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Entry
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- *600759 - PRESENILIN 2; PSEN2
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- OMIM
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<p>
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<span class="h4">*600759</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600759">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000143801;t=ENST00000366783" 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=5664" 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=600759" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000143801;t=ENST00000366783" 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_000447,NM_012486,XM_005273199,XM_017001835,XM_017001836,XM_047425596,XM_047425597,XM_047425601,XR_001737316,XR_007061979,XR_007061980,XR_949150" 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_000447" 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=600759" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=02860&isoform_id=02860_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/PSEN2" 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/950348,951203,1079576,1354265,1709858,13623517,16303806,30582807,119590202,119590203,119590204,119590205,119590206,156105679,156105681,158258030,194375245,530366342,545739140,1034560284,1034560286,1040736954,2217269285,2217269287,2217269289,2462511542,2462511544,2462511546,2462511548" 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/P49810" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5664" 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=ENSG00000143801;t=ENST00000366783" 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=PSEN2" 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=PSEN2" 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+5664" 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/PSEN2" 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:5664" 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/5664" 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=chr1&hgg_gene=ENST00000366783.8&hgg_start=226870616&hgg_end=226903668&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:9509" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/psen2" 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=600759[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=600759[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/PSEN2/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/ENSG00000143801" 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=PSEN2" 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=PSEN2" 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=PSEN2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://www.molgen.ua.ac.be/ADMutations/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PSEN2&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/PA33856" 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:9509" 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/FBgn0284421.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:109284" 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/PSEN2#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:109284" 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/5664/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=5664" 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=WBGene00004769;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-000330-9" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:600759" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5664" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=PSEN2&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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</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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600759
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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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PRESENILIN 2; PSEN2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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PS2<br />
|
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STM2
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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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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PSEN2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PSEN2</a></em></strong>
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Cytogenetic location: <a href="/geneMap/1/1763?start=-3&limit=10&highlight=1763">1q42.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:226870616-226903668&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'})">1:226,870,616-226,903,668</a> </span>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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Phenotype
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View Clinical Synopses
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<a href="/geneMap/1/1763?start=-3&limit=10&highlight=1763">
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1q42.13
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<span class="mim-font">
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Alzheimer disease-4
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<span class="mim-font">
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<a href="/entry/606889"> 606889 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Cardiomyopathy, dilated, 1V
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<span class="mim-font">
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<a href="/entry/613697"> 613697 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/600759" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/600759" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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</span>
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</span>
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<div>
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<a id="cloning" class="mim-anchor"></a>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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<p>Using both positional cloning and the candidate gene approach, <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> identified a candidate gene for the chromosome 1-linked locus for Alzheimer disease, designated AD4 (<a href="/entry/606889">606889</a>). By EST database searching, they identified a corresponding sequence that showed homology to the PSEN1 gene (<a href="/entry/104311">104311</a>), which is mutant in Alzheimer disease type 3 (AD3; <a href="/entry/607822">607822</a>). The deduced protein products of the 2 genes share share 80.5% sequence identity. Because the deduced protein had 7 transmembrane domains, <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> symbolized the gene STM2, for a second transmembrane gene associated with AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7638622" 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>Independent studies by <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> of ESTs with homology to the S182 (AD3) gene uncovered 3 ESTs with substantial homology to 2 different segments within the S182 open reading frame. Screening of a cDNA library detected 4 cDNAs, and sequencing demonstrated that all were derived from the same 2.3-kb transcript, which they designated E5-1. Northern blot analysis detected transcripts of the corresponding mRNA from several tissues, including most regions of the brain. In skeletal muscle, cardiac muscle, and pancreas, the E5-1 gene was expressed at higher levels as 2 different transcripts which were clearly different in size from that of the 2.7-kb S182 transcript, and did not cross-hybridize with S182 probes at high stringency. Both the E5-1 and the S182 proteins were predicted to be integral membrane proteins with 7 membrane-spanning domains and a large exposed loop between the sixth and seventh transmembrane domains. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7651536" 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 nucleotide and amino acid sequence database searches, <a href="#20" class="mim-tip-reference" title="Li, J., Ma, J., Potter, H. <strong>Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3.</strong> Proc. Nat. Acad. Sci. 92: 12180-12184, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8618867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8618867</a>] [<a href="https://doi.org/10.1073/pnas.92.26.12180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8618867">Li et al. (1995)</a> cloned the full-length STM2 cDNA, which encodes a 467-amino acid protein. Northern blot studies showed expression of the gene in a variety of tissues, including brain. <a href="#20" class="mim-tip-reference" title="Li, J., Ma, J., Potter, H. <strong>Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3.</strong> Proc. Nat. Acad. Sci. 92: 12180-12184, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8618867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8618867</a>] [<a href="https://doi.org/10.1073/pnas.92.26.12180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8618867">Li et al. (1995)</a> suggested that this might be the site of mutations causing AD4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8618867" 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="Levy-Lahad, E., Poorkaj, P., Wang, K., Fu, Y. H., Oshima, J., Mulligan, J., Schellenberg, G. D. <strong>Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene.</strong> Genomics 34: 198-204, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661049</a>] [<a href="https://doi.org/10.1006/geno.1996.0266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661049">Levy-Lahad et al. (1996)</a> reported that the primary AD4 gene transcript encodes a 448-amino acid polypeptide. They identified 2 transcripts of 2.4 and 2.8 kb in skeletal muscle, pancreas, and heart, with comparatively low levels observed in brain. In addition, they identified a splice variant of the 2.4-kb transcript that lacks a single glutamic acid residue (glu324), resulting from the use of an alternative splice acceptor site located in exon 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimGeneStructureFold" id="mimGeneStructureToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Gene Structure</strong>
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<p>The <a href="#2" class="mim-tip-reference" title="Alzheimer's Disease Collaborative Group. <strong>The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.</strong> Nature Genet. 11: 219-222, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550356</a>] [<a href="https://doi.org/10.1038/ng1095-219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550356">Alzheimer's Disease Collaborative Group (1995)</a> concluded that the structure of the AD4 gene, which they called presenilin-2, is very similar to that of the AD3 (presenilin-1) gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550356" 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="Levy-Lahad, E., Poorkaj, P., Wang, K., Fu, Y. H., Oshima, J., Mulligan, J., Schellenberg, G. D. <strong>Genomic structure and expression of STM2, the chromosome 1 familial Alzheimer disease gene.</strong> Genomics 34: 198-204, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8661049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8661049</a>] [<a href="https://doi.org/10.1006/geno.1996.0266" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8661049">Levy-Lahad et al. (1996)</a> determined that the AD4 gene contains 12 exons, including 10 coding exons. The first 2 exons encode the 5-prime untranslated region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8661049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using a somatic cell hybrid panel, <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> mapped the AD4 gene to chromosome 1. By using hybrid mapping panels and the CEPH mega-YAC physical map clones, <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> mapped the AD4 gene to human chromosome 1. <a href="#20" class="mim-tip-reference" title="Li, J., Ma, J., Potter, H. <strong>Identification and expression analysis of a potential familial Alzheimer disease gene on chromosome 1 related to AD3.</strong> Proc. Nat. Acad. Sci. 92: 12180-12184, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8618867/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8618867</a>] [<a href="https://doi.org/10.1073/pnas.92.26.12180" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8618867">Li et al. (1995)</a> assigned the STM2 gene to chromosome 1 by PCR screening of human/hamster somatic cell hybrids. PCR screening of a YAC contig library placed the gene between the 2 STS markers, D1S271E and D1S1644. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7638622+8618867+7651536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>PSEN2 Localization</em></strong>
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<p>By in situ hybridization to tissues, <a href="#14" class="mim-tip-reference" title="Kovacs, D. M., Fausett, H. J., Page, K. J., Kim, T.-W., Moir, R. D., Merriam, D. E., Hollister, R. D., Hallmark, O. G., Mancini, R., Felsenstein, K. M., Hyman, B. T., Tanzi, R. E., Wasco, W. <strong>Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.</strong> Nature Med. 2: 224-229, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8574969/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8574969</a>] [<a href="https://doi.org/10.1038/nm0296-224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8574969">Kovacs et al. (1996)</a> demonstrated that the expression patterns of PS1 and PS2 in the brain are extremely similar to each other and that messages for both are primarily detectable in neuronal populations. Immunochemical analyses indicated that PS1 and PS2 are similar in size and localize to similar intracellular compartments (endoplasmic reticulum and Golgi complex). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8574969" 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="#21" class="mim-tip-reference" title="Li, J., Xu, M., Zhou, H., Ma, J., Potter, H. <strong>Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation.</strong> Cell 90: 917-927, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9298903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9298903</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80356-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9298903">Li et al. (1997)</a> demonstrated that wildtype PS1 and PS2 are localized to the nuclear membrane, its associated interphase kinetochores, and the centrosomes. <a href="#21" class="mim-tip-reference" title="Li, J., Xu, M., Zhou, H., Ma, J., Potter, H. <strong>Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation.</strong> Cell 90: 917-927, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9298903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9298903</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80356-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9298903">Li et al. (1997)</a> stated that PS1 and PS2 localization to the membranes of the endoplasmic reticulum (ER) and Golgi is not unexpected for overexpressed membrane proteins because these locations are the sites of their synthesis and processing. They developed specific PS1 and PS2 antibodies directed at the N-terminal and loop domains. <a href="#21" class="mim-tip-reference" title="Li, J., Xu, M., Zhou, H., Ma, J., Potter, H. <strong>Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation.</strong> Cell 90: 917-927, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9298903/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9298903</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80356-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9298903">Li et al. (1997)</a> suggested that PS1 and PS2 play a role in chromosome organization and segregation. They discussed a pathogenic mechanism for familial AD in which mutant presenilins cause chromosome missegregation during mitosis, resulting in apoptosis and/or trisomy 21 mosaicism. An alternative hypothesis is that mutant presenilins not appropriately trafficked out of the endoplasmic reticulum may interfere with normal APP processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9298903" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Gamma-secretase Activity</em></strong>
