4382 lines
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Entry
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- *605481 - ABNORMAL SPINDLE-LIKE, MICROCEPHALY-ASSOCIATED; ASPM
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*605481</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#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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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605481">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</div>
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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=ENSG00000066279;t=ENST00000367409" 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=259266" 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=605481" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<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=ENSG00000066279;t=ENST00000367409" 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_001206846,NM_018136" 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_018136" 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=605481" 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=08384&isoform_id=08384_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/ASPM" 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/7022652,21961301,23884551,24061709,24061713,24061716,24061718,30313422,34193569,38155724,66474487,66474489,66474491,119611676,119611677,119611678,119611679,119611680,126116596,193784991,193785531,215273935,332205965" 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/Q8IZT6" 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=259266" 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=ENSG00000066279;t=ENST00000367409" 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=ASPM" 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=ASPM" 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+259266" 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/ASPM" 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:259266" 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/259266" 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=ENST00000367409.9&hgg_start=197084127&hgg_end=197146669&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:19048" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:19048" 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/aspm" 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=605481[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=605481[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/ASPM/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/ENSG00000066279" 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=ASPM" 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=ASPM" 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=ASPM" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ASPM&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/PA38782" 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:19048" 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/FBgn0000140.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:1334448" 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/ASPM#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:1334448" 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/259266/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002892/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=259266" 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=WBGene00008107;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-050208-620" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=ASPM&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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605481
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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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ABNORMAL SPINDLE-LIKE, MICROCEPHALY-ASSOCIATED; ASPM
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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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ASP, DROSOPHILA, HOMOLOG OF<br />
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MCPH5 GENE
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ASPM" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ASPM</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/1/1535?start=-3&limit=10&highlight=1535">1q31.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:197084127-197146669&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'})">1:197,084,127-197,146,669</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/1/1535?start=-3&limit=10&highlight=1535">
|
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1q31.3
|
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</a>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Microcephaly 5, primary, autosomal recessive
|
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|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/608716"> 608716 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605481" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605481" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The ASPM gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis (<a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> adopted a positional cloning strategy to identify the gene mutant in primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), an autosomal recessive form of primary microcephaly (MCPH) that maps to chromosome 1q31. They identified the ASPM gene within a 600-kb region defined by common haplotypes between families, and confirmed the predicted 10,434-bp open reading frame in overlapping segments of cDNA from fetal brain and colon. Northern blot analysis of mRNA from total mouse embryos showed high expression of an Aspm transcript of at least 9.5 kb between embryonic days (E) 11 to 17. In situ hybridization showed preferential expression during cerebral cortical neurogenesis, specifically in the cerebral cortical ventricular zone. Expression was also observed in the proliferative region of the medial and lateral ganglionic eminence and in the ventricular zone of the dorsal diencephalon. Aspm expression was quite intense at E14.5, when there are many progenitor cells in the cortical ventricular zone, but had decreased in intensity by E16.5. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Kouprina, N., Pavlicek, A., Collins, N. K., Nakano, M., Noskov, V. N., Ohzeki, J.-I., Mochida, G. H., Risinger, J. I., Goldsmith, P., Gunsior, M., Solomon, G., Gersch, W., Kim, J.-H., Barrett, J. C., Walsh, C. A., Jurka, J., Masumoto, H., Larionov, V. <strong>The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein.</strong> Hum. Molec. Genet. 14: 2155-2165, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15972725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15972725</a>] [<a href="https://doi.org/10.1093/hmg/ddi220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15972725">Kouprina et al. (2005)</a> demonstrated that ASPM was widely expressed in fetal and adult human tissues with lower levels in adult tissues. ASPM was upregulated in human ovarian and uterine cancer tissues. The predicted full-length protein contains 3,477 amino acids and has a calculated molecular mass of 410 kD. ASPM contains 2 conserved regions termed ASPM N-proximal (ASNP) repeats, and more than half of the protein consists of 81 C-terminal calmodulin-binding IQ motifs of variable length. Western blot analysis identified several predicted alternatively spliced ASPM variants with fewer IQ motifs. Immunostaining of cultured human cells revealed that ASPM was localized in the spindle poles during mitosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15972725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> noted that the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice, and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. The results of <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells. Humans with autosomal recessive primary microcephaly show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> suggested that genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Fish, J. L., Kosodo, Y., Enard, W., Paabo, S., Huttner, W. B. <strong>Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells.</strong> Proc. Nat. Acad. Sci. 103: 10438-10443, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16798874[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.0604066103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16798874">Fish et al. (2006)</a> found that Aspm was concentrated at mitotic spindle poles in mouse neuroepithelial cells, the primary stem and progenitor cells of the mammalian brain. Aspm expression was downregulated during the switch from proliferative to neurogenic cell divisions. Upon RNA interference in telencephalic neuroepithelial cells, Aspm mRNA was reduced, mitotic spindle poles lacked Aspm protein, and the cleavage plane was less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation increased the probability that the cells underwent asymmetric division, i.e., the apical plasma membrane was inherited by only 1 of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a large proportion of neuroepithelial cell progeny was found in the neuronal layer, implying a reduction in the number of neuroepithelial progenitor cells upon Aspm knockdown. <a href="#8" class="mim-tip-reference" title="Fish, J. L., Kosodo, Y., Enard, W., Paabo, S., Huttner, W. B. <strong>Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells.</strong> Proc. Nat. Acad. Sci. 103: 10438-10443, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16798874[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.0604066103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16798874">Fish et al. (2006)</a> concluded that ASPM is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative division of neuroepithelial cells during brain development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16798874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Horvath, S., Zhang, B., Carlson, M., Lu, K. V., Zhu, S., Felciano, R. M., Laurance, M. F., Zhao, W., Qi, S., Chen, Z., Lee, Y., Scheck, A. C., Liau, L. M., Wu, H., Geschwind, D. H., Febbo, P. G., Kornblum, H. I., Cloughesy, T. F., Nelson, S. F., Mischel, P. S. <strong>Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.</strong> Proc. Nat. Acad. Sci. 103: 17402-17407, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17090670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17090670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17090670[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.0608396103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17090670">Horvath et al. (2006)</a> identified ASPM as a highly connected 'hub' gene within a module of mitosis/cell cycle genes that are coexpressed in glioblastoma and breast cancer. They demonstrated ASPM overexpression in glioblastoma compared to normal tissues. Aspm expression was also high in fetal murine neural stem/progenitor cells, and its expression decreased during differentiation. Knockdown of ASPM by small interfering RNA inhibited proliferation in both a human glioblastoma cell line and murine neural stem/progenitor cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17090670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> determined that the ASPM gene contains 28 exons and spans 62 kb of genomic sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" 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 positional cloning, <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> identified the ASPM gene within the MCPH5 critical region on 1q31. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" 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 each of 4 consanguineous northern Pakistani families with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> found a homozygous truncating mutation in the ASPM gene (<a href="#0001">605481.0001</a>). <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> were unable to distinguish phenotypically between the 4 families in which these mutations were found. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bond, J., Scott, S., Hampshire, D. J., Springell, K., Corry, P., Abramowicz, M. J., Mochida, G. H., Hennekam, R. C. M., Maher, E. R., Fryns, J.-P., Alswaid, A., Jafri, H., Rashid, Y., Mubaidin, A., Walsh, C. A., Roberts, E., Woods, C. G. <strong>Protein-truncating mutations in ASPM cause variable reduction in brain size.</strong> Am. J. Hum. Genet. 73: 1170-1177, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14574646[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/10.1086/379085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14574646">Bond et al. (2003)</a> performed a comprehensive mutation screen of the 10.4-kb ASPM gene, identifying 19 mutations in a cohort of 23 consanguineous families. The mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5 to 11 SDs below normal) and of mental retardation (mild to severe), but appeared to be independent of mutation position in the gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14574646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 3 of 9 consanguineous Indian families with primary microcephaly, <a href="#13" class="mim-tip-reference" title="Kumar, A., Blanton, S. H., Babu, M., Markandaya, M., Girimaji, S. C. <strong>Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.</strong> Clin. Genet. 66: 341-348, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15355437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15355437</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15355437">Kumar et al. (2004)</a> identified 3 different truncating mutations in the ASPM gene (<a href="#0005">605481.0005</a>-<a href="#0007">605481.0007</a>). <a href="#13" class="mim-tip-reference" title="Kumar, A., Blanton, S. H., Babu, M., Markandaya, M., Girimaji, S. C. <strong>Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.</strong> Clin. Genet. 66: 341-348, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15355437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15355437</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15355437">Kumar et al. (2004)</a> stated that 24 mutations in the ASPM gene had been reported in families from Pakistan, Turkey, the Netherlands, Jordan, Saudi Arabia, Yemen, and India (their patients). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15355437" 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="#22" class="mim-tip-reference" title="Shen, J., Eyaid, W., Mochida, G. H., Al-Moayyad, F., Bodell, A., Woods, C. G., Walsh, C. A. <strong>ASPM mutation identified in patients with primary microcephaly and seizures. (Letter)</strong> J. Med. Genet. 42: 725-729, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16141009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16141009</a>] [<a href="https://doi.org/10.1136/jmg.2004.027706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16141009">Shen et al. (2005)</a> described a mutation (<a href="#0008">605481.0008</a>) of the ASPM gene in affected members of a family in which epilepsy was associated with primary microcephaly. They suggested that a history of seizures should not preclude the diagnosis of primary microcephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16141009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Gul, A., Hassan, M. J., Mahmood, S., Chen, W., Rahmani, S., Naseer, M. I., Dellefave, L., Muhammad, N., Rafiq, M. A., Ansar, M., Chishti, M. S., Ali, G., Siddique, T., Ahmad, W. <strong>Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene.</strong> Neurogenetics 7: 105-110, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16673149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16673149</a>] [<a href="https://doi.org/10.1007/s10048-006-0042-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16673149">Gul et al. (2006)</a> identified 6 different mutations in the ASPM gene in affected members of 9 unrelated consanguineous Pakistani families with primary microcephaly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16673149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Desir, J., Cassart, M., David, P., Van Bogaert, P., Abramowicz, M. <strong>Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.