerational French families with SPG31, Goizet et al. (2011) identified heterozygous mutations in the REEP1 gene (see, e.g., 609139.0002, 609139.0008, and 609139.0009). The mutations, which were found by direct sequencing of the REEP1 gene, segregated with the disorder in the families, although there was evidence of incomplete penetrance. The REEP1 mutation rate in their cohort of French families with spastic paraplegia was 4.5%. Skin fibroblasts derived from 1 patient showed abnormal mitochondrial morphology with elongated tubules, suggesting fission/fusion alterations. Muscle biopsy from the patient showed alteration of mitochondrial respiration with decreased oxygen consumption. </p><p>In affected members of 4 unrelated multigenerational families with SPG31, Toft et al. (2019) identified heterozygous mutations in the REEP1 gene (see, e.g., 609139.0001 and 609139.0005). Functional studies of the variants and studies of patient cells were not performed. </p><p><strong><em>Autosomal Dominant Distal Hereditary Motor Neuronopathy 12</em></strong></p><p>
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In affected members of an Austrian family with autosomal dominant distal hereditary motor neuronopathy-12 (HMND12; 614751), Beetz et al. (2012) identified a heterozygous splice site mutation in the REEP1 gene (609139.0006), resulting in skipping of exon 5 and a mutant protein lacking residues 102-139. The mutation was found by linkage analysis followed by exome sequencing. The patients had a purely lower motor neuron phenotype, with weakness and atrophy of the intrinsic hand muscles and milder peroneal weakness and atrophy. There were no signs of spasticity. A mutant REEP1 protein lacking exon 5 showed some localization similar to wildtype, but also accumulated in cytoplasmic compact structures of varying sizes, with the largest in the perinuclear regions. REEP1 lacking exon 5 showed colocalization with atlastin-1 (606439), including in the abnormal cytoplasmic structures. In contrast, the A20E mutant protein (609139.0004) associated with SPG31 showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the ER. Moreover, A20E did not colocalize with atlastin. These findings suggested a different pathomechanism of these 2 mutations, which may explain the different associated phenotypes. Beetz et al. (2012) postulated that loss-of-function REEP1 mutations (i.e., A20E) may cause upper motor neuron disease, whereas possible gain-of-function mutations (102_139del) may cause lower motor neuron disease. The findings expanded the phenotypic spectrum associated with REEP1 mutations, similar to that observed with BSCL2 (606158). </p><p><strong><em>Autosomal Recessive Distal Hereditary Motor Neuronopathy 6</em></strong></p><p>
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In a 5-year-old boy, born of consanguineous Lebanese parents, with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; 620011), Schottmann et al. (2015) identified a homozygous splice site mutation in the REEP1 gene (609139.0007). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the 1000 Genomes Project or ExAC databases. Studies of patient fibroblasts and muscle showed no full-length mRNA transcript and no REEP1 protein. Each parent was unaffected, despite being heterozygous for the mutation and haploinsufficient for REEP1, and Schottmann et al. (2015) suggested that additional genetic factors may have influenced the phenotype. </p><p>In a 14-year-old girl, born of consanguineous Iranian parents, with HMNR6, Maroofian et al. (2019) identified a homozygous missense mutation in the REEP1 gene (W42R; 609139.0008). The mutation, which was found by exome sequencing, was present in the heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. The authors suggested that incomplete penetrance in the carrier parents may have resulted from modifying genes or stochastic processes. </p><p>In a 2.5-year-old girl, born of consanguineous Pakistani parents (family PaC6), with HMNR6, Kanwal et al. (2021) identified a homozygous frameshift mutation in the REEP1 gene (609139.0010). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent and an unaffected sister. It was not present in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. </p>
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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>Beetz et al. (2013) produced a mouse line with a deletion of Reep1 exon 2 corresponding to a mutation identified in a patient with SPG31. Heterozygous mice had a gait disorder with weakness and spasticity of the hindlimbs closely resembling the human SPG31 phenotype. Homozygous knockout mice had a more severe phenotype with earlier onset and degeneration of cortical tract axons. Beetz et al. (2013) showed that the Reep1 protein was found in cellular membranes and enriched in endoplasmic reticulum where its binding to liposomes was proposed to normally increase membrane curvature. Whether the reduced complexity of ER structure in Reep1 knockout mice was causative remained uncertain. </p><p>Renvoise et al. (2016) found that Reep1 -/- mice bred normally. Reep1 -/- offspring appeared normal at birth, but they soon developed age-dependent spasticity and impaired motor function. Motoneurons of Reep1 -/- mice exhibited increased activity, and loss of Reep1 led to reduced neuronal axon length and decreased branching in the central nervous system (CNS). Reep1 -/- and wildtype mice had similar body weight, but Reep1 -/- mice appeared thinner and had a significant reduction in fat tissue, as Reep1 acted during adipocyte differentiation to regulate adipogenesis. Reep1 was also involved in CNS lipid metabolism, particularly in cerebral cortex, as lipid profiles in Reep1 -/- brain were changed. Reep1-/- mouse embryonic fibroblasts displayed altered ER morphology and LD defects with increased phosphorylation of perilipin A (PLIN1; 170290), which coats LDs and is involved in regulating lipid stores. Further analysis showed that Reep1 was important for LD formation and ER morphology and mechanistically linked atlastin-1 (ATL1; 606439) and Reep1. Immunoprecipitation analysis revealed that Reep1 also bound seipin (BSCL2; 606158), an ER protein involved in regulating LD formation and morphology. </p>