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<p>There is evidence that PS1 and PS2 are important determinants of gamma-secretase activity responsible for the proteolytic cleavage of the amyloid precursor protein (APP; <a href="/entry/104760">104760</a>) and the NOTCH receptor protein (<a href="/entry/600725">600725</a>). <a href="#13" class="mim-tip-reference" title="Kopan, R., Goate, A. <strong>A common enzyme connects Notch signaling and Alzheimer's disease.</strong> Genes Dev. 14: 2799-2806, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11090127/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11090127</a>] [<a href="https://doi.org/10.1101/gad.836900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11090127">Kopan and Goate (2000)</a> reviewed evidence that presenilins are founding members of a novel class of aspartyl proteases that hydrolyze peptide bonds embedded within a membrane. The authors stated that although PS1 and PS2 both appear to be gamma secretases, it is not clear if the 2 enzymes normally have similar or different substrates, since they reside in different complexes. They proposed that the key to the regulation of cleavage may depend on the characterization of other proteins that are present in the high molecular weight complex that contains gamma-secretase activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11090127" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Francis, R., McGrath, G., Zhang, J., Ruddy, D. A., Sym, M., Apfeld, J., Nicoll, M., Maxwell, M., Hai, B., Ellis, M. C., Parks, A. L., Xu, W., Li, J., Gurney, M., Myers, R. L., Himes, C. S., Hiebsch, R., Ruble, C., Nye, J. S., Curtis, D. <strong>aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation.</strong> Dev. Cell 3: 85-97, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110170</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00189-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110170">Francis et al. (2002)</a> observed a reduction in the levels of processed presenilin and a reduction in gamma-secretase cleavage of beta-APP and Notch substrates after RNA-mediated interference assays that inactivated Aph1, Pen2 (PSENEN; <a href="/entry/607632">607632</a>), or nicastrin in cultured Drosophila cells. They concluded that presenilin protein accumulation requires APH1 and PEN2. Using coimmunoprecipitation experiments, <a href="#33" class="mim-tip-reference" title="Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M., Haass, C. <strong>PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin.</strong> J. Biol. Chem. 277: 39062-39065, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198112</a>] [<a href="https://doi.org/10.1074/jbc.C200469200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198112">Steiner et al. (2002)</a> showed that PEN2 is a critical component of PSEN1/gamma-secretase and PSEN2/gamma-secretase complexes. They observed that the absence of Psen1 or both Psen1 and Psen2 in mice resulted in reduced PEN2 levels. Additionally, <a href="#33" class="mim-tip-reference" title="Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M., Haass, C. <strong>PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin.</strong> J. Biol. Chem. 277: 39062-39065, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12198112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12198112</a>] [<a href="https://doi.org/10.1074/jbc.C200469200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12198112">Steiner et al. (2002)</a> reported that downregulation of PEN2 by RNA interference was associated with reduced presenilin levels, impaired nicastrin maturation, and deficient gamma-secretase complex formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12110170+12198112" 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>Gamma-secretase activity requires the formation of a stable, high molecular mass protein complex that, in addition to the endoproteolyzed fragmented form of presenilin, contains essential cofactors including nicastrin, APH1, and PEN2. <a href="#34" class="mim-tip-reference" title="Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., Iwatsubo, T. <strong>The role of presenilin cofactors in the gamma-secretase complex.</strong> Nature 422: 438-441, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12660785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12660785</a>] [<a href="https://doi.org/10.1038/nature01506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12660785">Takasugi et al. (2003)</a> showed that Drosophila APH1 increases the stability of Drosophila presenilin holoprotein in the complex. Depletion of PEN2 by RNA interference prevented endoproteolysis of presenilin and promoted stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Coexpression of Drosophila Pen2 with Aph1 and nicastrin increased the formation of presenilin fragments as well as gamma-secretase activity. Thus, <a href="#34" class="mim-tip-reference" title="Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., Iwatsubo, T. <strong>The role of presenilin cofactors in the gamma-secretase complex.</strong> Nature 422: 438-441, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12660785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12660785</a>] [<a href="https://doi.org/10.1038/nature01506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12660785">Takasugi et al. (2003)</a> concluded that APH1 stabilizes the presenilin holoprotein in the complex, whereas PEN2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12660785" 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="#43" class="mim-tip-reference" title="Wilson, C. A., Doms, R. W., Zheng, H., Lee, V. M.-Y. <strong>Presenilins are not required for A-beta-42 production in the early secretory pathway.</strong> Nature Neurosci. 5: 849-855, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145638</a>] [<a href="https://doi.org/10.1038/nn898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145638">Wilson et al. (2002)</a> analyzed the production of several forms of secreted and intracellular beta-amyloid forms in mouse cells lacking PS1, PS2, or both proteins. Although most amyloid beta species were abolished in PS1/PS2 -/- cells, the production of intracellular A-beta-42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. <a href="#43" class="mim-tip-reference" title="Wilson, C. A., Doms, R. W., Zheng, H., Lee, V. M.-Y. <strong>Presenilins are not required for A-beta-42 production in the early secretory pathway.</strong> Nature Neurosci. 5: 849-855, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12145638/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12145638</a>] [<a href="https://doi.org/10.1038/nn898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12145638">Wilson et al. (2002)</a> concluded that production of this pool of amyloid beta occurs independently of PS1/PS2 and, therefore, that another gamma-secretase activity must be responsible for cleavage of APP within the early secretory compartments. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12145638" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Other Functions</em></strong>
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<p>PC12 cells that have been grown in the presence of nerve growth factor (NGF; <a href="/entry/162030">162030</a>) for more than 2 weeks become dependent on NGF. In neuronally differentiated PC12 cells, withdrawal of trophic support induces apoptosis, with the peak of DNA fragmentation occurring 2 days after withdrawal of trophic support. <a href="#44" class="mim-tip-reference" title="Wolozin, B., Iwasaki, K., Vito, P., Ganjei, J. K., Lacana, E., Sunderland, T., Zhao, B., Kusiak, J. W., Wasco, W., D'Adamio, L. <strong>Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.</strong> Science 274: 1710-1712, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939861</a>] [<a href="https://doi.org/10.1126/science.274.5293.1710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939861">Wolozin et al. (1996)</a> found that overexpression of the PS2 gene in NGF-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in these cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins were involved. <a href="#44" class="mim-tip-reference" title="Wolozin, B., Iwasaki, K., Vito, P., Ganjei, J. K., Lacana, E., Sunderland, T., Zhao, B., Kusiak, J. W., Wasco, W., D'Adamio, L. <strong>Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation.</strong> Science 274: 1710-1712, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8939861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8939861</a>] [<a href="https://doi.org/10.1126/science.274.5293.1710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8939861">Wolozin et al. (1996)</a> showed that the asn141-to-ile mutation associated with FAD (N141I; <a href="#0001">600759.0001</a>) generates a molecule with enhanced basal apoptotic activity. They speculated that this gain of function may accelerate the process of neurodegeneration that occurs in Alzheimer disease, leading to the earlier age of onset characteristic of familial Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8939861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By yeast 2-hybrid screening of a human fetal brain cDNA library to identify PS2-binding proteins, <a href="#32" class="mim-tip-reference" title="Stabler, S. M., Ostrowski, L. L., Janicki, S. M., Monteiro, M. J. <strong>A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein.</strong> J. Cell Biol. 145: 1277-1292, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10366599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10366599</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10366599[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/10.1083/jcb.145.6.1277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10366599">Stabler et al. (1999)</a> identified CIB1 (<a href="/entry/602293">602293</a>), which they called calmyrin. Expression analysis showed that calmyrin localization shifted from accumulation in nucleus and cytoplasm to almost complete colocalization with PS2 in ER following coexpression. Affinity chromatography and immunoprecipitation analyses in PS2-expressing HeLa cell lysates confirmed direct binding between calmyrin and PS2. Functional studies showed that calmyrin and PS2 increased cell death when cotransfected into HeLa cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10366599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using the yeast 2-hybrid system, <a href="#36" class="mim-tip-reference" title="Tanahashi, H., Tabira, T. <strong>Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein.</strong> Hum. Molec. Genet. 9: 2281-2289, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001931</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018919" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001931">Tanahashi and Tabira (2000)</a> screened for proteins interacting with presenilin-2 and cloned DRAL (<a href="/entry/602633">602633</a>). DRAL is a LIM-only protein, which has been shown to be a coactivator of the androgen receptor (AR; <a href="/entry/313700">313700</a>) as well as a protein interacting with a DNA replication regulatory protein, CDC47 (<a href="/entry/600592">600592</a>). DRAL interacted with a hydrophilic loop region (amino acids 269-298) in the endoproteolytic N-terminal fragment of PS2, but not that of PS1, although residues 269 to 298 of PS2 and the corresponding PS1 sequence differ by only 3 amino acids. Each of 9 PS2 point mutations within a region from residues 275 to 296 abolished the binding. The in vitro interaction was confirmed by affinity column assay and the physiologic interactions between endogenous PS2 and DRAL by coimmunoprecipitation from human lung fibroblast MRC5 cells. The authors suggested that DRAL functions as a link between PS2 and an intracellular signaling pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using coimmunoprecipitation and nickel affinity pull-down approaches, <a href="#15" class="mim-tip-reference" title="Lee, S.-F., Shah, S., Li, H., Yu, C., Han, W., Yu, G. <strong>Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch.</strong> J. Biol. Chem. 277: 45013-45019, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12297508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12297508</a>] [<a href="https://doi.org/10.1074/jbc.M208164200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12297508">Lee et al. (2002)</a> showed that nicastrin (<a href="/entry/605254">605254</a>) and presenilin heterodimers physically associated with APH1A (<a href="/entry/607629">607629</a>) and APH1B (<a href="/entry/607630">607630</a>) in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12297508" 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="#40" class="mim-tip-reference" title="Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S.-F., Hao, Y.-H., Serneels, L., De Strooper, B., Yu, G., Bezprozvanny, I. <strong>Presenilins form ER Ca(2+) leak channels, a function disrupted by familial Alzheimer's disease-linked mutations.</strong> Cell 126: 981-993, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16959576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16959576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16959576[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.cell.2006.06.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16959576">Tu et al. (2006)</a> showed that recombinant presenilins, but not PSEN1 with the met146-to-val (M146V; <a href="/entry/104311#0007">104311.0007</a>) mutation or PSEN2 with the N141I mutation, formed low-conductance cation-permeable channels in planar lipid bilayers following expression in insect cells. Embryonic fibroblasts from mice lacking both Psen1 and Psen2 had Ca(2+) signaling defects due to leakage from the ER, and the deficient calcium signaling in these cells could be rescued by expression of wildtype PSEN1 or PSEN2, but not by expression of PSEN1 with the M146V mutation or PSEN2 with the N141I mutation. The ER Ca(2+) leak function of presenilins was independent of their gamma-secretase activities. <a href="#40" class="mim-tip-reference" title="Tu, H., Nelson, O., Bezprozvanny, A., Wang, Z., Lee, S.-F., Hao, Y.-H., Serneels, L., De Strooper, B., Yu, G., Bezprozvanny, I. <strong>Presenilins form ER Ca(2+) leak channels, a function disrupted by familial Alzheimer's disease-linked mutations.</strong> Cell 126: 981-993, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16959576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16959576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16959576[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.cell.2006.06.059" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16959576">Tu et al. (2006)</a> proposed that presenilins have a Ca(2+) signaling function, supporting the connection between deranged neuronal Ca(2+) signaling and Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16959576" 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="#47" class="mim-tip-reference" title="Zhang, C., Wu, B., Beglopoulos, V., Wines-Samuelson, M., Zhang, D., Dragatsis, I., Sudhof, T. C., Shen, J. <strong>Presenilins are essential for regulating neurotransmitter release.</strong> Nature 460: 632-636, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19641596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19641596</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19641596[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19641596">Zhang et al. (2009)</a> used a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. They showed that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, they found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-D-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca(2+) stores by thapsigargin, or blockade of Ca(2+) release from these stores by ryanodine receptor (see RYR3, <a href="/entry/180903">180903</a>) inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. <a href="#47" class="mim-tip-reference" title="Zhang, C., Wu, B., Beglopoulos, V., Wines-Samuelson, M., Zhang, D., Dragatsis, I., Sudhof, T. C., Shen, J. <strong>Presenilins are essential for regulating neurotransmitter release.</strong> Nature 460: 632-636, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19641596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19641596</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19641596[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19641596">Zhang et al. (2009)</a> concluded that, collectively, their results indicated a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca(2+) release in presynaptic terminals, and further suggested that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19641596" 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="mim-changed mim-change"><p><a href="#46" class="mim-tip-reference" title="Zampese, E., Fasolato, C., Kipanyula, M. J., Bortolozzi, M., Pozzan, T., Pizzo, P. <strong>Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk.</strong> Proc. Nat. Acad. Sci. 108: 2777-2782, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21285369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21285369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21285369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1100735108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21285369">Zampese et al. (2011)</a> showed that PS2 overexpression increased mitochondrial Ca(2+) uptake in SH-SY5Y human neuroblastoma cells, although it reduced store Ca(2+) content and concentration peaks. Increased mitochondrial Ca(2+) uptake due to PS2 overexpression was not caused by direct PS2 action on the mitochondrial Ca(2+) uptake machinery, but rather by increased physical interaction between ER and mitochondria that augmented the frequency of Ca(2+) hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane (OMM). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21285369" 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></div>
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<p><strong><em>Alzheimer Disease 4</em></strong></p><p>