</strong> Am. J. Med. Genet. 146A: 1439-1443, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18452193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18452193</a>] [<a href="https://doi.org/10.1002/ajmg.a.32312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18452193">Desir et al. (2008)</a> identified a homozygous mutation in the ASPM gene (<a href="#0009">605481.0009</a>) in 2 sibs with MCPH5 (<a href="/entry/608716">608716</a>). Brain MRI showed a simplified gyral pattern. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18452193" 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="#17" class="mim-tip-reference" title="Nicholas, A. K., Swanson, E. A., Cox, J. J., Karbani, G., Malik, S., Springell, K., Hampshire, D., Ahmed, M., Bond, J., Di Benedetto, D., Fichera, M., Romano, C., Dobyns, W. B., Woods, C. G. <strong>The molecular landscape of ASPM mutations in primary microcephaly.</strong> J. Med. Genet. 46: 249-253, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028728</a>] [<a href="https://doi.org/10.1136/jmg.2008.062380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19028728">Nicholas et al. (2009)</a> sequenced the ASPM gene in 3 cohorts of microcephalic children. Pathogenic ASPM mutations were identified in 39% of 99 consanguineous MCPH families, and in 11 (40%) of 27 nonconsanguineous predominantly Caucasian families with a strict diagnosis of MCPH. In contrast, only 3 (7%) of 45 families with a less restricted phenotype, including microcephaly and mental retardation, had an ASPM mutation. Overall, the report identified 27 novel mutations in the ASPM gene, which almost doubled the number of MCPH-associated ASPM mutations. All but 1 of the mutations resulted in premature termination. There were no definitive missense mutations and no genotype/phenotype correlations. <a href="#17" class="mim-tip-reference" title="Nicholas, A. K., Swanson, E. A., Cox, J. J., Karbani, G., Malik, S., Springell, K., Hampshire, D., Ahmed, M., Bond, J., Di Benedetto, D., Fichera, M., Romano, C., Dobyns, W. B., Woods, C. G. <strong>The molecular landscape of ASPM mutations in primary microcephaly.</strong> J. Med. Genet. 46: 249-253, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028728</a>] [<a href="https://doi.org/10.1136/jmg.2008.062380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19028728">Nicholas et al. (2009)</a> concluded that ASPM mutations are the most common cause of strict MCPH. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19028728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Passemard, S., Titomanlio, L., Elmaleh, M., Afenjar, A., Alessandri, J.-L., Andria, G., Billette de Villemeur, T., Boespflug-Tanguy, O., Burglen, L., Del Giudice, E., Guimiot, F., Hyon, C., and 11 others. <strong>Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.</strong> Neurology 73: 962-969, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19770472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19770472</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181b8799a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19770472">Passemard et al. (2009)</a> identified homozygous or compound heterozygous mutations in the ASPM gene in 11 (22%) of 52 probands with MCPH. Sixteen novel mutations were identified, and all 18 mutations were truncating or nonsense mutations. The findings of this study expanded the phenotypic spectrum of MCPH5 to include a decrease in OFC with age and mild structural brain imaging anomalies, including simplified gyral pattern, enlarged ventricles, and partial agenesis of the corpus callosum. Two patients had evidence of cortical dysplasia. The anomalies found in these patients suggested that ASPM may be involved not only in mitosis control, but also as an accessory factor in other developmental processes such as migration and cortical layering. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19770472" 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>Among 112 consanguineous Iranian families with primary microcephaly, <a href="#4" class="mim-tip-reference" title="Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others. <strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong> J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20978018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20978018</a>] [<a href="https://doi.org/10.1136/jmg.2009.076398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20978018">Darvish et al. (2010)</a> found that 13 (14.1%) showed linkage to the MCPH5 locus. However, homozygous mutations in the ASPM gene were found in only 11 of the families. One of the mutations had been previously reported by <a href="#17" class="mim-tip-reference" title="Nicholas, A. K., Swanson, E. A., Cox, J. J., Karbani, G., Malik, S., Springell, K., Hampshire, D., Ahmed, M., Bond, J., Di Benedetto, D., Fichera, M., Romano, C., Dobyns, W. B., Woods, C. G. <strong>The molecular landscape of ASPM mutations in primary microcephaly.</strong> J. Med. Genet. 46: 249-253, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19028728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19028728</a>] [<a href="https://doi.org/10.1136/jmg.2008.062380" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19028728">Nicholas et al. (2009)</a>, and 10 mutations were novel, 9 of which were predicted to result in a truncated protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20978018+19028728" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Sajid Hussain, M., Marriam Bakhtiar, S., Farooq, M., Anjum, I., Janzen, E., Reza Toliat, M., Eiberg, H., Kjaer, K. W., Tommerup, N., Noegel, A. A., Nurnberg, P., Baig, S. M., Hansen, L. <strong>Genetic heterogeneity in Pakistani microcephaly families.</strong> Clin. Genet. 83: 446-451, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22775483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22775483</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2012.01932.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22775483">Sajid Hussain et al. (2013)</a> found linkage to 5 different MCPH disease loci in 34 of 57 consanguineous Pakistani families with autosomal recessive primary microcephaly. Pathogenic mutations were found in 27 of the 34 families. Eighteen families showed linkage to the ASPM gene, and pathogenic mutations were found in 17 families. ASPM was the most commonly mutated gene: the homozygous W1326X mutation (<a href="#0006">605481.0006</a>) was present in 8 families, suggesting a founder effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22775483" 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>Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, <a href="#6" class="mim-tip-reference" title="Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. <strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong> Cell 119: 1027-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15620360">Dorus et al. (2004)</a> examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including ASPM, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. <a href="#6" class="mim-tip-reference" title="Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T. <strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong> Cell 119: 1027-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15620360/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15620360</a>] [<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15620360">Dorus et al. (2004)</a> concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15620360" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Mekel-Bobrov, N., Gilbert, S. L., Evans, P. D., Vallender, E. J., Anderson, J. R., Hudson, R. R., Tishkoff, S. A., Lahn, B. T. <strong>Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.