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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>10 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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<h4>
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<span class="mim-font">
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<strong>.0001 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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REEP1, 1-BP DEL, 507C
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<br />
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SNP: rs387906263,
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gnomAD: rs387906263,
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ClinVar: RCV000001936, RCV001847562
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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 14 affected members of a large 3-generational family (DUK2299) with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Zuchner et al. (2006) identified a heterozygous 1-bp deletion (c.507delC, NM_022912) in the REEP1 gene, predicted to result in a frameshift and premature termination (Pro170fs). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to trigger nonsense-mediated mRNA decay, resulting in a loss of function and haploinsufficiency. </p><p>Toft et al. (2019) identified this heterozygous 1-bp deletion in the REEP1 gene in a father and son (family B) with SPG31; these authors referred to the mutation as c.512delC (c.512delC, NM_022912.2), predicted to result in a frameshift and premature termination (Pro171HisfsTer52). Functional studies of the variant and studies of patient cells were not performed. </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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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REEP1, IVS3AS, A-G, -2
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<br />
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SNP: rs387906264,
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ClinVar: RCV000001937
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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 5 affected members of a 3-generational family (DUK2036) with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Zuchner et al. (2006) identified a heterozygous A-to-G transition in intron 3 of the REEP1 gene (c.182-2A-G, NM_022912), predicted to result in a splicing alteration, a frameshift, and premature termination (Trp61fs). The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to trigger nonsense-mediated mRNA decay, resulting in a loss of function and haploinsufficiency. </p><p>Goizet et al. (2011) identified this heterozygous mutation, which they referred to as c.183-2A-G, in a 74-year-old French man (FSP-731) with onset of SPG31 at 2 years of age. He had a family history of the disorder, but family members were not available for segregation studies. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a splicing defect. The phenotype was a pure form of SPG31. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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REEP1, 606+43G-T, 3-PRIME UTR
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<br />
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SNP: rs377637314,
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gnomAD: rs377637314,
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ClinVar: RCV000001938, RCV001333150, RCV001703411, RCV001847563, RCV003258655, RCV003904794
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient (family DUK2354) with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Zuchner et al. (2006) identified a heterozygous G-to-T transversion (c.606+43G-T, NM_022912) in a highly conserved domain of the 3-prime untranslated region of the REEP1 gene. The mutation occurred in a microRNA-binding site (MIRN140; 611894), and was predicted to foster suppressive miRNA-mediated effects on translation, leading to less available REEP1 protein. </p><p>Beetz et al. (2008) identified the c.606+43G-T mutation in 2 unrelated probands with SPG31. </p><p>Hewamadduma et al. (2009) identified a heterozygous c.606+43G-T mutation in affected members of 2 unrelated British families with SPG31. The proband of the first family developed unsteady gait and increased tone and hyperreflexia in the upper and lower limbs at age 25 years. The disease progressed, and she became wheelchair-bound. She also had mild distal sensory loss. The proband of the second family had difficulties in running and walking since age 9. At age 27, she had severe spastic tetraparesis with spastic dysarthria and dysphagia, indicating bulbar involvement. The findings indicated an expanded phenotypic spectrum associated with REEP1 mutations. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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REEP1, ALA20GLU
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<br />
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SNP: rs121918262,
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gnomAD: rs121918262,
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ClinVar: RCV000001939, RCV000713454, RCV001003951, RCV001847564, RCV004955248