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In affected members of 7 families of the Volga German group with Alzheimer disease (AD4; <a href="/entry/606889">606889</a>), <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> identified heterozygosity for an asn141-to-ile mutation (N141I; <a href="#0001">600759.0001</a>) in the PSEN2 gene. Two affected patients from the families with AD lacked the mutation; age of onset and APOE4 (see <a href="/entry/107741">107741</a>) status suggested that these patients had a phenocopy (or genocopy) of the AD4 present in most of their relatives. <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> found that all the affected Volga German individuals, except one who did not have the N141I mutation, shared a haplotype between D1S238 and D1S235. The age of onset in the person without the mutation , 67 years, was greater than 2 standard deviations above the family mean. <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> noted that the N141L mutation in STM2 and all 5 mutations previously identified in the AD3 gene (S182) occur at residues conserved among the new chromosome 1 gene, S182, and the mouse homolog of S182. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7638622" 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>Studying DNA from affected members of 23 pedigrees with early-onset familial Alzheimer disease in which mutations in the chromosome 21 and chromosome 14 genes had been excluded, <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> identified a heterozygous mutation in the PSEN2 gene (<a href="#0002">600759.0002</a>) in all 4 affected members of an extended pedigree of Italian origin with early-onset, pathologically confirmed FAD (onset at 50 years). In addition, the N141L mutation was found in a public database from affected probands of 3 of 4 pedigrees of Volga German ancestry. The appearance of the same mutation in affected members of 3 different Volga German pedigrees reflected a founder effect. <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> suggested that the patient without the N141L mutation in the fourth Volga German family, aged 77 years, had another type of AD. This interpretation was supported by the fact that late-onset AD may affect at least 5% of the population older than 70 years, and by the fact that while the Volga German populations are probably drawn from a limited number of founders, they are unlikely to represent a pure population isolate, particularly after immigration to North America. The atypical subject was also homozygous for the APOE4 allele. <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> found neither of the AD4 gene mutations in 284 normal Caucasian controls or in affected members of pedigrees with the AD3 type of AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7651536" 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="#6" class="mim-tip-reference" title="Clark, R. F., Hutton, M., Talbot, C., Wragg, M., Lendon, C., Busfield, F., Han, S. W., Perez-Tur, J., Adams, M., Fuldner, R., Roberts, G., Karran, E., Hardy, J., Goate, A. <strong>The role of presenilin 1 in the genetics of Alzheimer's disease.</strong> Cold Spring Harbor Symp. Quant. Biol. 61: 551-558, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246481</a>]" pmid="9246481">Clark et al. (1996)</a> and <a href="#31" class="mim-tip-reference" title="St. George-Hyslop, P. H., Levesque, G., Levesque, L., Rommens, J., Westaway, D., Fraser, P. E. <strong>Two homologous genes causing early-onset familial Alzheimer's disease.</strong> Cold Spring Harbor Symp. Quant. Biol. 61: 559-564, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246482</a>]" pmid="9246482">St. George-Hyslop et al. (1996)</a> reviewed the role of PS1 and PS2 in familial early-onset Alzheimer disease. <a href="#6" class="mim-tip-reference" title="Clark, R. F., Hutton, M., Talbot, C., Wragg, M., Lendon, C., Busfield, F., Han, S. W., Perez-Tur, J., Adams, M., Fuldner, R., Roberts, G., Karran, E., Hardy, J., Goate, A. <strong>The role of presenilin 1 in the genetics of Alzheimer's disease.</strong> Cold Spring Harbor Symp. Quant. Biol. 61: 551-558, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246481</a>]" pmid="9246481">Clark et al. (1996)</a> tabulated mutations in the 2 genes, most of which occurred in the PS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9246481+9246482" 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="Cruts, M., Van Broeckhoven, C. <strong>Presenilin mutations in Alzheimer's disease.</strong> Hum. Mutat. 11: 183-190, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9521418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9521418</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<183::AID-HUMU1>3.0.CO;2-J" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9521418">Cruts and Van Broeckhoven (1998)</a> counted 43 mutations that had been identified in the PS1 gene that led to familial presenile AD (onset before age 65 years). By contrast, only 3 mutations had been identified in PS2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9521418" 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>Dilated Cardiomyopathy 1V</em></strong></p><p>
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The presenilins are expressed in the heart and are critical to cardiac development. <a href="#19" class="mim-tip-reference" title="Li, D., Parks, S. B., Kushner, J. D., Nauman, D., Burgess, D., Ludwigsen, S., Partain, J., Nixon, R. R., Allen, C. N., Irwin, R. P., Jakobs, P. M., Litt, M., Hershberger, R. E. <strong>Mutations of presenilin genes in dilated cardiomyopathy and heart failure.</strong> Am. J. Hum. Genet. 79: 1030-1039, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17186461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17186461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17186461[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/10.1086/509900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17186461">Li et al. (2006)</a> hypothesized that mutations in presenilins may also be associated with dilated cardiomyopathy (see CMD1V; <a href="/entry/613697">613697</a>) and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. They evaluated a total of 315 index patients with DCM for sequence variation in PSEN1 and PSEN2. <a href="#19" class="mim-tip-reference" title="Li, D., Parks, S. B., Kushner, J. D., Nauman, D., Burgess, D., Ludwigsen, S., Partain, J., Nixon, R. R., Allen, C. N., Irwin, R. P., Jakobs, P. M., Litt, M., Hershberger, R. E. <strong>Mutations of presenilin genes in dilated cardiomyopathy and heart failure.</strong> Am. J. Hum. Genet. 79: 1030-1039, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17186461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17186461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17186461[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/10.1086/509900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17186461">Li et al. (2006)</a> identified a single PSEN2 missense mutation (<a href="#0008">600759.0008</a>) in 2 families, and a novel PSEN1 missense mutation (<a href="/entry/104311#0034">104311.0034</a>) in 1 family. Both mutations, present in heterozygous state, segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured fibroblasts from PSEN1 and PSEN2 mutation carriers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17186461" 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>Presenilin homologs with high sequence similarity are known in plants, invertebrates, and vertebrates. <a href="#27" class="mim-tip-reference" title="Ponting, C. P., Hutton, M., Nyborg, A., Baker, M., Jansen, K., Golde, T. E. <strong>Identification of a novel family of presenilin homologues.</strong> Hum. Molec. Genet. 11: 1037-1044, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978763</a>] [<a href="https://doi.org/10.1093/hmg/11.9.1037" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11978763">Ponting et al. (2002)</a> searched various databases to identify a family of proteins homologous to presenilins. Members of this family, which they termed presenilin homologs, have significant sequence similarities to presenilins and also possess 2 conserved aspartic acid residues within adjacent predicted transmembrane segments. The presenilin homolog family was found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five presenilin homologs were detected in the human genome, of which 3 possess 'protease-associated' domains that are consistent with the proposed protease function of presenilins. Based on these findings, the authors proposed that presenilins and presenilin homologs represent different subbranches of a larger family of polytopic membrane-associated aspartyl proteases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978763" 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 transfected cell lines, <a href="#5" class="mim-tip-reference" title="Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim. S., Schenk, D., Fraser, P., St George Hyslop, P., Selkoe, D. J. <strong>Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.</strong> Nature Med. 3: 67-72, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8986743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8986743</a>] [<a href="https://doi.org/10.1038/nm0197-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8986743">Citron et al. (1997)</a> found that mutant human PS1 and PS2 resulted in a highly significant increase in secretion of amyloid beta-42. The PS2 Volga mutation (<a href="#0001">600759.0001</a>) led to a 6- to 8-fold increase in the production of total amyloid beta-42; none of the PS1 mutations had such a dramatic effect, suggesting an intrinsic difference in the effects of PS1 and PS2 mutations. The mutations caused an increase in gamma-secretase activity which resulted in increased proteolysis of APP at the amyloid beta-42 site, leading to heightened amyloid beta-42 production. <a href="#5" class="mim-tip-reference" title="Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim. S., Schenk, D., Fraser, P., St George Hyslop, P., Selkoe, D. J. <strong>Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.</strong> Nature Med. 3: 67-72, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8986743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8986743</a>] [<a href="https://doi.org/10.1038/nm0197-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8986743">Citron et al. (1997)</a> stated that their combined in vitro and in vivo data clearly demonstrated that the FAD-linked presenilin mutations directly or indirectly altered the level of gamma-secretase, but not of alpha- or beta-secretase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8986743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To delineate the relationships of presenilin-1 and -2 activities and to determine whether PS2 mutations involve gain or loss of function, <a href="#12" class="mim-tip-reference" title="Herreman, A., Hartmann, D, Annaert, W., Saftig, P., Craessaerts, K., Serneels, L., Umans, L., Schrijvers, V., Checler, F., Vanderstichele, H., Baekelandt, V., Dressel, R., Cupers, P., Huylebroeck, D., Zwijsen, A., Van Leuven, F., De Strooper, B. <strong>Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency.</strong> Proc. Nat. Acad. Sci. 96: 11872-11877, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10518543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10518543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10518543[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.21.11872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10518543">Herreman et al. (1999)</a> generated PS2 homozygous deficient (-/-) and PS1/PS2 double homozygous deficient mice. In contrast to PS1 -/- mice, PS2 -/- mice were viable and fertile and developed only mild pulmonary fibrosis and hemorrhage with age. Absence of PS2 did not detectably alter processing of amyloid precursor protein and had little or no effect on physiologically important apoptotic processes, suggesting that Alzheimer disease-causing mutations in PS2, as in PS1, result in gain of function. Although PS1 +/- PS2 -/- mice survived in relatively good health, complete deletion of both PS2 and PS1 genes caused a phenotype closely resembling full Notch-1 (<a href="/entry/190198">190198</a>) deficiency. These results demonstrated in vivo that the PS1 and PS2 have partially overlapping functions and that PS1 is essential and PS2 is redundant for normal Notch signaling during mammalian embryologic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10518543" 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="#8" class="mim-tip-reference" title="Donoviel, D. B., Hadjantonakis, A.-K., Ikeda, M., Zheng, H., St George Hyslop, P., Bernstein, A. <strong>Mice lacking both presenilin genes exhibit early embryonic patterning defects.</strong> Genes Dev. 13: 2801-2810, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10557208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10557208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10557208[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/10.1101/gad.13.21.2801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10557208">Donoviel et al. (1999)</a> generated PS2-null mice by gene targeting, and subsequently, PS1/PS2 double-null mice. Mice homozygous for a targeted null mutation in PS2 exhibited no obvious defects; however, loss of PS2 on a PS1-null background led to embryonic lethality at embryonic day 9.5. Embryos lacking both presenilins and, surprisingly, those carrying only a single copy of PS2 on a PS1-null background exhibited multiple early patterning defects, including lack of somite segmentation, disorganization of the trunk ventral neural tube, midbrain mesenchyme cell loss, anterior neuropore closure delays, and abnormal heart and second branchial arch development. In addition, Delta-like-1 (<a href="/entry/176290">176290</a>) and Hes5, 2 genes that lie downstream in the Notch pathway, were misexpressed in presenilin double-null embryos. Hes5 expression was undetectable in these mice, whereas Delta-like-1 was expressed ectopically in the neural tube and brain of double-null embryos. <a href="#8" class="mim-tip-reference" title="Donoviel, D. B., Hadjantonakis, A.-K., Ikeda, M., Zheng, H., St George Hyslop, P., Bernstein, A. <strong>Mice lacking both presenilin genes exhibit early embryonic patterning defects.</strong> Genes Dev. 13: 2801-2810, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10557208/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10557208</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10557208[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/10.1101/gad.13.21.2801" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10557208">Donoviel et al. (1999)</a> concluded that the presenilins play a widespread role in embryogenesis, that there is functional redundancy between PS1 and PS2, and that both vertebrate presenilins, like their invertebrate homologs, are essential for Notch signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10557208" 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="#30" class="mim-tip-reference" title="Sawamura, N., Morishima-Kawashima, M., Waki, H., Kobayashi, K., Kuramochi, T., Frosch, M. P., Ding, K., Ito, M., Kim, T.-W., Tanzi, R. E., Oyama, F., Tabira, T., Ando, S., Ihara, Y. <strong>Mutant presenilin 2 transgenic mice: a large increase in the levels of A-beta-42 is presumably associated with the low density membrane domain that contains decreased levels of glycerophospholipids and sphingomyelin.</strong> J. Biol. Chem. 275: 27901-27908, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10846187/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10846187</a>] [<a href="https://doi.org/10.1074/jbc.M004308200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10846187">Sawamura et al. (2000)</a> reported that levels of amyloid beta-42 in transgenic mice expressing the N141I mutation were increased in both Tris-saline-soluble and -insoluble fractions. Analysis of the low density membrane fraction from brains of 2 independent lines of mutant PS2 transgenic mice showed markedly increased levels of amyloid beta-42 and significantly low levels of glycerophospholipids and sphingomyelin. The authors concluded that there is a link between mutant PS2 and the metabolism of glycerophospholipids and sphingomyelin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10846187" 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="#29" class="mim-tip-reference" title="Saura, C. A., Choi, S.-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B. S., Chattarji, S., Kelleher, R. J., III, Kandel, E. R., Duff, K., Kirkwood, A., Shen, J. <strong>Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.</strong> Neuron 42: 23-36, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15066262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15066262</a>] [<a href="https://doi.org/10.1016/s0896-6273(04)00182-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15066262">Saura et al. (2004)</a> generated a transgenic conditional double knockout mouse lacking both Psen1 and Psen2 in the postnatal forebrain. The mice showed impairments in hippocampal memory and synaptic plasticity at the age of 2 months, and later developed neurodegeneration of the cerebral cortex accompanied by increased levels of the Cdk5 activator p25 (<a href="/entry/603460">603460</a>) and hyperphosphorylated tau. The authors concluded that PSEN1 and PSEN2 have essential roles in synaptic plasticity, learning, and memory. <a href="#3" class="mim-tip-reference" title="Beglopoulos, V., Sun, X., Saura, C. A., Lemere, C. A., Kim, R. D., Shen, J. <strong>Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.</strong> J. Biol. Chem. 279: 46907-46914, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345711</a>] [<a href="https://doi.org/10.1074/jbc.M409544200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345711">Beglopoulos et al. (2004)</a> found that double knockout mice lacking Psen1 and Psen2 in the postnatal forebrain had reduced levels of the toxic beta-amyloid peptides beta-40 and beta-42 and strong microglial activation in the cerebral cortex. Gene expression profiling showed an upregulation of genes associated with inflammatory responses. The results suggested that the memory deficits and neurodegeneration observed in the double knockout mice were not caused by beta-amyloid accumulation and implicated an inflammatory component to the neurodegenerative process. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15066262+15345711" 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="#39" class="mim-tip-reference" title="Tournoy, J., Bossuyt, X., Snellinx, A., Regent, M., Garmyn, M., Serneels, L., Saftig, P., Craessaerts, K., De Strooper, B., Hartmann, D. <strong>Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice.</strong> Hum. Molec. Genet. 13: 1321-1331, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15128703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15128703</a>] [<a href="https://doi.org/10.1093/hmg/ddh151" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15128703">Tournoy et al. (2004)</a> reported that in PS1 +/- PS2 -/- mice, PS1 protein concentration was considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>) downregulation. Their phenotype was normal up to 6 months, when the majority of the mice developed an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis, and vasculitis, as seen in human systemic lupus erythematosus (<a href="/entry/152700">152700</a>). Besides B cell-dominated infiltrates, the authors observed a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies, and an increased CD4+/CD8+ ratio. The mice further developed a benign skin hyperplasia similar to human seborrheic keratosis (<a href="/entry/182000">182000</a>) as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15128703" 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="mim-changed mim-change"><p><a href="#35" class="mim-tip-reference" title="Takeda, T., Asahi, M., Yamaguchi, O., Hikoso, S., Nakayama, H., Kusakari, Y., Kawai, M., Hongo, K., Higuchi, Y., Kashiwase, K., Watanabe, T., Taniike, M., and 9 others. <strong>Presenilin 2 regulates the systolic function of heart by modulating Ca2+ signaling.</strong> FASEB J. 19: 2069-2071, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16204356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16204356</a>] [<a href="https://doi.org/10.1096/fj.05-3744fje" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16204356">Takeda et al. (2005)</a> found that Ps2 -/- mice developed normally with no evidence of cardiac hypertrophy or fibrosis. However, cardiac contractility was significantly increased in Ps2 -/- mice compared with wildtype. Isolated papillary muscle from Ps2 -/- heart showed significantly higher peak amplitudes of Ca(2+) transients and peak tension compared with controls, but Ps2 -/- heart exhibited no change in expression of calcium regulatory proteins. Ps2 interacted with Ryr2 (<a href="/entry/180902">180902</a>) and sorcin (SRI; <a href="/entry/182520">182520</a>) both in vitro and in mouse heart in vivo, and Ps2 preferentially colocalized with Ryr2 and sorcin along Z-lines in heart. Elevated Ca(2+) attenuated association of Ryr2 with Ps2, whereas it enhanced association of sorcin with Ps2. Enhanced Ca(2+) transients and contractility in Ps2 -/- mice were observed at low extracellular Ca(2+) concentration, but not at high levels of Ca(2+) concentration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16204356" 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></div>