</strong> Science 309: 1720-1722, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151010</a>] [<a href="https://doi.org/10.1126/science.1116815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151010">Mekel-Bobrov et al. (2005)</a> showed that one genetic variant of ASPM in humans arose nearly about 5,800 years ago and has since swept to high frequency under strong positive selection. They sequenced the entire 62.1-kb genomic region of ASPM in samples from 90 ethnically diverse individuals obtained through the Coriell Institute and from a common chimpanzee. <a href="#15" class="mim-tip-reference" title="Mekel-Bobrov, N., Gilbert, S. L., Evans, P. D., Vallender, E. J., Anderson, J. R., Hudson, R. R., Tishkoff, S. A., Lahn, B. T. <strong>Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.</strong> Science 309: 1720-1722, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151010</a>] [<a href="https://doi.org/10.1126/science.1116815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151010">Mekel-Bobrov et al. (2005)</a> showed that haplotype 63 had an unusually high frequency of 21%, whereas the other haplotypes ranged from 0.56 to 3.3%. Haplotype 63 differed consistently from the others at multiple polymorphic sites, 2 of which were nonsynonymous, both in exon 18, and are denoted A44871G and C45126A (the numbers indicate genetic positions from the start codon, and letters at the beginning and end indicate ancestral and derived alleles, respectively). These 2 sites reside in a region of open reading frame that was shown to have experienced particularly strong positive selection in the lineage leading to humans (<a href="#7" class="mim-tip-reference" title="Evans, P. D., Anderson, J. R., Vallender, E. J., Gilbert, S. L., Malcom, C. M., Dorus, S., Lahn, B. T. <strong>Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans.</strong> Hum. Molec. Genet. 13: 489-494, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722158</a>] [<a href="https://doi.org/10.1093/hmg/ddh055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14722158">Evans et al., 2004</a>). These findings, especially the remarkably young age of the positively selected variant, suggested that the human brain is still undergoing rapid adaptive evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14722158+16151010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Currat et al. (2006)</a> commented on the paper by <a href="#15" class="mim-tip-reference" title="Mekel-Bobrov, N., Gilbert, S. L., Evans, P. D., Vallender, E. J., Anderson, J. R., Hudson, R. R., Tishkoff, S. A., Lahn, B. T. <strong>Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.</strong> Science 309: 1720-1722, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151010</a>] [<a href="https://doi.org/10.1126/science.1116815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151010">Mekel-Bobrov et al. (2005)</a>, stating that they had developed models of human history including both population growth and spatial structure that could generate the observed pattern of ASPM haplotypes without selection. <a href="#14" class="mim-tip-reference" title="Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Mekel-Bobrov et al. (2006)</a> responded that the demographic models adopted by <a href="#3" class="mim-tip-reference" title="Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Currat et al. (2006)</a> strongly contradicted a decade of empirical research on human demographic history and did not account for the critical features of the data on which <a href="#14" class="mim-tip-reference" title="Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong> Science 313: 172 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>] [<a href="https://doi.org/10.1126/science.1122822" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16840683">Mekel-Bobrov et al. (2006)</a> had developed their argument for selection. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16840683+16151010" 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="Yu, F., Hill, R. S., Schaffner, S. F., Sabeti, P. C., Wang, E. T., Mignault, A. A., Ferland, R. J., Moyzis, R. K., Walsh, C. A., Reich, D. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.'</strong> Science 316: 370 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17446375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17446375</a>] [<a href="https://doi.org/10.1126/science.316.5823.370a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17446375">Yu et al. (2007)</a> did further studies based on the conclusions of <a href="#15" class="mim-tip-reference" title="Mekel-Bobrov, N., Gilbert, S. L., Evans, P. D., Vallender, E. J., Anderson, J. R., Hudson, R. R., Tishkoff, S. A., Lahn, B. T. <strong>Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.</strong> Science 309: 1720-1722, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151010</a>] [<a href="https://doi.org/10.1126/science.1116815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16151010">Mekel-Bobrov et al. (2005)</a>. <a href="#23" class="mim-tip-reference" title="Yu, F., Hill, R. S., Schaffner, S. F., Sabeti, P. C., Wang, E. T., Mignault, A. A., Ferland, R. J., Moyzis, R. K., Walsh, C. A., Reich, D. <strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.'</strong> Science 316: 370 only, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17446375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17446375</a>] [<a href="https://doi.org/10.1126/science.316.5823.370a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17446375">Yu et al. (2007)</a> compared ASPM empirically to a large number of other loci and found that its variation is not unusual and does not support selection. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17446375+16151010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 5 independent population-based samples comprising 2,393 individuals, <a href="#16" class="mim-tip-reference" title="Mekel-Bobrov, N., Posthuma, D., Gilbert, S. L., Lind, P., Gosso, M. F., Luciano, M., Harris, S. E., Bates, T. C., Polderman, T. J. C., Whalley, L. J., Fox, H., Starr, J. M., and 10 others. <strong>The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence.</strong> Hum. Molec. Genet. 16: 600-608, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220170</a>] [<a href="https://doi.org/10.1093/hmg/ddl487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17220170">Mekel-Bobrov et al. (2007)</a> did not find a detectable association between the recent adaptive evolution of either the ASPM or microcephalin (MCPH1; <a href="/entry/607117">607117</a>) genes and normal variation in IQ. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220170" 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="#19" class="mim-tip-reference" title="Pulvers, J. N., Bryk, J., Fish, J. L., Wilsch-Brauninger, M., Arai, Y., Schreier, D., Naumann, R., Helppi, J., Habermann, B., Vogt, J., Nitsch, R., Toth, A., Enard, W., Paabo, S., Huttner, W. B. <strong>Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline.</strong> Proc. Nat. Acad. Sci. 107: 16595-16600, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20823249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20823249</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20823249[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.1010494107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20823249">Pulvers et al. (2010)</a> developed a line of mice expressing truncated forms of Aspm similar to those causing microcephaly in humans. Heterozygous Aspm mutant mice were indistinguishable from wildtype, but homozygous Aspm mutant mice showed mild microcephaly associated with reduced relative brain weight and cortical thickness. Microcephaly in mutant mice appeared to be due to reduced neural stem cells, since cortical layering appeared normal. In embryonic day-11.5 telencephalon, mutant Aspm localized to spindle poles in metaphase, but it failed to localize to the midbody in telophase. Truncated Aspm proteins also caused massive loss of germ cells, resulting in reduced testis and ovary size accompanied by reduced fertility. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20823249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Johnson, M. B., Sun, X., Kodani, A., Borges-Monroy, R., Girskis, K. M., Ryu, S. C., Wang, P. P., Patel, K., Gonzalez, D. M., Woo, Y. M., Yan, Z., Liang, B., and 13 others. <strong>Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size.</strong> Nature 556: 370-375, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643508</a>] [<a href="https://doi.org/10.1038/s41586-018-0035-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29643508">Johnson et al. (2018)</a> used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25 to 40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients, suggesting that loss of 'cortical units' has occurred. The cortex of fetal Aspm knockout ferrets displayed a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates. These data suggested an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a consanguineous northern Pakistani family with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> identified a homozygous 2-bp deletion in exon 3 of the ASPM gene, 719-720delCT, causing a frameshift leading to premature termination 15 codons downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Pakistani family with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> found that affected members were homozygous for a 7-bp deletion of the ASPM gene, 1258-1264delTCTCAAG, in exon 3, causing a frameshift leading to premature termination 31 codons downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</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> rs189678019 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs189678019;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/rs189678019?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=rs189678019" 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=rs189678019" 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=RCV000005246" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005246" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005246</a>
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<p>In a Pakistani family with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> found that affected individuals were homozygous for a nonsense mutation resulting from a 7761T-G transversion in exon 18 of the ASPM gene, producing immediate truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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ASPM, 1-BP DEL, 9159A
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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> rs199422184 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422184;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/rs199422184?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=rs199422184" 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=rs199422184" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005247" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005247" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005247</a>
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<p>In a consanguineous Pakistani family with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#1" class="mim-tip-reference" title="Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G. <strong>ASPM is a major determinant of cerebral cortical size.</strong> Nature Genet. 32: 316-320, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>] [<a href="https://doi.org/10.1038/ng995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12355089">Bond et al. (2002)</a> found a 1-bp deletion, 9159delA, in exon 21 of the ASPM gene, causing a frameshift leading to premature termination 4 codons downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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ASPM, GLN3060TER
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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> rs137852994 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852994;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/rs137852994?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=rs137852994" 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=rs137852994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005248 OR RCV000214564 OR RCV001193347 OR RCV004955250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005248, RCV000214564, RCV001193347, RCV004955250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005248...</a>
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<p>In 2 sibs with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#13" class="mim-tip-reference" title="Kumar, A., Blanton, S. H., Babu, M., Markandaya, M., Girimaji, S. C. <strong>Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.</strong> Clin. Genet. 66: 341-348, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15355437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15355437</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15355437">Kumar et al. (2004)</a> identified a homozygous 9178C-T transition in exon 21 of the ASPM gene, resulting in a gln3060-to-ter (Q3060X) substitution. The family was from southern India, and the parents were related. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15355437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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ASPM, TRP1326TER
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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> rs137852995 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852995;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/rs137852995?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=rs137852995" 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=rs137852995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005249 OR RCV002512801" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005249, RCV002512801" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005249...</a>
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<p>In a child with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), born of consanguineous parents from southern India, <a href="#13" class="mim-tip-reference" title="Kumar, A., Blanton, S. H., Babu, M., Markandaya, M., Girimaji, S. C. <strong>Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.</strong> Clin. Genet. 66: 341-348, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15355437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15355437</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15355437">Kumar et al. (2004)</a> identified a homozygous 3978G-A transition in exon 17 of the ASPM gene, resulting in a trp1326-to-ter (W1326X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15355437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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ASPM, ARG117TER
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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> rs137852996 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852996;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/rs137852996?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=rs137852996" 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=rs137852996" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000005250" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005250" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005250</a>
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</span>