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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 8 affected members of a family (DUK2189) with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Zuchner et al. (2006) identified a heterozygous c.59C-A transversion (c.59C-A, NM_022912) in the REEP1 gene, resulting in an ala20-to-glu (A20E) substitution. The variant was not present in 730 control chromosomes. Functional studies of the variant and studies of patient cells were not performed. </p><p>In 2 unrelated probands with SPG31, Beetz et al. (2008) identified a heterozygous c.59C-A transversion in exon 2 of the REEP1 gene, resulting in an ala20-to-glu (A20E) substitution in the first transmembrane domain. One of the patients had a family history of the disorder. </p><p><strong><em>Variant Function</em></strong></p><p>
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|
In HeLa cells, Beetz et al. (2012) found that the A20E mutant protein showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the ER, as was found with wildtype REEP1. The mutant A20E REEP1 protein showed no interaction with atlastin-1 (606439). </p><p>In in vitro functional expression studies, Lim et al. (2015) found that the A20E mutation interfered with the ability of REEP1 to facilitate ER-mitochondria interactions when coexpressed with the wildtype gene, consistent with a dominant-negative effect. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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REEP1, ARG113TER
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<br />
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SNP: rs121918263,
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ClinVar: RCV000001940, RCV001847565, RCV002243614
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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 3 affected members of a British family with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Hewamadduma et al. (2009) identified a heterozygous c.337C-T transition (c.337C-T, NM_022912.1) in exon 5 of the REEP1 gene, resulting in an arg113-to-ter (R113X) substitution. The mutation was not identified in 132 British control individuals. The age at onset ranged between 15 and 30 years. The proband had increased tone and hyperreflexia of all 4 limbs. Both he and his affected father also had profound lower limb wasting. All 3 had pes cavus and severe gait disturbances, necessitating wheelchair use by the early thirties. Neurophysiologic studies of the proband showed chronic denervation in the peroneal and quadriceps muscles, consistent with a motor neuropathy. The amyotrophy and neuropathy in this family were reminiscent of distal motor neuronopathy type VB (614751) (Beetz et al., 2012). Beetz et al. (2012) suggested that the R113X mutation may partially escape nonsense-mediated mRNA decay and thus also have a toxic gain-of-function effect causing lower motor neuron disease. </p><p>In 9 affected individuals from 2 unrelated multigenerational families (families A and C) with SPG31, Toft et al. (2019) identified a heterozygous R113X substitution in the REEP1 gene. One additional family member with the mutation was asymptomatic at age 85 years, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 12 (1 family)</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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REEP1, IVS4AS, A-G, -2
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<br />
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SNP: rs387907242,
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ClinVar: RCV000029244, RCV000789557
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of an Austrian family with autosomal dominant distal hereditary motor neuronopathy-12 (HMND12; 614751), Beetz et al. (2012) identified a heterozygous A-to-G transition in intron 4 of the REEP1 gene (c.305-2A-G), resulting in the skipping of exon 5. The mutant transcript was translated into a protein with internal deletion of a highly conserved portion of the protein (102_139del). The variant was not detected in over 10,000 available control chromosomes or in 88 local control individuals. The patients had a purely lower motor neuron phenotype, with weakness and atrophy of the intrinsic hand muscles and milder peroneal weakness and atrophy. There were no signs of spasticity. In HeLa cells, human wildtype REEP1 localized to a cytoplasmic network consistent with the tubular portion of the peripheral endoplasmic reticulum. Mutant REEP1 lacking exon 5 showed some localization similar to wildtype, but also accumulated in cytoplasmic compact structures of varying sizes, with the largest in the perinuclear regions. REEP1 lacking exon 5 showed colocalization with atlastin-1 (606439), including in the abnormal cytoplasmic structures. The A20E mutant protein (609139.0004) showed severely altered localization to numerous punctate small structures throughout the cytoplasm and no localization to the ER. Moreover, A20E did not colocalize with atlastin. These findings suggested a different pathomechanism of these 2 mutations, which may explain the different associated phenotypes. Beetz et al. (2012) postulated that loss-of-function REEP1 mutations (i.e., A20E) may cause upper motor neuron disease, whereas possible gain-of-function mutations (102_139del) may cause lower motor neuron disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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REEP1, IVS4DS, +1-7, GTAATAT-AC
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<br />
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SNP: rs869320621,
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ClinVar: RCV002280583