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<div class="mim-changed mim-change"><p><a href="#25" class="mim-tip-reference" title="Nam, H., Lee, Y., Kim, B., Lee, J. W., Hwang, S., An, H. K., Chung, K. M., Park, Y., Hong, J., Kim, K., Kim, E. K., Choe, H. K., Yu, S. W. <strong>Presenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERB-alpha.</strong> Nature Commun. 13: 1972, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35418126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35418126</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35418126[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-022-29653-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35418126">Nam et al. (2022)</a> found that knockin mice heterozygous for the N141I mutation had normal levels of Psen2 expression and normal expression of Psen2 downstream target of the Notch pathway in primary microglia and bone marrow-derived macrophages (BMDMs). However, mutant mice displayed hyperimmunity, overproducing clock gene-controlled cytokines, including Il6 (<a href="/entry/147620">147620</a>), in microglia and BMDMs in response to stimulation by lipopolysaccharide (LPS). Immunohistochemical analyses showed that a low dose of LPS induced a hyperactive immune response and caused memory deficit through overproduction of clock gene-controlled cytokines in mutant mice, while the same dose of LPS was inoccuous in wildtype mice. The Psen2 N141I mutation induced secretion of clock gene-controlled cytokines and resulted in memory deficits in mutant mice in response to fibrillar amyloid-beta. RT-PCR analysis revealed that Psen2 N141I decreased expression of clock genes, including Nr1d1 (<a href="/entry/602408">602408</a>), in innate immune cells from mutant mice, but that those cells remained rhythmic. Downregulation of Nr1d1 led to selective elevation of clock-controlled Il6 production in response to LPS. Further analysis indicated that the Psen2 N141I mutation repressed expression via DNA hypermethylation, as the Nr1d1 promoter was hypermethylated in innate immune cells from mice heterozygous for Psen2 N141I, and hypermethylation of the promoter was critical for reducing Nr1d1 expression. An antipsychotic drug, chlorpromazine, restored Nr1d1 expression and prevented LPS-induced hyperactive immune response and cognitive decline in mutant mice. Further analysis demonstrated that chlorpromazine rescued Nr1d1 expression by rectifying DNA hypermethylation through inhibition of the PI3K (see <a href="/entry/171834">171834</a>)/Akt1 (<a href="/entry/164730">164730</a>) pathway in microglia of mutant mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35418126" 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></div>
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<p>AD3 and AD4 are the symbols for the Alzheimer disease-related genes on chromosomes 14 and 1, respectively. As the genes were isolated and characterized, other designations, such as S182 for AD3 and STM2 for AD4 (<a href="#18" class="mim-tip-reference" title="Levy-Lahad, E., Wijsman, E. M., Nemens, E., Anderson, L., Goddard, K. A. B., Weber, J. L., Bird, T. D., Schellenberg, G. D. <strong>A familial Alzheimer's disease locus on chromosome 1.</strong> Science 269: 970-973, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638621</a>] [<a href="https://doi.org/10.1126/science.7638621" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638621">Levy-Lahad et al., 1995</a>), have also been used. <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> suggested that the unique features shared by the chromosomes 14 (presenilin-1) and 1 (presenilin-2) genes indicate that they constitute a distinct gene family which, because of the association with Alzheimer disease, might be called the 'presenilin' family. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7651536+7638621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The <a href="#2" class="mim-tip-reference" title="Alzheimer's Disease Collaborative Group. <strong>The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.</strong> Nature Genet. 11: 219-222, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550356/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550356</a>] [<a href="https://doi.org/10.1038/ng1095-219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550356">Alzheimer's Disease Collaborative Group (1995)</a> used gene symbols PS1 and PS2 for the genes encoding presenilin-1 and presenilin-2, respectively. They stated that the number of predicted transmembrane domains in the presenilins varies between 6 and 9, depending on the secondary structure prediction program and calculation window used; for this reason, they suggested that the name 'seven transmembrane protein' (STM) may be unwise. Notably, STM is the symbol already reserved for the monoamine-preferring sulfotransferase gene (<a href="/entry/600641">600641</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550356" 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="#41" class="mim-tip-reference" title="Vito, P., Lacana, E., D'Adamio, L. <strong>Interfering with apoptosis: Ca(2+)-binding protein ALG-2 and Alzheimer's disease gene ALG-3.</strong> Science 271: 521-524, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8560270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8560270</a>] [<a href="https://doi.org/10.1126/science.271.5248.521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8560270">Vito et al. (1996)</a> found that the mouse gene originally designated Alg3, and now symbolized Psen2, is the homolog of human PSEN2. The designation ALG3 is used for a gene on chromosome 16 (<a href="/entry/601100">601100</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8560270" 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=600759[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 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs63750215 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750215;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=rs63750215" 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=rs63750215" 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 total of 7 Volga German families with early-onset familial Alzheimer disease (AD4; <a href="/entry/606889">606889</a>), <a href="#17" class="mim-tip-reference" title="Levy-Lahad, E., Wasco, W., Poorkaj, P., Romano, D. M., Oshima, J., Pettingell, W. H., Yu, C., Jondro, P. D., Schmidt, S. D., Wang, K., Crowley, A. C., Fu, Y.-H., Guenette, S. Y., Galas, D., Nemens, E., Wijsman, E. M., Bird, T. D., Schellenberg, G. D., Tanzi, R. E. <strong>Candidate gene for the chromosome 1 familial Alzheimer's disease locus.</strong> Science 269: 973-977, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7638622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7638622</a>] [<a href="https://doi.org/10.1126/science.7638622" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7638622">Levy-Lahad et al. (1995)</a> found an A-T transversion in the PSEN2 gene, resulting in an asn141-to-ile (N141I) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7638622" 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 3 of 4 pedigrees of Volga German ancestry, <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> found heterozygosity for the N141I mutation, suggesting founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7651536" 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>To gain insight into the significance of the presenilins in the pathogenetic mechanisms of early-onset familial Alzheimer disease, <a href="#38" class="mim-tip-reference" title="Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grunberg, J., Haass, C., Iwatsubo, T., Obata, K. <strong>The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue.</strong> Proc. Nat. Acad. Sci. 94: 2025-2030, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9050898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9050898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9050898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.5.2025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9050898">Tomita et al. (1997)</a> expressed cDNAs for wildtype PSEN2 and PSEN2 with the Volga German mutation (N141I) in cultured cells and then examined the metabolism of the transfected proteins and their effect on the C-terminal properties of secreted amyloid beta protein (A-beta). PSEN2 was identified as a 50- to 55-kD protein that was cleaved to produce N-terminal fragments of 35 to 40 kD and C-terminal fragments of 19 to 23 kD. The N141I mutation did not cause any significant change in the metabolism of PSEN2. COS-1 cells doubly transfected with the mutant N141I PSEN2 gene and human beta-amyloid precursor protein, as well as mouse neuroblastoma cells stably transfected with N141I mutant PSEN2 alone, secreted 1.5- to 10-fold more beta-amyloid 42 or 43 compared with those expressing the wildtype PSEN2. These results strongly suggested to <a href="#38" class="mim-tip-reference" title="Tomita, T., Maruyama, K., Saido, T. C., Kume, H., Shinozaki, K., Tokuhiro, S., Capell, A., Walter, J., Grunberg, J., Haass, C., Iwatsubo, T., Obata, K. <strong>The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid beta protein ending at the 42nd (or 43rd) residue.</strong> Proc. Nat. Acad. Sci. 94: 2025-2030, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9050898/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9050898</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9050898[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.5.2025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9050898">Tomita et al. (1997)</a> that the N141I mutation linked to FAD alters the metabolism of APP to foster the production of the form of A-beta that most readily deposits in amyloid plaques. Thus, mutant PSEN2 may lead to AD by altering the metabolism of APP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9050898" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Marambaud, P., Alves da Costa, C., Ancolio, K., Checler, F. <strong>Alzheimer's disease-linked mutation of presenilin 2 (N141I-PS2) drastically lowers APP-alpha secretion: control by the proteasome.</strong> Biochem. Biophys. Res. Commun. 252: 134-138, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9813158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9813158</a>] [<a href="https://doi.org/10.1006/bbrc.1998.9619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9813158">Marambaud et al. (1998)</a> showed that the expression of wildtype PSEN2 in human HEK293 cells increases the production of the physiologic alpha-secretase-derived product APP-alpha. By contrast, APP-alpha secretion was drastically reduced in cells expressing the N141I mutation of PSEN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9813158" 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="#42" class="mim-tip-reference" title="Wijsman, E. M., Daw, E. W., Yu, X., Steinbart, E. J., Nochlin, D., Bird, T. D., Schellenberg, G. D. <strong>APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation.</strong> Am. J. Med. Genet. 132B: 14-20, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389756</a>] [<a href="https://doi.org/10.1002/ajmg.b.30087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389756">Wijsman et al. (2005)</a> noted the wide range in age at onset of Alzheimer disease in Volga German families with the N141I mutation in PSEN2. To examine evidence for a genetic basis for the variation in age at onset, the authors performed a Bayesian oligogenic segregation and linkage analysis on 9 Volga German families known to have a least 1 affected PSEN2 mutation carrier. The analysis was designed to estimate the effects of APOE and PSEN2 and the number and effects of additional loci and the environment (family effects) affecting age at onset of AD. The analysis showed that APOE plays a small but significant role in modifying the age at onset in these Volga German families. There was evidence of a dose-dependent relationship between the number of E4 alleles and age at onset. <a href="#42" class="mim-tip-reference" title="Wijsman, E. M., Daw, E. W., Yu, X., Steinbart, E. J., Nochlin, D., Bird, T. D., Schellenberg, G. D. <strong>APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation.</strong> Am. J. Med. Genet. 132B: 14-20, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15389756/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15389756</a>] [<a href="https://doi.org/10.1002/ajmg.b.30087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15389756">Wijsman et al. (2005)</a> calculated an approximately 83% posterior probability of at least one modifier locus in addition to APOE; the fraction of the variance in age at onset attributable to PSEN2, APOE, other loci, and family effects was approximately 70%, 2%, 6.5%, and 8.5%, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15389756" 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="#45" class="mim-tip-reference" title="Yu, C.-E., Marchani, E., Nikisch, G., Muller, U., Nolte, D., Hertel, A., Wijsman, E. M., Bird, T. D. <strong>The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease.</strong> Arch. Neurol. 67: 631-633, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20457965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20457965</a>] [<a href="https://doi.org/10.1001/archneurol.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20457965">Yu et al. (2010)</a> demonstrated that a family from Fulda (Hesse), Germany with AD4 caused by the N141I mutation shared the same haplotype as the Volga German families reported earlier. This finding indicated that the mutation must have occurred prior to the emigration of the Volga Germans from the Hesse region of Germany to Russia in the 1760s during the reign of Catherine the Great. In addition, the original patient with AD reported by <a href="#1" class="mim-tip-reference" title="Alzheimer, A. <strong>Ueber eine eigenartige Erkrankung der Hirnrinde.</strong> Allg. Z. Psychiat. Med. 64: 146-148, 1907."None>Alzheimer (1907)</a> also lived in the same Hesse region as the modern family, which raised the possibility that the original patient may have had the N141I mutation. However, <a href="#24" class="mim-tip-reference" title="Muller, U., Winter, P., Graeber, M. B. <strong>Alois Alzheimer's case, Auguste D., did not carry the N141I mutation in PSEN2 characteristic of Alzheimer disease in Volga Germans. (Letter)</strong> Arch. Neurol. 68: 1210-1211, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21911706/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21911706</a>] [<a href="https://doi.org/10.1001/archneurol.2011.218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21911706">Muller et al. (2011)</a> sequenced exon 5 of the PSEN2 gene in DNA extracted from a tissue section prepared from the brain of the original patient with AD ('Auguste D'), and found that she did not carry the N141I mutation, thus disproving the hypothesis of <a href="#45" class="mim-tip-reference" title="Yu, C.-E., Marchani, E., Nikisch, G., Muller, U., Nolte, D., Hertel, A., Wijsman, E. M., Bird, T. D. <strong>The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease.</strong> Arch. Neurol. 67: 631-633, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20457965/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20457965</a>] [<a href="https://doi.org/10.1001/archneurol.2010.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20457965">Yu et al. (2010)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21911706+20457965" 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> rs28936379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936379;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/rs28936379?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=rs28936379" 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=rs28936379" 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=RCV000009394 OR RCV000084265" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009394, RCV000084265" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009394...</a>