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<p>In 2 sibs with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), born of consanguineous parents from southern India, <a href="#13" class="mim-tip-reference" title="Kumar, A., Blanton, S. H., Babu, M., Markandaya, M., Girimaji, S. C. <strong>Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.</strong> Clin. Genet. 66: 341-348, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15355437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15355437</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2004.00304.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15355437">Kumar et al. (2004)</a> identified a homozygous 349C-T transition in the ASPM gene, resulting in an arg117-to-ter (R117X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15355437" 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">rs137852997 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852997;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=rs137852997" 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=rs137852997" 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=RCV000005251" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005251" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005251</a>
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<p>In 3 sibs with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>) from a consanguineous family from Saudi Arabia, <a href="#22" class="mim-tip-reference" title="Shen, J., Eyaid, W., Mochida, G. H., Al-Moayyad, F., Bodell, A., Woods, C. G., Walsh, C. A. <strong>ASPM mutation identified in patients with primary microcephaly and seizures. (Letter)</strong> J. Med. Genet. 42: 725-729, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16141009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16141009</a>] [<a href="https://doi.org/10.1136/jmg.2004.027706" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16141009">Shen et al. (2005)</a> identified homozygosity for a 6189T-G transversion in exon 18 of the ASPM gene, resulting in a tyr2063-to-ter (Y2063X) substitution. Two of the sibs had seizures, whereas the other did not. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16141009" 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 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
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ASPM, 1-BP INS, 4195A
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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> rs199422163 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422163;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/rs199422163?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=rs199422163" 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=rs199422163" 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=RCV000005252" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005252" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005252</a>
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<p>In 2 sibs, born of consanguineous Moroccan parents, with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>) and simplified gyration pattern on brain MRI, <a href="#5" class="mim-tip-reference" title="Desir, J., Cassart, M., David, P., Van Bogaert, P., Abramowicz, M. <strong>Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.</strong> Am. J. Med. Genet. 146A: 1439-1443, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18452193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18452193</a>] [<a href="https://doi.org/10.1002/ajmg.a.32312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18452193">Desir et al. (2008)</a> identified a homozygous 1-bp insertion (4195insA) in exon 18 of the ASPM gene, resulting in a frameshift and premature termination. The unaffected parents were heterozygous for the mutation. MRI in both patients showed that the simplified gyration was more severe in the anterior cortex. The data indicated that at least 1 form of primary microcephaly is allelic to a form of microcephaly with simplified gyral pattern (<a href="/entry/603802">603802</a>). However, <a href="#5" class="mim-tip-reference" title="Desir, J., Cassart, M., David, P., Van Bogaert, P., Abramowicz, M. <strong>Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.</strong> Am. J. Med. Genet. 146A: 1439-1443, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18452193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18452193</a>] [<a href="https://doi.org/10.1002/ajmg.a.32312" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18452193">Desir et al. (2008)</a> noted that prenatal and postnatal brain imaging of patients with microcephaly has rarely been reported, suggesting that the 2 disorders may actually represent a phenotypic continuum. The findings also indicated that neuronal depletion of the ASPM gene predominantly affects the anterior cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18452193" 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>.0010 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</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> rs145489194 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs145489194;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/rs145489194?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=rs145489194" 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=rs145489194" 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=RCV000005253 OR RCV001851664" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000005253, RCV001851664" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000005253...</a>
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<p>In 3 of 5 sibs, born of consanguineous Algerian parents, with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>), <a href="#20" class="mim-tip-reference" title="Saadi, A., Borck, G., Boddaert, N., Chekkour, M. C., Imessaoudene, B., Munnich, A., Colleaux, L., Chaouch, M. <strong>Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.</strong> Europ. J. Med. Genet. 52: 180-184, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332161</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19332161">Saadi et al. (2009)</a> identified compound heterozygosity for 2 mutations in the ASPM gene: a 2389C-T transition in exon 6, resulting in an arg797-to-ter (R797X) substitution, and a 2-bp deletion in exon 18 (7781delAG; <a href="#0011">605481.0011</a>), resulting in a frameshift and premature termination. All 3 sibs had low to low-normal birth weight, variable speech impairment, and mental retardation. Brain MRI showed severe hypoplasia of the frontal lobes, moderate posterior parietal atrophy, an anterior orientation of the insula, a thick corpus callosum, and global gyral simplification. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332161" 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>.0011 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</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> rs199422173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs199422173;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/rs199422173?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=rs199422173" 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=rs199422173" 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=RCV000020796 OR RCV000365777 OR RCV000856804 OR RCV002513150 OR RCV003421927" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000020796, RCV000365777, RCV000856804, RCV002513150, RCV003421927" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000020796...</a>
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<p>For discussion of the 2-bp deletion in the ASPM gene (7781delAG) that was found in compound heterozygous state in sibs with primary microcephaly-5 (MCPH5; <a href="/entry/608716">608716</a>) by <a href="#20" class="mim-tip-reference" title="Saadi, A., Borck, G., Boddaert, N., Chekkour, M. C., Imessaoudene, B., Munnich, A., Colleaux, L., Chaouch, M. <strong>Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.</strong> Europ. J. Med. Genet. 52: 180-184, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332161</a>] [<a href="https://doi.org/10.1016/j.ejmg.2009.03.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19332161">Saadi et al. (2009)</a>, see <a href="#0010">605481.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332161" 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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Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G.