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 5-year-old boy, born of consanguineous Lebanese parents, with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; 620011), Schottmann et al. (2015) identified a homozygous splice site mutation at the donor splice site of exon 4 of the REEP1 gene (c.303+1-7GTAATAT-AC, NM_022912), resulting in a frameshift and premature termination (Phe62Lysfs23Ter). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, segregated with the disorder in the family, and was not found in the 1000 Genomes Project or ExAC databases. Studies of patient fibroblasts and muscle showed no full-length mRNA transcript and no REEP1 protein. The patient presented at birth with equinovarus foot deformity, contractures of the distal phalanges, and a high-arched palate. He later developed progressive distal muscle weakness and hypotonia, hyperreflexia, and respiratory distress. Nerve conduction studies of sensory nerves showed reduced amplitudes and normal nerve conduction velocities, consistent with an axonal neuropathy. There were no motor nerve responses. Each parent was unaffected, despite being heterozygous for the mutation and haploinsufficient for REEP1, and Schottmann et al. (2015) suggested that additional genetic factors may have influenced the phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 6, INCLUDED
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</span>
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<span class="mim-text-font">
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REEP1, TRP42ARG
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<br />
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ClinVar: RCV002280598, RCV002280599
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<span class="mim-text-font">
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<p><strong><em>Autosomal Dominant Spastic Paraplegia 31</em></strong></p><p>
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In 4 affected members of a 3-generation French family (FSP-418) with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Goizet et al. (2011) identified a heterozygous c.124T-C transition (c.124T-C, NM_022912.2) in exon 3 of the REEP1 gene, resulting in a trp42-to-arg (W42R) substitution at a highly conserved residue. The mutation, which was found by direct sequencing of the REEP1 gene, segregated with the disorder in the family, although there was evidence of incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed. The patients had a complex form of SPG31 with an axonal sensorimotor peripheral neuropathy. </p><p><strong><em>Autosomal Recessive Distal Hereditary Motor Neuronopathy 6</em></strong></p><p>
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In a 14-year-old girl, born of consanguineous Iranian parents, with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; 620011), Maroofian et al. (2019) identified a homozygous c.124T-C transition in the REEP1 gene, resulting in a trp42-to-arg (W42R) substitution. The mutation, which was found by exome sequencing, was present in the heterozygous state in each unaffected parent. Functional studies of the variant and studies of patient cells were not performed. The authors suggested that incomplete penetrance in the carrier parents may have resulted from modifying genes or stochastic processes. </p>
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</span>
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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>.0009 SPASTIC PARAPLEGIA 31, AUTOSOMAL DOMINANT</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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REEP1, 1-BP DEL, 106G
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<br />
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ClinVar: RCV002280067, RCV002280597
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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 48-year-old French man (family N08-1658) with autosomal dominant spastic paraplegia-31 (SPG31; 610250), Goizet et al. (2011) identified a heterozygous 1-bp deletion (c.106delG, NM_022912.2) in exon 3 of the REEP1 gene, predicted to result in a frameshift and premature termination (Val36SerfsTer4). The patient had a similarly affected father and brother, but both were deceased and unavailable for study. Patient-derived skin fibroblasts showed abnormal mitochondrial morphology with elongated tubules, suggesting fission/fusion alterations. Muscle biopsy from the patient showed alteration mitochondrial respiration with decreased oxygen consumption. </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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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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REEP1, 1-BP DEL, 247G
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<br />
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SNP: rs2104244539,
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ClinVar: RCV001526840, RCV002280585
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 2.5-year-old girl, born of consanguineous Pakistani parents (family PaC6), with autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6; 620011), Kanwal et al. (2021) identified a homozygous 1-bp deletion (c.247delG, NM_022912.3) in the REEP1 gene, predicted to result in a frameshift and premature termination (Gly83AlafsTer44). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in the heterozygous state in each unaffected parent. It was not present in the 1000 Genomes Project or gnomAD databases. Functional studies of the variant and studies of patient cells were not performed. </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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</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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<ol>
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<li>
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<p class="mim-text-font">
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Beetz, C., Koch, N., Khundadze, M., Zimmer, G., Nietzsche, S., Hertel, N., Huebner, A.-K., Mumtaz, R., Schweizer, M., Dirren, E., Karle, K. N., Irintchev, A., Alvarez, V., Redies, C., Westermann, M., Kurth, I., Deufel, T., Kessels, M. M., Qualmann, B., Hubner, C. A.