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<p>In all 4 affected members of an extended pedigree of Italian origin with early-onset (at or before 50 years), pathologically confirmed familial AD (AD4; <a href="/entry/606889">606889</a>), <a href="#28" class="mim-tip-reference" title="Rogaev, E. I., Sherrington, R., Rogaeva, E. A., Levesque, G., Ikeda, M., Liang, Y., Chi, H., Lin, C., Holman, K., Tsuda, T., Mar, L., Sorbi, S., Nacmias, B., Placentini, S., Amaducci, L., Chumakov, I., Cohen, D., Lannfelt, L., Fraser, P. E., Rommens, J. M., St George-Hyslop, P. H. <strong>Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.</strong> Nature 376: 775-778, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7651536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7651536</a>] [<a href="https://doi.org/10.1038/376775a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7651536">Rogaev et al. (1995)</a> observed heterozygosity for a 1080A-G substitution in the PSEN2 gene, resulting in a met239-to-val (M239V) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7651536" 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> rs63750110 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750110;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/rs63750110?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=rs63750110" 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=rs63750110" 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=RCV000009395 OR RCV000084269 OR RCV000172102" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009395, RCV000084269, RCV000172102" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009395...</a>
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<p>In a patient with early-onset (age 52 years) Alzheimer disease (AD4; <a href="/entry/606889">606889</a>) who was heterozygous for the E2/E3 isoforms of apolipoprotein E (<a href="/entry/107741#0001">107741.0001</a>/ <a href="/entry/107741#0015">107741.0015</a>), <a href="#22" class="mim-tip-reference" title="Lleo, A., Blesa, R., Gendre, J., Castellvi, M., Pastor, P., Queralt, R., Oliva, R. <strong>A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease.</strong> Neurology 57: 1926-1928, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11723295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11723295</a>] [<a href="https://doi.org/10.1212/wnl.57.10.1926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11723295">Lleo et al. (2001)</a> identified a heterozygous A-to-C transversion in exon 12 of the PSEN2 gene, resulting in an asp439-to-ala (D439A) substitution in the C-terminal portion of the protein. Haplotype analysis indicated a maternal origin, but the patient's mother was deceased and had been adopted, precluding familial analysis. Six asymptomatic sibs did not carry the mutation. <a href="#22" class="mim-tip-reference" title="Lleo, A., Blesa, R., Gendre, J., Castellvi, M., Pastor, P., Queralt, R., Oliva, R. <strong>A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease.</strong> Neurology 57: 1926-1928, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11723295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11723295</a>] [<a href="https://doi.org/10.1212/wnl.57.10.1926" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11723295">Lleo et al. (2001)</a> suggested that the mutation may alter the endoproteolytic processing of the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11723295" 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> rs63750666 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750666;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/rs63750666?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=rs63750666" 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=rs63750666" 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=RCV000009396 OR RCV000084268" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009396, RCV000084268" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009396...</a>
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<p>In affected members of a family with early-onset Alzheimer disease (AD4; <a href="/entry/606889">606889</a>), <a href="#9" class="mim-tip-reference" title="Ezquerra, M., Lleo, A., Castellvi, M., Queralt, R., Santacruz, P., Pastor, P., Molinuevo, J. L., Blesa, R., Oliva, R. <strong>A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease.</strong> Arch. Neurol. 60: 1149-1151, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925374</a>] [<a href="https://doi.org/10.1001/archneur.60.8.1149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925374">Ezquerra et al. (2003)</a> identified a C-to-T change in exon 12 of the PSEN2 gene, resulting in a thr430-to-met (T430M) substitution. The mutation was also found in a cognitively healthy sib older than the proband, suggesting either reduced penetrance or a later onset in this individual. Age at disease onset in this family was variable (45 to 65 years). The T430M mutation is located in the C terminus of the protein, which may disrupt endoproteolytic processing and protein function. The mutation was not detected in 50 unrelated healthy controls or in 80 unrelated patients with AD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12925374" 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">rs63749851 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63749851;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=rs63749851" 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=rs63749851" 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=RCV000009397 OR RCV000084260" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009397, RCV000084260" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009397...</a>
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<p>In 3 affected members of a family with early-onset AD (AD4; <a href="/entry/606889">606889</a>), <a href="#10" class="mim-tip-reference" title="Finckh, U., Muller-Thomsen, T., Mann, U., Eggers, C., Marksteiner, J., Meins, W., Binetti, G., Alberici, A., Hock, C., Nitsch, R. M., Gal, A. <strong>High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.</strong> Am. J. Hum. Genet. 66: 110-117, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631141</a>] [<a href="https://doi.org/10.1086/302702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631141">Finckh et al. (2000)</a> identified a thr122-to-pro (T122P) mutation in the PSEN2 gene. The proband had disease onset at age 46 years. Her clinical course was similar to that of her mother and grandmother, both mutation carriers, who died at ages 48 and 51 years, respectively. <a href="#10" class="mim-tip-reference" title="Finckh, U., Muller-Thomsen, T., Mann, U., Eggers, C., Marksteiner, J., Meins, W., Binetti, G., Alberici, A., Hock, C., Nitsch, R. M., Gal, A. <strong>High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.</strong> Am. J. Hum. Genet. 66: 110-117, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631141</a>] [<a href="https://doi.org/10.1086/302702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631141">Finckh et al. (2000)</a> commented on the similar clinical phenotype and high penetrance of the T122P mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631141" 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="mim-changed mim-change"><p><a href="#46" class="mim-tip-reference" title="Zampese, E., Fasolato, C., Kipanyula, M. J., Bortolozzi, M., Pozzan, T., Pizzo, P. <strong>Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk.</strong> Proc. Nat. Acad. Sci. 108: 2777-2782, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21285369/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21285369</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21285369[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1100735108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21285369">Zampese et al. (2011)</a> found that expression of the FAD-linked T122R mutation of PS2 increased the number of SH-SY5Y cells with high mitochondrial Ca(2+) response and increased the physical and functional interactions between ER and mitochondria. This effect on ER-mitochondria interactions was specific to PS2, as ER-mitochondria interactions were affected by other PS2 mutations but not by PS1 (<a href="/entry/104311">104311</a>) mutations. Similar to PS2 overexpression, expression of the PS2 T122R mutation favored generation of Ca(2+) hot spots on the OMM. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21285369" 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></div>
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<strong>.0006 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs63749884 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63749884;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=rs63749884" 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=rs63749884" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an Italian family in which 4 members had early-onset AD (AD4; <a href="/entry/606889">606889</a>), <a href="#10" class="mim-tip-reference" title="Finckh, U., Muller-Thomsen, T., Mann, U., Eggers, C., Marksteiner, J., Meins, W., Binetti, G., Alberici, A., Hock, C., Nitsch, R. M., Gal, A. <strong>High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.</strong> Am. J. Hum. Genet. 66: 110-117, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10631141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10631141</a>] [<a href="https://doi.org/10.1086/302702" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10631141">Finckh et al. (2000)</a> identified heterozygosity for a met239-to-ile (M239I) mutation in the PSEN2 gene. Age at onset was 58 years in the proband. Five sibs carried the mutation, but only 3 of them had AD. The authors noted that this phenotypic variability or reduced penetrance is not uncommon with PSEN2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10631141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28936380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28936380;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/rs28936380?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=rs28936380" 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=rs28936380" 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=RCV000009399 OR RCV000084579" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009399, RCV000084579" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009399...</a>
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<p>In 3 Italian sibs, 2 of whom were monozygotic twin sisters, <a href="#4" class="mim-tip-reference" title="Binetti, G., Signorini, S., Squitti, R., Alberici, A., Benussi, L., Cassetta, E., Frisoni, G. B., Barbiero, L., Feudatari, E., Nicosia, F., Testa, C., Zanetti, O., Gennarelli, M., Perani, D., Anchisi, D., Ghidoni, R., Rossini, P. M. <strong>Atypical dementia associated with a novel presenilin-2 mutation.</strong> Ann. Neurol. 54: 832-836, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681895</a>] [<a href="https://doi.org/10.1002/ana.10760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681895">Binetti et al. (2003)</a> identified a heterozygous 365C-G transversion in exon 5 of the PSEN2 gene, resulting in a thr122-to-arg (T122R) substitution. The proband, a male, and 1 of the twin sisters had early-onset atypical dementia, presumably a variant of Alzheimer disease (AD4; <a href="/entry/606889">606889</a>). The other twin sister, who carried the mutation, did not have symptomatic disease at age 60 years. The brother showed attention deficits, language impairment, apraxia, and global cognitive decline. The affected twin sister showed early symptoms of apathy and depression, followed by inappropriate and uninhibited behavior as well as memory and language deficits. Their mother, maternal aunt, and maternal grandmother were reportedly affected by a similar illness. The proband also had the prion protein M129V polymorphism (<a href="/entry/176640#0005">176640.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681895" 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 CARDIOMYOPATHY, DILATED, 1V</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> rs63750197 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750197;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/rs63750197?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=rs63750197" 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=rs63750197" 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=RCV000009400 OR RCV000009401 OR RCV000084261 OR RCV000172588 OR RCV001642203 OR RCV003934816" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009400, RCV000009401, RCV000084261, RCV000172588, RCV001642203, RCV003934816" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009400...</a>
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<p>In 2 families, <a href="#19" class="mim-tip-reference" title="Li, D., Parks, S. B., Kushner, J. D., Nauman, D., Burgess, D., Ludwigsen, S., Partain, J., Nixon, R. R., Allen, C. N., Irwin, R. P., Jakobs, P. M., Litt, M., Hershberger, R. E. <strong>Mutations of presenilin genes in dilated cardiomyopathy and heart failure.</strong> Am. J. Hum. Genet. 79: 1030-1039, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17186461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17186461</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17186461[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/10.1086/509900" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17186461">Li et al. (2006)</a> found that idiopathic dilated cardiomyopathy (CMD1V; <a href="/entry/613697">613697</a>) segregated with a 756C-T transition in exon 5 of the PSEN2 gene, predicting to result in an ser130-to-leu (S130L) amino acid change. The mutation was present in heterozygous state. Both were white families. This mutation had been reported in association with Alzheimer disease (AD4; <a href="/entry/606889">606889</a>) in a small kindred by <a href="#37" class="mim-tip-reference" title="Tedde, A., Nacmias, B., Ciantelli, M., Forleo, P., Cellini, E., Bagnoli, S., Piccini, C., Caffarra, P., Ghidoni, E., Paganini, M., Bracco, L., Sorbi, S. <strong>Identification of new presenilin gene mutations in early-onset familial Alzheimer disease.</strong> Arch. Neurol. 60: 1541-1544, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623725</a>] [<a href="https://doi.org/10.1001/archneur.60.11.1541" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623725">Tedde et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17186461+14623725" 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>.0009 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs63750048 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs63750048;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/rs63750048?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=rs63750048" 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=rs63750048" 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=RCV000009402 OR RCV000084259" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009402, RCV000084259" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009402...</a>
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<p>In affected members of a Sardinian family with Alzheimer disease (AD4; <a href="/entry/606889">606889</a>), <a href="#26" class="mim-tip-reference" title="Piscopo, P., Marcon, G., Piras, M. R., Crestini, A., Campeggi, L. M., Deiana, E., Cherchi, R., Tanda, F., Deplano, A., Vanacore, N., Tagliavini, F., Pocchiari, M., Giaccone, G., Confaloni, A. <strong>A novel PSEN2 mutation associated with a peculiar phenotype.</strong> Neurology 70: 1549-1554, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18427071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18427071</a>] [<a href="https://doi.org/10.1212/01.wnl.0000310643.53587.87" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18427071">Piscopo et al. (2008)</a> identified a heterozygous C-to-T transition in exon 4 of the PSEN2 gene, resulting in an ala85-to-val (A85V) substitution in the N-terminal cytoplasmic portion of PSEN2 close to transmembrane domain 1. The phenotype was somewhat atypical in this family: 3 of 4 patients had signs of parkinsonism, including rigidity, postural instability, and bradykinesia, in addition to classic signs of AD. Two patients had visual hallucinations. Neuropathologic findings in 1 patient showed beta-amyloid plaques and neurofibrillary tangles as well as many diffuse Lewy bodies throughout the brain. These findings were also compatible with a clinical diagnosis of Lewy body dementia (<a href="/entry/127750">127750</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18427071" 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/10.1073/pnas.96.21.11872" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19641596/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19641596</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19641596[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=19641596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature08177" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 03/10/2025
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Bao Lige - updated : 12/07/2018<br>Cassandra L. Kniffin - updated : 4/4/2012<br>Cassandra L. Kniffin - updated : 6/22/2010<br>Ada Hamosh - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 10/1/2008<br>Paul J. Converse - updated : 3/6/2007<br>Victor A. McKusick - updated : 11/27/2006<br>George E. Tiller - updated : 9/11/2006<br>John Logan Black, III - updated : 7/22/2005<br>Cassandra L. Kniffin - updated : 1/20/2005<br>Cassandra L. Kniffin - updated : 3/1/2004<br>Cassandra L. Kniffin - reorganized : 2/19/2004<br>Ada Hamosh - updated : 4/3/2003<br>Dawn Watkins-Chow - updated : 3/17/2003<br>George E. Tiller - updated : 12/13/2002<br>Cassandra L. Kniffin - updated : 11/27/2002<br>Ada Hamosh - updated : 9/30/2002<br>Paul J. Converse - updated : 5/29/2002<br>Paul J. Converse - updated : 4/9/2001<br>George E. Tiller - updated : 12/14/2000<br>Ada Hamosh - updated : 2/3/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Victor A. McKusick - updated : 1/22/1999<br>Victor A. McKusick - updated : 7/13/1998<br>Victor A. McKusick - updated : 7/9/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Ada Hamosh - updated : 1/20/1998<br>Victor A. McKusick - updated : 9/9/1997<br>Victor A. McKusick - updated : 4/7/1997<br>Victor A. McKusick - updated : 2/3/1997<br>Moyra Smith - updated : 1/23/1997
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 10/10/1995
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<span class="mim-text-font">
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mgross : 03/10/2025
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<div class="row collapse" id="mimCollapseEditHistory">