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<strong>ASPM is a major determinant of cerebral cortical size.</strong>
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Nature Genet. 32: 316-320, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12355089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12355089</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12355089" 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/ng995" target="_blank">Full Text</a>]
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Bond, J., Scott, S., Hampshire, D. J., Springell, K., Corry, P., Abramowicz, M. J., Mochida, G. H., Hennekam, R. C. M., Maher, E. R., Fryns, J.-P., Alswaid, A., Jafri, H., Rashid, Y., Mubaidin, A., Walsh, C. A., Roberts, E., Woods, C. G.
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<strong>Protein-truncating mutations in ASPM cause variable reduction in brain size.</strong>
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Am. J. Hum. Genet. 73: 1170-1177, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14574646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14574646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14574646[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=14574646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1086/379085" target="_blank">Full Text</a>]
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16840683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1122822" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2009.076398" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32312" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2004.11.040" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14722158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14722158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14722158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddh055" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16798874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16798874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16798874[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=16798874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0604066103" target="_blank">Full Text</a>]
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<strong>Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16673149/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16673149</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16673149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-006-0042-4" target="_blank">Full Text</a>]
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<strong>Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17090670/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17090670</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17090670[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=17090670" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0608396103" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643508</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643508" 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/s41586-018-0035-0" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15972725/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15972725</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15972725" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddi220" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2004.00304.x" target="_blank">Full Text</a>]
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
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Science 313: 172 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16840683/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16840683</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16840683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1122822" target="_blank">Full Text</a>]
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<strong>Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16151010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16151010</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16151010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1116815" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17220170/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17220170</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17220170" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddl487" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.062380" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19770472/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19770472</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19770472" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3181b8799a" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Pulvers2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pulvers, J. N., Bryk, J., Fish, J. L., Wilsch-Brauninger, M., Arai, Y., Schreier, D., Naumann, R., Helppi, J., Habermann, B., Vogt, J., Nitsch, R., Toth, A., Enard, W., Paabo, S., Huttner, W. B.
|
|
<strong>Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline.</strong>
|
|
Proc. Nat. Acad. Sci. 107: 16595-16600, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20823249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20823249</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20823249[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=20823249" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.1010494107" target="_blank">Full Text</a>]
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</p>
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<a id="20" class="mim-anchor"></a>
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<a id="Saadi2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Saadi, A., Borck, G., Boddaert, N., Chekkour, M. C., Imessaoudene, B., Munnich, A., Colleaux, L., Chaouch, M.
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<strong>Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.</strong>
|
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Europ. J. Med. Genet. 52: 180-184, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19332161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19332161</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19332161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ejmg.2009.03.013" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Sajid Hussain2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sajid Hussain, M., Marriam Bakhtiar, S., Farooq, M., Anjum, I., Janzen, E., Reza Toliat, M., Eiberg, H., Kjaer, K. W., Tommerup, N., Noegel, A. A., Nurnberg, P., Baig, S. M., Hansen, L.
|
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<strong>Genetic heterogeneity in Pakistani microcephaly families.</strong>
|
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Clin. Genet. 83: 446-451, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22775483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22775483</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22775483" 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/10.1111/j.1399-0004.2012.01932.x" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Shen2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shen, J., Eyaid, W., Mochida, G. H., Al-Moayyad, F., Bodell, A., Woods, C. G., Walsh, C. A.
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<strong>ASPM mutation identified in patients with primary microcephaly and seizures. (Letter)</strong>
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J. Med. Genet. 42: 725-729, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16141009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16141009</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16141009" 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/10.1136/jmg.2004.027706" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Yu2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yu, F., Hill, R. S., Schaffner, S. F., Sabeti, P. C., Wang, E. T., Mignault, A. A., Ferland, R. J., Moyzis, R. K., Walsh, C. A., Reich, D.