|
|
<strong>A spastic paraplegia mouse model reveals REEP1-dependent ER shaping.</strong>
|
|
J. Clin. Invest. 123: 4273-82, 2013. Note: Erratum: J. Clin. Invest. 124: 2809 only, 2014.
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[PubMed: 24051375]
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[Full Text: https://doi.org/10.1172/JCI65665]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beetz, C., Pieber, T. R., Hertel, N., Schabhuttl, M., Fischer, C., Trajanoski, S., Graf, E., Keiner, S., Kurth, I., Wieland, T., Varga, R. E., Timmerman, V., Reilly, M. M., Strom, T. M., Auer-Grumbach, M.
|
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<strong>Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V.</strong>
|
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Am. J. Hum. Genet. 91: 139-145, 2012.
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[PubMed: 22703882]
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[Full Text: https://doi.org/10.1016/j.ajhg.2012.05.007]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Beetz, C., Schule, R., Deconinck, T., Tran-Viet, K.-N., Zhu, H., Kremer, B. P. H., Frints, S. G. M., van Zelst-Stams, W. A. G., Byrne, P., Otto, S., Nygren, A. O. H., Baets, J., and 18 others.
|
|
<strong>REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31.</strong>
|
|
Brain 131: 1078-1086, 2008.
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[PubMed: 18321925]
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[Full Text: https://doi.org/10.1093/brain/awn026]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Behrens, M., Bartelt, J., Reichling, C., Winnig, M., Kuhn, C., Meyerhof, W.
|
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<strong>Members of RTP and REEP gene families influence functional bitter taste receptor expression.</strong>
|
|
J. Biol. Chem. 281: 20650-20659, 2006.
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[PubMed: 16720576]
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[Full Text: https://doi.org/10.1074/jbc.M513637200]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Goizet, C., Depienne, C., Benard, G., Boukhris, A., Mundwiller, E., Sole, G., Coupry, I., Pilliod, J., Martin-Negrier, M.-L., Fedirko, E., Forlani, S., Cazeneuve, C., and 17 others.
|
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<strong>REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial morpho-functional dysfunction.</strong>
|
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Hum. Mutat. 32: 1118-27, 2011.
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[PubMed: 21618648]
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[Full Text: https://doi.org/10.1002/humu.21542]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hartz, P. A.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 8/21/2015.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hewamadduma, C., McDermott, C., Kirby, J., Grierson, A., Panayi, M., Dalton, A., Rajabally, Y., Shaw, P.
|
|
<strong>New pedigrees and novel mutation expand the phenotype of REEP1-associated hereditary spastic paraplegia (HSP).</strong>
|
|
Neurogenetics 10: 105-110, 2009.
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[PubMed: 19034539]
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[Full Text: https://doi.org/10.1007/s10048-008-0163-z]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Hurt, C. M., Bjork, S., Ho, V. K., Gilsbach, R., Hein, L., Angelotti, T.
|
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<strong>REEP1 and REEP2 proteins are preferentially expressed in neuronal and neuronal-like exocytotic tissues.</strong>
|
|
Brain Res. 1545: 12-22, 2014.
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[PubMed: 24355597]
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[Full Text: https://doi.org/10.1016/j.brainres.2013.12.008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kanwal, S., Choi, Y. J., Lim, S. O., Choi, H. J., Park, J. H., Nuzhat, R., Khan, A., Perveen, S., Choi, B.-O., Chung, K. W.
|
|
<strong>Novel homozygous mutations in Pakistani families with Charcot-Marie-Tooth disease.</strong>
|
|
BMC Med. Genomics 14: 174, 2021.