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carol : 09/12/2023<br>mgross : 12/07/2018<br>carol : 02/01/2017<br>carol : 01/31/2017<br>carol : 09/13/2016<br>carol : 02/26/2015<br>carol : 4/6/2012<br>ckniffin : 4/4/2012<br>alopez : 1/14/2011<br>wwang : 7/7/2010<br>ckniffin : 6/22/2010<br>alopez : 9/4/2009<br>terry : 8/27/2009<br>wwang : 10/29/2008<br>wwang : 10/1/2008<br>ckniffin : 10/1/2008<br>wwang : 11/26/2007<br>carol : 5/31/2007<br>mgross : 3/6/2007<br>alopez : 11/29/2006<br>terry : 11/27/2006<br>alopez : 9/11/2006<br>mgross : 3/31/2006<br>terry : 2/23/2006<br>carol : 2/15/2006<br>carol : 7/28/2005<br>terry : 7/22/2005<br>tkritzer : 1/26/2005<br>ckniffin : 1/20/2005<br>tkritzer : 3/4/2004<br>ckniffin : 3/1/2004<br>carol : 2/19/2004<br>ckniffin : 1/27/2004<br>ckniffin : 5/28/2003<br>alopez : 4/8/2003<br>terry : 4/3/2003<br>mgross : 3/17/2003<br>cwells : 12/13/2002<br>carol : 12/6/2002<br>tkritzer : 12/6/2002<br>ckniffin : 11/27/2002<br>alopez : 10/1/2002<br>tkritzer : 9/30/2002<br>carol : 9/30/2002<br>mgross : 5/29/2002<br>mgross : 4/9/2001<br>carol : 2/26/2001<br>cwells : 1/12/2001<br>terry : 12/14/2000<br>alopez : 2/3/2000<br>alopez : 2/3/2000<br>alopez : 11/15/1999<br>carol : 11/15/1999<br>terry : 11/9/1999<br>carol : 2/1/1999<br>terry : 1/22/1999<br>dkim : 12/16/1998<br>carol : 7/13/1998<br>terry : 7/13/1998<br>carol : 7/9/1998<br>carol : 4/20/1998<br>carol : 4/20/1998<br>terry : 4/20/1998<br>terry : 4/6/1998<br>alopez : 1/21/1998<br>alopez : 1/21/1998<br>alopez : 1/20/1998<br>terry : 11/11/1997<br>jenny : 9/9/1997<br>joanna : 8/29/1997<br>mark : 7/16/1997<br>joanna : 4/17/1997<br>mark : 4/7/1997<br>terry : 4/2/1997<br>mark : 3/13/1997<br>terry : 3/12/1997<br>mark : 3/12/1997<br>mark : 2/3/1997<br>terry : 2/3/1997<br>mark : 1/29/1997<br>terry : 1/24/1997<br>terry : 1/23/1997<br>terry : 1/23/1997<br>mark : 1/23/1997<br>mark : 1/23/1997<br>mark : 12/9/1996<br>terry : 12/6/1996<br>mark : 6/26/1996<br>terry : 6/26/1996<br>terry : 6/20/1996<br>mark : 2/19/1996<br>terry : 2/15/1996<br>mark : 2/10/1996<br>terry : 11/17/1995<br>mimadm : 11/3/1995<br>mark : 10/10/1995
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<span class="mim-font">
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<strong>*</strong> 600759
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<h3>
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PRESENILIN 2; PSEN2
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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PS2<br />
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STM2
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<strong><em>HGNC Approved Gene Symbol: PSEN2</em></strong>
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Cytogenetic location: 1q42.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:226,870,616-226,903,668 </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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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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1q42.13
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Alzheimer disease-4
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<span class="mim-font">
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606889
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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Cardiomyopathy, dilated, 1V
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<span class="mim-font">
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613697
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</h4>
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<h4>
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>Using both positional cloning and the candidate gene approach, Levy-Lahad et al. (1995) identified a candidate gene for the chromosome 1-linked locus for Alzheimer disease, designated AD4 (606889). By EST database searching, they identified a corresponding sequence that showed homology to the PSEN1 gene (104311), which is mutant in Alzheimer disease type 3 (AD3; 607822). The deduced protein products of the 2 genes share share 80.5% sequence identity. Because the deduced protein had 7 transmembrane domains, Levy-Lahad et al. (1995) symbolized the gene STM2, for a second transmembrane gene associated with AD. </p><p>Independent studies by Rogaev et al. (1995) of ESTs with homology to the S182 (AD3) gene uncovered 3 ESTs with substantial homology to 2 different segments within the S182 open reading frame. Screening of a cDNA library detected 4 cDNAs, and sequencing demonstrated that all were derived from the same 2.3-kb transcript, which they designated E5-1. Northern blot analysis detected transcripts of the corresponding mRNA from several tissues, including most regions of the brain. In skeletal muscle, cardiac muscle, and pancreas, the E5-1 gene was expressed at higher levels as 2 different transcripts which were clearly different in size from that of the 2.7-kb S182 transcript, and did not cross-hybridize with S182 probes at high stringency. Both the E5-1 and the S182 proteins were predicted to be integral membrane proteins with 7 membrane-spanning domains and a large exposed loop between the sixth and seventh transmembrane domains. </p><p>By nucleotide and amino acid sequence database searches, Li et al. (1995) cloned the full-length STM2 cDNA, which encodes a 467-amino acid protein. Northern blot studies showed expression of the gene in a variety of tissues, including brain. Li et al. (1995) suggested that this might be the site of mutations causing AD4. </p><p>Levy-Lahad et al. (1996) reported that the primary AD4 gene transcript encodes a 448-amino acid polypeptide. They identified 2 transcripts of 2.4 and 2.8 kb in skeletal muscle, pancreas, and heart, with comparatively low levels observed in brain. In addition, they identified a splice variant of the 2.4-kb transcript that lacks a single glutamic acid residue (glu324), resulting from the use of an alternative splice acceptor site located in exon 10. </p>
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<div>
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<h4>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>The Alzheimer's Disease Collaborative Group (1995) concluded that the structure of the AD4 gene, which they called presenilin-2, is very similar to that of the AD3 (presenilin-1) gene. </p><p>Levy-Lahad et al. (1996) determined that the AD4 gene contains 12 exons, including 10 coding exons. The first 2 exons encode the 5-prime untranslated region. </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>Mapping</strong>
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</div>
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<span class="mim-text-font">
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<p>Using a somatic cell hybrid panel, Levy-Lahad et al. (1995) mapped the AD4 gene to chromosome 1. By using hybrid mapping panels and the CEPH mega-YAC physical map clones, Rogaev et al. (1995) mapped the AD4 gene to human chromosome 1. Li et al. (1995) assigned the STM2 gene to chromosome 1 by PCR screening of human/hamster somatic cell hybrids. PCR screening of a YAC contig library placed the gene between the 2 STS markers, D1S271E and D1S1644. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p><strong><em>PSEN2 Localization</em></strong></p><p>
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By in situ hybridization to tissues, Kovacs et al. (1996) demonstrated that the expression patterns of PS1 and PS2 in the brain are extremely similar to each other and that messages for both are primarily detectable in neuronal populations. Immunochemical analyses indicated that PS1 and PS2 are similar in size and localize to similar intracellular compartments (endoplasmic reticulum and Golgi complex). </p><p>Li et al. (1997) demonstrated that wildtype PS1 and PS2 are localized to the nuclear membrane, its associated interphase kinetochores, and the centrosomes. Li et al. (1997) stated that PS1 and PS2 localization to the membranes of the endoplasmic reticulum (ER) and Golgi is not unexpected for overexpressed membrane proteins because these locations are the sites of their synthesis and processing. They developed specific PS1 and PS2 antibodies directed at the N-terminal and loop domains. Li et al. (1997) suggested that PS1 and PS2 play a role in chromosome organization and segregation. They discussed a pathogenic mechanism for familial AD in which mutant presenilins cause chromosome missegregation during mitosis, resulting in apoptosis and/or trisomy 21 mosaicism. An alternative hypothesis is that mutant presenilins not appropriately trafficked out of the endoplasmic reticulum may interfere with normal APP processing. </p><p><strong><em>Gamma-secretase Activity</em></strong></p><p>
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There is evidence that PS1 and PS2 are important determinants of gamma-secretase activity responsible for the proteolytic cleavage of the amyloid precursor protein (APP; 104760) and the NOTCH receptor protein (600725). Kopan and Goate (2000) reviewed evidence that presenilins are founding members of a novel class of aspartyl proteases that hydrolyze peptide bonds embedded within a membrane. The authors stated that although PS1 and PS2 both appear to be gamma secretases, it is not clear if the 2 enzymes normally have similar or different substrates, since they reside in different complexes. They proposed that the key to the regulation of cleavage may depend on the characterization of other proteins that are present in the high molecular weight complex that contains gamma-secretase activity. </p><p>Francis et al. (2002) observed a reduction in the levels of processed presenilin and a reduction in gamma-secretase cleavage of beta-APP and Notch substrates after RNA-mediated interference assays that inactivated Aph1, Pen2 (PSENEN; 607632), or nicastrin in cultured Drosophila cells. They concluded that presenilin protein accumulation requires APH1 and PEN2. Using coimmunoprecipitation experiments, Steiner et al. (2002) showed that PEN2 is a critical component of PSEN1/gamma-secretase and PSEN2/gamma-secretase complexes. They observed that the absence of Psen1 or both Psen1 and Psen2 in mice resulted in reduced PEN2 levels. Additionally, Steiner et al. (2002) reported that downregulation of PEN2 by RNA interference was associated with reduced presenilin levels, impaired nicastrin maturation, and deficient gamma-secretase complex formation. </p><p>Gamma-secretase activity requires the formation of a stable, high molecular mass protein complex that, in addition to the endoproteolyzed fragmented form of presenilin, contains essential cofactors including nicastrin, APH1, and PEN2. Takasugi et al. (2003) showed that Drosophila APH1 increases the stability of Drosophila presenilin holoprotein in the complex. Depletion of PEN2 by RNA interference prevented endoproteolysis of presenilin and promoted stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Coexpression of Drosophila Pen2 with Aph1 and nicastrin increased the formation of presenilin fragments as well as gamma-secretase activity. Thus, Takasugi et al. (2003) concluded that APH1 stabilizes the presenilin holoprotein in the complex, whereas PEN2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex. </p><p>Wilson et al. (2002) analyzed the production of several forms of secreted and intracellular beta-amyloid forms in mouse cells lacking PS1, PS2, or both proteins. Although most amyloid beta species were abolished in PS1/PS2 -/- cells, the production of intracellular A-beta-42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. Wilson et al. (2002) concluded that production of this pool of amyloid beta occurs independently of PS1/PS2 and, therefore, that another gamma-secretase activity must be responsible for cleavage of APP within the early secretory compartments. </p><p><strong><em>Other Functions</em></strong></p><p>
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PC12 cells that have been grown in the presence of nerve growth factor (NGF; 162030) for more than 2 weeks become dependent on NGF. In neuronally differentiated PC12 cells, withdrawal of trophic support induces apoptosis, with the peak of DNA fragmentation occurring 2 days after withdrawal of trophic support. Wolozin et al. (1996) found that overexpression of the PS2 gene in NGF-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or beta-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in these cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins were involved. Wolozin et al. (1996) showed that the asn141-to-ile mutation associated with FAD (N141I; 600759.0001) generates a molecule with enhanced basal apoptotic activity. They speculated that this gain of function may accelerate the process of neurodegeneration that occurs in Alzheimer disease, leading to the earlier age of onset characteristic of familial Alzheimer disease. </p><p>By yeast 2-hybrid screening of a human fetal brain cDNA library to identify PS2-binding proteins, Stabler et al. (1999) identified CIB1 (602293), which they called calmyrin. Expression analysis showed that calmyrin localization shifted from accumulation in nucleus and cytoplasm to almost complete colocalization with PS2 in ER following coexpression. Affinity chromatography and immunoprecipitation analyses in PS2-expressing HeLa cell lysates confirmed direct binding between calmyrin and PS2. Functional studies showed that calmyrin and PS2 increased cell death when cotransfected into HeLa cells. </p><p>Using the yeast 2-hybrid system, Tanahashi and Tabira (2000) screened for proteins interacting with presenilin-2 and cloned DRAL (602633). DRAL is a LIM-only protein, which has been shown to be a coactivator of the androgen receptor (AR; 313700) as well as a protein interacting with a DNA replication regulatory protein, CDC47 (600592). DRAL interacted with a hydrophilic loop region (amino acids 269-298) in the endoproteolytic N-terminal fragment of PS2, but not that of PS1, although residues 269 to 298 of PS2 and the corresponding PS1 sequence differ by only 3 amino acids. Each of 9 PS2 point mutations within a region from residues 275 to 296 abolished the binding. The in vitro interaction was confirmed by affinity column assay and the physiologic interactions between endogenous PS2 and DRAL by coimmunoprecipitation from human lung fibroblast MRC5 cells. The authors suggested that DRAL functions as a link between PS2 and an intracellular signaling pathway. </p><p>Using coimmunoprecipitation and nickel affinity pull-down approaches, Lee et al. (2002) showed that nicastrin (605254) and presenilin heterodimers physically associated with APH1A (607629) and APH1B (607630) in vivo. </p><p>Tu et al. (2006) showed that recombinant presenilins, but not PSEN1 with the met146-to-val (M146V; 104311.0007) mutation or PSEN2 with the N141I mutation, formed low-conductance cation-permeable channels in planar lipid bilayers following expression in insect cells. Embryonic fibroblasts from mice lacking both Psen1 and Psen2 had Ca(2+) signaling defects due to leakage from the ER, and the deficient calcium signaling in these cells could be rescued by expression of wildtype PSEN1 or PSEN2, but not by expression of PSEN1 with the M146V mutation or PSEN2 with the N141I mutation. The ER Ca(2+) leak function of presenilins was independent of their gamma-secretase activities. Tu et al. (2006) proposed that presenilins have a Ca(2+) signaling function, supporting the connection between deranged neuronal Ca(2+) signaling and Alzheimer disease. </p><p>Zhang et al. (2009) used a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. They showed that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, they found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-D-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca(2+) stores by thapsigargin, or blockade of Ca(2+) release from these stores by ryanodine receptor (see RYR3, 180903) inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Zhang et al. (2009) concluded that, collectively, their results indicated a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca(2+) release in presynaptic terminals, and further suggested that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer disease. </p><p>Zampese et al. (2011) showed that PS2 overexpression increased mitochondrial Ca(2+) uptake in SH-SY5Y human neuroblastoma cells, although it reduced store Ca(2+) content and concentration peaks. Increased mitochondrial Ca(2+) uptake due to PS2 overexpression was not caused by direct PS2 action on the mitochondrial Ca(2+) uptake machinery, but rather by increased physical interaction between ER and mitochondria that augmented the frequency of Ca(2+) hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane (OMM). </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Alzheimer Disease 4</em></strong></p><p>
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In affected members of 7 families of the Volga German group with Alzheimer disease (AD4; 606889), Levy-Lahad et al. (1995) identified heterozygosity for an asn141-to-ile mutation (N141I; 600759.0001) in the PSEN2 gene. Two affected patients from the families with AD lacked the mutation; age of onset and APOE4 (see 107741) status suggested that these patients had a phenocopy (or genocopy) of the AD4 present in most of their relatives. Levy-Lahad et al. (1995) found that all the affected Volga German individuals, except one who did not have the N141I mutation, shared a haplotype between D1S238 and D1S235. The age of onset in the person without the mutation , 67 years, was greater than 2 standard deviations above the family mean. Levy-Lahad et al. (1995) noted that the N141L mutation in STM2 and all 5 mutations previously identified in the AD3 gene (S182) occur at residues conserved among the new chromosome 1 gene, S182, and the mouse homolog of S182. </p><p>Studying DNA from affected members of 23 pedigrees with early-onset familial Alzheimer disease in which mutations in the chromosome 21 and chromosome 14 genes had been excluded, Rogaev et al. (1995) identified a heterozygous mutation in the PSEN2 gene (600759.0002) in all 4 affected members of an extended pedigree of Italian origin with early-onset, pathologically confirmed FAD (onset at 50 years). In addition, the N141L mutation was found in a public database from affected probands of 3 of 4 pedigrees of Volga German ancestry. The appearance of the same mutation in affected members of 3 different Volga German pedigrees reflected a founder effect. Rogaev et al. (1995) suggested that the patient without the N141L mutation in the fourth Volga German family, aged 77 years, had another type of AD. This interpretation was supported by the fact that late-onset AD may affect at least 5% of the population older than 70 years, and by the fact that while the Volga German populations are probably drawn from a limited number of founders, they are unlikely to represent a pure population isolate, particularly after immigration to North America. The atypical subject was also homozygous for the APOE4 allele. Rogaev et al. (1995) found neither of the AD4 gene mutations in 284 normal Caucasian controls or in affected members of pedigrees with the AD3 type of AD. </p><p>Clark et al. (1996) and St. George-Hyslop et al. (1996) reviewed the role of PS1 and PS2 in familial early-onset Alzheimer disease. Clark et al. (1996) tabulated mutations in the 2 genes, most of which occurred in the PS1 gene. </p><p>Cruts and Van Broeckhoven (1998) counted 43 mutations that had been identified in the PS1 gene that led to familial presenile AD (onset before age 65 years). By contrast, only 3 mutations had been identified in PS2. </p><p><strong><em>Dilated Cardiomyopathy 1V</em></strong></p><p>
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The presenilins are expressed in the heart and are critical to cardiac development. Li et al. (2006) hypothesized that mutations in presenilins may also be associated with dilated cardiomyopathy (see CMD1V; 613697) and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. They evaluated a total of 315 index patients with DCM for sequence variation in PSEN1 and PSEN2. Li et al. (2006) identified a single PSEN2 missense mutation (600759.0008) in 2 families, and a novel PSEN1 missense mutation (104311.0034) in 1 family. Both mutations, present in heterozygous state, segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured fibroblasts from PSEN1 and PSEN2 mutation carriers. </p>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</h4>
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<span class="mim-text-font">
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<p>Presenilin homologs with high sequence similarity are known in plants, invertebrates, and vertebrates. Ponting et al. (2002) searched various databases to identify a family of proteins homologous to presenilins. Members of this family, which they termed presenilin homologs, have significant sequence similarities to presenilins and also possess 2 conserved aspartic acid residues within adjacent predicted transmembrane segments. The presenilin homolog family was found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five presenilin homologs were detected in the human genome, of which 3 possess 'protease-associated' domains that are consistent with the proposed protease function of presenilins. Based on these findings, the authors proposed that presenilins and presenilin homologs represent different subbranches of a larger family of polytopic membrane-associated aspartyl proteases. </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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</h4>
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<span class="mim-text-font">
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<p>In transfected cell lines, Citron et al. (1997) found that mutant human PS1 and PS2 resulted in a highly significant increase in secretion of amyloid beta-42. The PS2 Volga mutation (600759.0001) led to a 6- to 8-fold increase in the production of total amyloid beta-42; none of the PS1 mutations had such a dramatic effect, suggesting an intrinsic difference in the effects of PS1 and PS2 mutations. The mutations caused an increase in gamma-secretase activity which resulted in increased proteolysis of APP at the amyloid beta-42 site, leading to heightened amyloid beta-42 production. Citron et al. (1997) stated that their combined in vitro and in vivo data clearly demonstrated that the FAD-linked presenilin mutations directly or indirectly altered the level of gamma-secretase, but not of alpha- or beta-secretase. </p><p>To delineate the relationships of presenilin-1 and -2 activities and to determine whether PS2 mutations involve gain or loss of function, Herreman et al. (1999) generated PS2 homozygous deficient (-/-) and PS1/PS2 double homozygous deficient mice. In contrast to PS1 -/- mice, PS2 -/- mice were viable and fertile and developed only mild pulmonary fibrosis and hemorrhage with age. Absence of PS2 did not detectably alter processing of amyloid precursor protein and had little or no effect on physiologically important apoptotic processes, suggesting that Alzheimer disease-causing mutations in PS2, as in PS1, result in gain of function. Although PS1 +/- PS2 -/- mice survived in relatively good health, complete deletion of both PS2 and PS1 genes caused a phenotype closely resembling full Notch-1 (190198) deficiency. These results demonstrated in vivo that the PS1 and PS2 have partially overlapping functions and that PS1 is essential and PS2 is redundant for normal Notch signaling during mammalian embryologic development. </p><p>Donoviel et al. (1999) generated PS2-null mice by gene targeting, and subsequently, PS1/PS2 double-null mice. Mice homozygous for a targeted null mutation in PS2 exhibited no obvious defects; however, loss of PS2 on a PS1-null background led to embryonic lethality at embryonic day 9.5. Embryos lacking both presenilins and, surprisingly, those carrying only a single copy of PS2 on a PS1-null background exhibited multiple early patterning defects, including lack of somite segmentation, disorganization of the trunk ventral neural tube, midbrain mesenchyme cell loss, anterior neuropore closure delays, and abnormal heart and second branchial arch development. In addition, Delta-like-1 (176290) and Hes5, 2 genes that lie downstream in the Notch pathway, were misexpressed in presenilin double-null embryos. Hes5 expression was undetectable in these mice, whereas Delta-like-1 was expressed ectopically in the neural tube and brain of double-null embryos. Donoviel et al. (1999) concluded that the presenilins play a widespread role in embryogenesis, that there is functional redundancy between PS1 and PS2, and that both vertebrate presenilins, like their invertebrate homologs, are essential for Notch signaling. </p><p>Sawamura et al. (2000) reported that levels of amyloid beta-42 in transgenic mice expressing the N141I mutation were increased in both Tris-saline-soluble and -insoluble fractions. Analysis of the low density membrane fraction from brains of 2 independent lines of mutant PS2 transgenic mice showed markedly increased levels of amyloid beta-42 and significantly low levels of glycerophospholipids and sphingomyelin. The authors concluded that there is a link between mutant PS2 and the metabolism of glycerophospholipids and sphingomyelin. </p><p>Saura et al. (2004) generated a transgenic conditional double knockout mouse lacking both Psen1 and Psen2 in the postnatal forebrain. The mice showed impairments in hippocampal memory and synaptic plasticity at the age of 2 months, and later developed neurodegeneration of the cerebral cortex accompanied by increased levels of the Cdk5 activator p25 (603460) and hyperphosphorylated tau. The authors concluded that PSEN1 and PSEN2 have essential roles in synaptic plasticity, learning, and memory. Beglopoulos et al. (2004) found that double knockout mice lacking Psen1 and Psen2 in the postnatal forebrain had reduced levels of the toxic beta-amyloid peptides beta-40 and beta-42 and strong microglial activation in the cerebral cortex. Gene expression profiling showed an upregulation of genes associated with inflammatory responses. The results suggested that the memory deficits and neurodegeneration observed in the double knockout mice were not caused by beta-amyloid accumulation and implicated an inflammatory component to the neurodegenerative process. </p><p>Tournoy et al. (2004) reported that in PS1 +/- PS2 -/- mice, PS1 protein concentration was considerably lowered, functionally reflected by reduced gamma-secretase activity and impaired beta-catenin (CTNNB1; 116806) downregulation. Their phenotype was normal up to 6 months, when the majority of the mice developed an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis, and vasculitis, as seen in human systemic lupus erythematosus (152700). Besides B cell-dominated infiltrates, the authors observed a hypergammaglobulinemia with immune complex deposits in several tissues, high-titer nuclear autoantibodies, and an increased CD4+/CD8+ ratio. The mice further developed a benign skin hyperplasia similar to human seborrheic keratosis (182000) as opposed to malignant keratocarcinomata observed in skin-specific PS1 'full' knockouts. </p><p>Takeda et al. (2005) found that Ps2 -/- mice developed normally with no evidence of cardiac hypertrophy or fibrosis. However, cardiac contractility was significantly increased in Ps2 -/- mice compared with wildtype. Isolated papillary muscle from Ps2 -/- heart showed significantly higher peak amplitudes of Ca(2+) transients and peak tension compared with controls, but Ps2 -/- heart exhibited no change in expression of calcium regulatory proteins. Ps2 interacted with Ryr2 (180902) and sorcin (SRI; 182520) both in vitro and in mouse heart in vivo, and Ps2 preferentially colocalized with Ryr2 and sorcin along Z-lines in heart. Elevated Ca(2+) attenuated association of Ryr2 with Ps2, whereas it enhanced association of sorcin with Ps2. Enhanced Ca(2+) transients and contractility in Ps2 -/- mice were observed at low extracellular Ca(2+) concentration, but not at high levels of Ca(2+) concentration. </p><p>Nam et al. (2022) found that knockin mice heterozygous for the N141I mutation had normal levels of Psen2 expression and normal expression of Psen2 downstream target of the Notch pathway in primary microglia and bone marrow-derived macrophages (BMDMs). However, mutant mice displayed hyperimmunity, overproducing clock gene-controlled cytokines, including Il6 (147620), in microglia and BMDMs in response to stimulation by lipopolysaccharide (LPS). Immunohistochemical analyses showed that a low dose of LPS induced a hyperactive immune response and caused memory deficit through overproduction of clock gene-controlled cytokines in mutant mice, while the same dose of LPS was inoccuous in wildtype mice. The Psen2 N141I mutation induced secretion of clock gene-controlled cytokines and resulted in memory deficits in mutant mice in response to fibrillar amyloid-beta. RT-PCR analysis revealed that Psen2 N141I decreased expression of clock genes, including Nr1d1 (602408), in innate immune cells from mutant mice, but that those cells remained rhythmic. Downregulation of Nr1d1 led to selective elevation of clock-controlled Il6 production in response to LPS. Further analysis indicated that the Psen2 N141I mutation repressed expression via DNA hypermethylation, as the Nr1d1 promoter was hypermethylated in innate immune cells from mice heterozygous for Psen2 N141I, and hypermethylation of the promoter was critical for reducing Nr1d1 expression. An antipsychotic drug, chlorpromazine, restored Nr1d1 expression and prevented LPS-induced hyperactive immune response and cognitive decline in mutant mice. Further analysis demonstrated that chlorpromazine rescued Nr1d1 expression by rectifying DNA hypermethylation through inhibition of the PI3K (see 171834)/Akt1 (164730) pathway in microglia of mutant mice. </p>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>AD3 and AD4 are the symbols for the Alzheimer disease-related genes on chromosomes 14 and 1, respectively. As the genes were isolated and characterized, other designations, such as S182 for AD3 and STM2 for AD4 (Levy-Lahad et al., 1995), have also been used. Rogaev et al. (1995) suggested that the unique features shared by the chromosomes 14 (presenilin-1) and 1 (presenilin-2) genes indicate that they constitute a distinct gene family which, because of the association with Alzheimer disease, might be called the 'presenilin' family. </p><p>The Alzheimer's Disease Collaborative Group (1995) used gene symbols PS1 and PS2 for the genes encoding presenilin-1 and presenilin-2, respectively. They stated that the number of predicted transmembrane domains in the presenilins varies between 6 and 9, depending on the secondary structure prediction program and calculation window used; for this reason, they suggested that the name 'seven transmembrane protein' (STM) may be unwise. Notably, STM is the symbol already reserved for the monoamine-preferring sulfotransferase gene (600641). </p><p>Vito et al. (1996) found that the mouse gene originally designated Alg3, and now symbolized Psen2, is the homolog of human PSEN2. The designation ALG3 is used for a gene on chromosome 16 (601100). </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 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 ALZHEIMER DISEASE, FAMILIAL, 4</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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PSEN2, ASN141ILE
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<br />
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SNP: rs63750215,
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ClinVar: RCV000009393, RCV000084262
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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 total of 7 Volga German families with early-onset familial Alzheimer disease (AD4; 606889), Levy-Lahad et al. (1995) found an A-T transversion in the PSEN2 gene, resulting in an asn141-to-ile (N141I) substitution. </p><p>In 3 of 4 pedigrees of Volga German ancestry, Rogaev et al. (1995) found heterozygosity for the N141I mutation, suggesting founder effect. </p><p>To gain insight into the significance of the presenilins in the pathogenetic mechanisms of early-onset familial Alzheimer disease, Tomita et al. (1997) expressed cDNAs for wildtype PSEN2 and PSEN2 with the Volga German mutation (N141I) in cultured cells and then examined the metabolism of the transfected proteins and their effect on the C-terminal properties of secreted amyloid beta protein (A-beta). PSEN2 was identified as a 50- to 55-kD protein that was cleaved to produce N-terminal fragments of 35 to 40 kD and C-terminal fragments of 19 to 23 kD. The N141I mutation did not cause any significant change in the metabolism of PSEN2. COS-1 cells doubly transfected with the mutant N141I PSEN2 gene and human beta-amyloid precursor protein, as well as mouse neuroblastoma cells stably transfected with N141I mutant PSEN2 alone, secreted 1.5- to 10-fold more beta-amyloid 42 or 43 compared with those expressing the wildtype PSEN2. These results strongly suggested to Tomita et al. (1997) that the N141I mutation linked to FAD alters the metabolism of APP to foster the production of the form of A-beta that most readily deposits in amyloid plaques. Thus, mutant PSEN2 may lead to AD by altering the metabolism of APP. </p><p>Marambaud et al. (1998) showed that the expression of wildtype PSEN2 in human HEK293 cells increases the production of the physiologic alpha-secretase-derived product APP-alpha. By contrast, APP-alpha secretion was drastically reduced in cells expressing the N141I mutation of PSEN2. </p><p>Wijsman et al. (2005) noted the wide range in age at onset of Alzheimer disease in Volga German families with the N141I mutation in PSEN2. To examine evidence for a genetic basis for the variation in age at onset, the authors performed a Bayesian oligogenic segregation and linkage analysis on 9 Volga German families known to have a least 1 affected PSEN2 mutation carrier. The analysis was designed to estimate the effects of APOE and PSEN2 and the number and effects of additional loci and the environment (family effects) affecting age at onset of AD. The analysis showed that APOE plays a small but significant role in modifying the age at onset in these Volga German families. There was evidence of a dose-dependent relationship between the number of E4 alleles and age at onset. Wijsman et al. (2005) calculated an approximately 83% posterior probability of at least one modifier locus in addition to APOE; the fraction of the variance in age at onset attributable to PSEN2, APOE, other loci, and family effects was approximately 70%, 2%, 6.5%, and 8.5%, respectively. </p><p>Yu et al. (2010) demonstrated that a family from Fulda (Hesse), Germany with AD4 caused by the N141I mutation shared the same haplotype as the Volga German families reported earlier. This finding indicated that the mutation must have occurred prior to the emigration of the Volga Germans from the Hesse region of Germany to Russia in the 1760s during the reign of Catherine the Great. In addition, the original patient with AD reported by Alzheimer (1907) also lived in the same Hesse region as the modern family, which raised the possibility that the original patient may have had the N141I mutation. However, Muller et al. (2011) sequenced exon 5 of the PSEN2 gene in DNA extracted from a tissue section prepared from the brain of the original patient with AD ('Auguste D'), and found that she did not carry the N141I mutation, thus disproving the hypothesis of Yu et al. (2010). </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>.0002 ALZHEIMER DISEASE, FAMILIAL, 4</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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PSEN2, MET239VAL
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<br />
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SNP: rs28936379,
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gnomAD: rs28936379,
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ClinVar: RCV000009394, RCV000084265
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</span>
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<span class="mim-text-font">