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[PubMed: 34193129]
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[Full Text: https://doi.org/10.1186/s12920-021-01019-5]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lim, Y., Cho, I.-T., Schoel, L. J., Cho, G., Golden, J. A.
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<strong>Hereditary spastic paraplegia-linked REEP1 modulates endoplasmic reticulum/mitochondria contacts.</strong>
|
|
Ann. Neurol. 78: 679-696, 2015.
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[PubMed: 26201691]
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[Full Text: https://doi.org/10.1002/ana.24488]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Maroofian, R., Behnam, M., Kaiyrzhanov, R., Salpietro, V., Salehi, M., Houlden, H.
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<strong>Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.</strong>
|
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Neurol. Genet. 5: e379, 2019.
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[PubMed: 31872057]
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[Full Text: https://doi.org/10.1212/NXG.0000000000000379]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Renvoise, B., Malone, B., Falgairolle, M., Munasinghe, J., Stadler, J., Sibilla, C., Park, S. H., Blackstone, C.
|
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<strong>Reep1 null mice reveal a converging role for hereditary spastic paraplegia proteins in lipid droplet regulation.</strong>
|
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Hum. Molec. Genet. 25: 5111-5125, 2016.
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[PubMed: 27638887]
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[Full Text: https://doi.org/10.1093/hmg/ddw315]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Saito, H., Kubota, M., Roberts, R. W., Chi, Q., Matsunami, H.
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<strong>RTP family members induce functional expression of mammalian odorant receptors.</strong>
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Cell 119: 679-691, 2004.
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[PubMed: 15550249]
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[Full Text: https://doi.org/10.1016/j.cell.2004.11.021]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Schottmann, G., Seelow, D., Seifert, F., Morales-Gonzalez, S., Gill, E., von Au, K., von Moers, A., Stenzel, W., Schuelke, M.
|
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<strong>Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.</strong>
|
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Neurol. Genet. 1: e32, 2015.
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[PubMed: 27066569]
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[Full Text: https://doi.org/10.1212/NXG.0000000000000032]
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</li>
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<li>
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<p class="mim-text-font">
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Toft, A., Birk, S., Ballegaard, M., Duno, M., Hjermind, L. E., Nielsen, J. E., Svenstrup, K.
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<strong>Peripheral neuropathy in hereditary spastic paraplegia caused by REEP1 variants.</strong>
|
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J. Neurol. 266: 735-744, 2019.
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[PubMed: 30637453]
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[Full Text: https://doi.org/10.1007/s00415-019-09196-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Zuchner, S., Wang, G., Tran-Viet, K.-N., Nance, M. A., Gaskell, P. C., Vance, J. M., Ashley-Koch, A. E., Pericak-Vance, M. A.
|
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<strong>Mutations in the novel mitochondrial protein REEP1 cause hereditary spastic paraplegia type 31.</strong>
|
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Am. J. Hum. Genet. 79: 365-369, 2006.
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[PubMed: 16826527]
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[Full Text: https://doi.org/10.1086/505361]
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</li>
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</ol>
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Bao Lige - updated : 10/06/2022<br>Alan F. Scott - updated : 08/30/2022<br>Cassandra L. Kniffin - updated : 08/24/2022<br>Cassandra L. Kniffin - updated : 11/10/2015<br>Patricia A. Hartz - updated : 8/21/2015<br>Cassandra L. Kniffin - updated : 7/31/2012<br>Cassandra L. Kniffin - updated : 5/14/2009<br>Victor A. McKusick - updated : 7/7/2006
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<span class="mim-text-font">
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Stylianos E. Antonarakis : 1/5/2005
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alopez : 10/17/2023<br>mgross : 10/06/2022<br>alopez : 08/30/2022<br>carol : 08/30/2022<br>carol : 08/30/2022<br>ckniffin : 08/24/2022<br>alopez : 10/04/2016<br>alopez : 11/13/2015<br>ckniffin : 11/10/2015<br>mgross : 8/24/2015<br>mcolton : 8/21/2015<br>carol : 1/21/2015<br>carol : 8/1/2012<br>carol : 8/1/2012<br>ckniffin : 7/31/2012<br>wwang : 2/21/2011<br>wwang : 5/21/2009<br>ckniffin : 5/14/2009<br>alopez : 7/12/2006<br>terry : 7/7/2006<br>mgross : 1/5/2005
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