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<p>In all 4 affected members of an extended pedigree of Italian origin with early-onset (at or before 50 years), pathologically confirmed familial AD (AD4; 606889), Rogaev et al. (1995) observed heterozygosity for a 1080A-G substitution in the PSEN2 gene, resulting in a met239-to-val (M239V) substitution. </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>.0003 ALZHEIMER DISEASE, FAMILIAL, 4</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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PSEN2, ASP439ALA
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<br />
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SNP: rs63750110,
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gnomAD: rs63750110,
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ClinVar: RCV000009395, RCV000084269, RCV000172102
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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 patient with early-onset (age 52 years) Alzheimer disease (AD4; 606889) who was heterozygous for the E2/E3 isoforms of apolipoprotein E (107741.0001/ 107741.0015), Lleo et al. (2001) identified a heterozygous A-to-C transversion in exon 12 of the PSEN2 gene, resulting in an asp439-to-ala (D439A) substitution in the C-terminal portion of the protein. Haplotype analysis indicated a maternal origin, but the patient's mother was deceased and had been adopted, precluding familial analysis. Six asymptomatic sibs did not carry the mutation. Lleo et al. (2001) suggested that the mutation may alter the endoproteolytic processing of the protein. </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 ALZHEIMER DISEASE, FAMILIAL, 4</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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PSEN2, THR430MET
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<br />
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SNP: rs63750666,
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gnomAD: rs63750666,
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ClinVar: RCV000009396, RCV000084268
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a family with early-onset Alzheimer disease (AD4; 606889), Ezquerra et al. (2003) identified a C-to-T change in exon 12 of the PSEN2 gene, resulting in a thr430-to-met (T430M) substitution. The mutation was also found in a cognitively healthy sib older than the proband, suggesting either reduced penetrance or a later onset in this individual. Age at disease onset in this family was variable (45 to 65 years). The T430M mutation is located in the C terminus of the protein, which may disrupt endoproteolytic processing and protein function. The mutation was not detected in 50 unrelated healthy controls or in 80 unrelated patients with AD. </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 ALZHEIMER DISEASE, FAMILIAL, 4</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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PSEN2, THR122PRO
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<br />
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SNP: rs63749851,
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ClinVar: RCV000009397, RCV000084260
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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 family with early-onset AD (AD4; 606889), Finckh et al. (2000) identified a thr122-to-pro (T122P) mutation in the PSEN2 gene. The proband had disease onset at age 46 years. Her clinical course was similar to that of her mother and grandmother, both mutation carriers, who died at ages 48 and 51 years, respectively. Finckh et al. (2000) commented on the similar clinical phenotype and high penetrance of the T122P mutation. </p>
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|
|
<div class="mim-changed mim-change"><p>Zampese et al. (2011) found that expression of the FAD-linked T122R mutation of PS2 increased the number of SH-SY5Y cells with high mitochondrial Ca(2+) response and increased the physical and functional interactions between ER and mitochondria. This effect on ER-mitochondria interactions was specific to PS2, as ER-mitochondria interactions were affected by other PS2 mutations but not by PS1 (104311) mutations. Similar to PS2 overexpression, expression of the PS2 T122R mutation favored generation of Ca(2+) hot spots on the OMM. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PSEN2, MET239ILE
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<br />
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SNP: rs63749884,
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ClinVar: RCV000009398, RCV000084266
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In an Italian family in which 4 members had early-onset AD (AD4; 606889), Finckh et al. (2000) identified heterozygosity for a met239-to-ile (M239I) mutation in the PSEN2 gene. Age at onset was 58 years in the proband. Five sibs carried the mutation, but only 3 of them had AD. The authors noted that this phenotypic variability or reduced penetrance is not uncommon with PSEN2 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">
|
|
<strong>.0007 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PSEN2, THR122ARG
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<br />
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SNP: rs28936380,
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|
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gnomAD: rs28936380,
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|
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ClinVar: RCV000009399, RCV000084579
|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 3 Italian sibs, 2 of whom were monozygotic twin sisters, Binetti et al. (2003) identified a heterozygous 365C-G transversion in exon 5 of the PSEN2 gene, resulting in a thr122-to-arg (T122R) substitution. The proband, a male, and 1 of the twin sisters had early-onset atypical dementia, presumably a variant of Alzheimer disease (AD4; 606889). The other twin sister, who carried the mutation, did not have symptomatic disease at age 60 years. The brother showed attention deficits, language impairment, apraxia, and global cognitive decline. The affected twin sister showed early symptoms of apathy and depression, followed by inappropriate and uninhibited behavior as well as memory and language deficits. Their mother, maternal aunt, and maternal grandmother were reportedly affected by a similar illness. The proband also had the prion protein M129V polymorphism (176640.0005). </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 CARDIOMYOPATHY, DILATED, 1V</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
ALZHEIMER DISEASE, FAMILIAL, 4, INCLUDED
|
|
</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
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PSEN2, SER130LEU
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<br />
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|
|
SNP: rs63750197,
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|
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gnomAD: rs63750197,
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|
|
ClinVar: RCV000009400, RCV000009401, RCV000084261, RCV000172588, RCV001642203, RCV003934816
|
|
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 families, Li et al. (2006) found that idiopathic dilated cardiomyopathy (CMD1V; 613697) segregated with a 756C-T transition in exon 5 of the PSEN2 gene, predicting to result in an ser130-to-leu (S130L) amino acid change. The mutation was present in heterozygous state. Both were white families. This mutation had been reported in association with Alzheimer disease (AD4; 606889) in a small kindred by Tedde et al. (2003). </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 ALZHEIMER DISEASE, FAMILIAL, 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PSEN2, ALA85VAL
|
|
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|
|
<br />
|
|
|
|
SNP: rs63750048,
|
|
|
|
|
|
gnomAD: rs63750048,
|
|
|
|
|
|
ClinVar: RCV000009402, RCV000084259
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Sardinian family with Alzheimer disease (AD4; 606889), Piscopo et al. (2008) identified a heterozygous C-to-T transition in exon 4 of the PSEN2 gene, resulting in an ala85-to-val (A85V) substitution in the N-terminal cytoplasmic portion of PSEN2 close to transmembrane domain 1. The phenotype was somewhat atypical in this family: 3 of 4 patients had signs of parkinsonism, including rigidity, postural instability, and bradykinesia, in addition to classic signs of AD. Two patients had visual hallucinations. Neuropathologic findings in 1 patient showed beta-amyloid plaques and neurofibrillary tangles as well as many diffuse Lewy bodies throughout the brain. These findings were also compatible with a clinical diagnosis of Lewy body dementia (127750). </p>
|
|
</span>
|
|
</div>
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
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|
|
|
</div>
|
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Alzheimer, A.
|
|
<strong>Ueber eine eigenartige Erkrankung der Hirnrinde.</strong>
|
|
Allg. Z. Psychiat. Med. 64: 146-148, 1907.
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Alzheimer's Disease Collaborative Group.
|
|
<strong>The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families.</strong>
|
|
Nature Genet. 11: 219-222, 1995.
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[PubMed: 7550356]
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[Full Text: https://doi.org/10.1038/ng1095-219]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Beglopoulos, V., Sun, X., Saura, C. A., Lemere, C. A., Kim, R. D., Shen, J.
|
|
<strong>Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice.</strong>
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J. Biol. Chem. 279: 46907-46914, 2004.
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[PubMed: 15345711]
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[Full Text: https://doi.org/10.1074/jbc.M409544200]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Binetti, G., Signorini, S., Squitti, R., Alberici, A., Benussi, L., Cassetta, E., Frisoni, G. B., Barbiero, L., Feudatari, E., Nicosia, F., Testa, C., Zanetti, O., Gennarelli, M., Perani, D., Anchisi, D., Ghidoni, R., Rossini, P. M.
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<strong>Atypical dementia associated with a novel presenilin-2 mutation.</strong>
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Ann. Neurol. 54: 832-836, 2003.
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[PubMed: 14681895]
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[Full Text: https://doi.org/10.1002/ana.10760]
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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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Citron, M., Westaway, D., Xia, W., Carlson, G., Diehl, T., Levesque, G., Johnson-Wood, K., Lee, M., Seubert, P., Davis, A., Kholodenko, D., Motter, R., Sherrington, R., Perry, B., Yao, H., Strome, R., Lieberburg, I., Rommens, J., Kim. S., Schenk, D., Fraser, P., St George Hyslop, P., Selkoe, D. J.
|
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<strong>Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.</strong>
|
|
Nature Med. 3: 67-72, 1997.
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[PubMed: 8986743]
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[Full Text: https://doi.org/10.1038/nm0197-67]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Clark, R. F., Hutton, M., Talbot, C., Wragg, M., Lendon, C., Busfield, F., Han, S. W., Perez-Tur, J., Adams, M., Fuldner, R., Roberts, G., Karran, E., Hardy, J., Goate, A.
|
|
<strong>The role of presenilin 1 in the genetics of Alzheimer's disease.</strong>
|
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Cold Spring Harbor Symp. Quant. Biol. 61: 551-558, 1996.
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[PubMed: 9246481]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cruts, M., Van Broeckhoven, C.
|
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<strong>Presenilin mutations in Alzheimer's disease.</strong>
|
|
Hum. Mutat. 11: 183-190, 1998.
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|
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[PubMed: 9521418]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1998)11:3<183::AID-HUMU1>3.0.CO;2-J]
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|
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</p>
|
|
</li>
|
|
|
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<li>
|
|
<p class="mim-text-font">
|
|
Donoviel, D. B., Hadjantonakis, A.-K., Ikeda, M., Zheng, H., St George Hyslop, P., Bernstein, A.
|
|
<strong>Mice lacking both presenilin genes exhibit early embryonic patterning defects.</strong>
|
|
Genes Dev. 13: 2801-2810, 1999.
|
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|
|
|
|
[PubMed: 10557208]
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|
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[Full Text: https://doi.org/10.1101/gad.13.21.2801]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ezquerra, M., Lleo, A., Castellvi, M., Queralt, R., Santacruz, P., Pastor, P., Molinuevo, J. L., Blesa, R., Oliva, R.
|
|
<strong>A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease.</strong>
|
|
Arch. Neurol. 60: 1149-1151, 2003.
|
|
|
|
|
|
[PubMed: 12925374]
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|
|
[Full Text: https://doi.org/10.1001/archneur.60.8.1149]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Finckh, U., Muller-Thomsen, T., Mann, U., Eggers, C., Marksteiner, J., Meins, W., Binetti, G., Alberici, A., Hock, C., Nitsch, R. M., Gal, A.
|
|
<strong>High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes.</strong>
|
|
Am. J. Hum. Genet. 66: 110-117, 2000.
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[PubMed: 10631141]
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[Full Text: https://doi.org/10.1086/302702]
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Francis, R., McGrath, G., Zhang, J., Ruddy, D. A., Sym, M., Apfeld, J., Nicoll, M., Maxwell, M., Hai, B., Ellis, M. C., Parks, A. L., Xu, W., Li, J., Gurney, M., Myers, R. L., Himes, C. S., Hiebsch, R., Ruble, C., Nye, J. S., Curtis, D.
|
|
<strong>aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation.</strong>
|
|
Dev. Cell 3: 85-97, 2002.
|
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|
|
[PubMed: 12110170]
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|
|
[Full Text: https://doi.org/10.1016/s1534-5807(02)00189-2]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Herreman, A., Hartmann, D, Annaert, W., Saftig, P., Craessaerts, K., Serneels, L., Umans, L., Schrijvers, V., Checler, F., Vanderstichele, H., Baekelandt, V., Dressel, R., Cupers, P., Huylebroeck, D., Zwijsen, A., Van Leuven, F., De Strooper, B.
|
|
<strong>Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency.</strong>
|
|
Proc. Nat. Acad. Sci. 96: 11872-11877, 1999.
|
|
|
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|
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[PubMed: 10518543]
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|
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|
|
|
[Full Text: https://doi.org/10.1073/pnas.96.21.11872]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kopan, R., Goate, A.
|
|
<strong>A common enzyme connects Notch signaling and Alzheimer's disease.</strong>
|
|
Genes Dev. 14: 2799-2806, 2000.
|
|
|
|
|
|
[PubMed: 11090127]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gad.836900]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kovacs, D. M., Fausett, H. J., Page, K. J., Kim, T.-W., Moir, R. D., Merriam, D. E., Hollister, R. D., Hallmark, O. G., Mancini, R., Felsenstein, K. M., Hyman, B. T., Tanzi, R. E., Wasco, W.
|
|
<strong>Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and localization to intracellular membranes in mammalian cells.</strong>
|
|
Nature Med. 2: 224-229, 1996.
|
|
|
|
|
|
[PubMed: 8574969]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nm0296-224]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Lee, S.-F., Shah, S., Li, H., Yu, C., Han, W., Yu, G.
|
|
<strong>Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch.</strong>
|
|
J. Biol. Chem. 277: 45013-45019, 2002.
|
|
|
|
|
|
[PubMed: 12297508]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M208164200]
|
|
|
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|
|
</p>
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[PubMed: 19641596]
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[Full Text: https://doi.org/10.1038/nature08177]
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Bao Lige - updated : 03/10/2025<br>Bao Lige - updated : 12/07/2018<br>Cassandra L. Kniffin - updated : 4/4/2012<br>Cassandra L. Kniffin - updated : 6/22/2010<br>Ada Hamosh - updated : 8/27/2009<br>Cassandra L. Kniffin - updated : 10/1/2008<br>Paul J. Converse - updated : 3/6/2007<br>Victor A. McKusick - updated : 11/27/2006<br>George E. Tiller - updated : 9/11/2006<br>John Logan Black, III - updated : 7/22/2005<br>Cassandra L. Kniffin - updated : 1/20/2005<br>Cassandra L. Kniffin - updated : 3/1/2004<br>Cassandra L. Kniffin - reorganized : 2/19/2004<br>Ada Hamosh - updated : 4/3/2003<br>Dawn Watkins-Chow - updated : 3/17/2003<br>George E. Tiller - updated : 12/13/2002<br>Cassandra L. Kniffin - updated : 11/27/2002<br>Ada Hamosh - updated : 9/30/2002<br>Paul J. Converse - updated : 5/29/2002<br>Paul J. Converse - updated : 4/9/2001<br>George E. Tiller - updated : 12/14/2000<br>Ada Hamosh - updated : 2/3/2000<br>Victor A. McKusick - updated : 11/9/1999<br>Victor A. McKusick - updated : 1/22/1999<br>Victor A. McKusick - updated : 7/13/1998<br>Victor A. McKusick - updated : 7/9/1998<br>Victor A. McKusick - updated : 4/20/1998<br>Ada Hamosh - updated : 1/20/1998<br>Victor A. McKusick - updated : 9/9/1997<br>Victor A. McKusick - updated : 4/7/1997<br>Victor A. McKusick - updated : 2/3/1997<br>Moyra Smith - updated : 1/23/1997
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Victor A. McKusick : 10/10/1995
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