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.'</strong>
|
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Science 316: 370 only, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17446375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17446375</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17446375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.316.5823.370a" target="_blank">Full Text</a>]
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</p>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/07/2018
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/17/2013<br>Patricia A. Hartz - updated : 11/5/2012<br>Cassandra L. Kniffin - updated : 2/21/2011<br>Cassandra L. Kniffin - updated : 9/21/2010<br>Cassandra L. Kniffin - updated : 7/12/2010<br>Cassandra L. Kniffin - updated : 5/21/2009<br>George E. Tiller - updated : 11/19/2008<br>Cassandra L. Kniffin - updated : 7/8/2008<br>Ada Hamosh - updated : 5/30/2007<br>Patricia A. Hartz - updated : 12/18/2006<br>Cassandra L. Kniffin - updated : 9/5/2006<br>Patricia A. Hartz - updated : 8/16/2006<br>Ada Hamosh - updated : 8/7/2006<br>Victor A. McKusick - updated : 12/20/2005<br>Ada Hamosh - updated : 9/27/2005<br>Cassandra L. Kniffin - updated : 6/13/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Victor A. McKusick - updated : 12/12/2003<br>Victor A. McKusick - updated : 9/24/2002<br>Victor A. McKusick - updated : 3/12/2001
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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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 : 12/19/2000
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/08/2018
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 09/07/2018<br>carol : 05/15/2015<br>mcolton : 5/12/2015<br>carol : 3/5/2014<br>carol : 12/19/2013<br>ckniffin : 12/17/2013<br>carol : 9/16/2013<br>mgross : 11/7/2012<br>terry : 11/5/2012<br>wwang : 6/2/2011<br>carol : 3/10/2011<br>wwang : 3/2/2011<br>ckniffin : 2/21/2011<br>wwang : 9/21/2010<br>ckniffin : 9/21/2010<br>wwang : 7/14/2010<br>ckniffin : 7/12/2010<br>carol : 12/24/2009<br>wwang : 10/28/2009<br>ckniffin : 5/21/2009<br>wwang : 11/19/2008<br>wwang : 7/11/2008<br>ckniffin : 7/8/2008<br>alopez : 6/14/2007<br>terry : 5/30/2007<br>wwang : 12/21/2006<br>terry : 12/18/2006<br>wwang : 9/7/2006<br>ckniffin : 9/5/2006<br>mgross : 8/23/2006<br>terry : 8/16/2006<br>alopez : 8/9/2006<br>terry : 8/7/2006<br>carol : 1/3/2006<br>wwang : 1/3/2006<br>wwang : 12/28/2005<br>terry : 12/20/2005<br>alopez : 9/29/2005<br>terry : 9/27/2005<br>wwang : 6/16/2005<br>ckniffin : 6/13/2005<br>mgross : 1/10/2005<br>carol : 6/8/2004<br>carol : 6/8/2004<br>terry : 6/2/2004<br>cwells : 12/17/2003<br>terry : 12/12/2003<br>alopez : 9/24/2002<br>mgross : 8/6/2002<br>carol : 3/12/2001<br>terry : 3/12/2001<br>carol : 1/8/2001<br>carol : 12/19/2000
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605481
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<div>
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<h3>
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<span class="mim-font">
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ABNORMAL SPINDLE-LIKE, MICROCEPHALY-ASSOCIATED; ASPM
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</h3>
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</div>
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<div>
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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<div>
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<h4>
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<span class="mim-font">
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ASP, DROSOPHILA, HOMOLOG OF<br />
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MCPH5 GENE
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ASPM</em></strong>
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</span>
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</p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 1q31.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:197,084,127-197,146,669 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<td rowspan="1">
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<span class="mim-font">
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1q31.3
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<td>
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<span class="mim-font">
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Microcephaly 5, primary, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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608716
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<td>
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<span class="mim-font">
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Autosomal recessive
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</td>
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<td>
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<span class="mim-font">
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3
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<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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<span class="mim-font">
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<strong>Description</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ASPM gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. The mouse gene Aspm is expressed specifically in the primary sites of prenatal cerebral cortical neurogenesis (Bond et al., 2002). </p>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Bond et al. (2002) adopted a positional cloning strategy to identify the gene mutant in primary microcephaly-5 (MCPH5; 608716), an autosomal recessive form of primary microcephaly (MCPH) that maps to chromosome 1q31. They identified the ASPM gene within a 600-kb region defined by common haplotypes between families, and confirmed the predicted 10,434-bp open reading frame in overlapping segments of cDNA from fetal brain and colon. Northern blot analysis of mRNA from total mouse embryos showed high expression of an Aspm transcript of at least 9.5 kb between embryonic days (E) 11 to 17. In situ hybridization showed preferential expression during cerebral cortical neurogenesis, specifically in the cerebral cortical ventricular zone. Expression was also observed in the proliferative region of the medial and lateral ganglionic eminence and in the ventricular zone of the dorsal diencephalon. Aspm expression was quite intense at E14.5, when there are many progenitor cells in the cortical ventricular zone, but had decreased in intensity by E16.5. </p><p>Kouprina et al. (2005) demonstrated that ASPM was widely expressed in fetal and adult human tissues with lower levels in adult tissues. ASPM was upregulated in human ovarian and uterine cancer tissues. The predicted full-length protein contains 3,477 amino acids and has a calculated molecular mass of 410 kD. ASPM contains 2 conserved regions termed ASPM N-proximal (ASNP) repeats, and more than half of the protein consists of 81 C-terminal calmodulin-binding IQ motifs of variable length. Western blot analysis identified several predicted alternatively spliced ASPM variants with fewer IQ motifs. Immunostaining of cultured human cells revealed that ASPM was localized in the spindle poles during mitosis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Bond et al. (2002) noted that the predicted ASPM proteins encode systematically larger numbers of repeated 'IQ' domains between flies, mice, and humans, with the predominant difference between Aspm and ASPM being a single large insertion coding for IQ domains. One of the most notable trends in mammalian evolution is the massive increase in size of the cerebral cortex, especially in primates. The results of Bond et al. (2002) and evolutionary considerations suggest that brain size is controlled in part through modulation of mitotic spindle activity in neuronal progenitor cells. Humans with autosomal recessive primary microcephaly show a small but otherwise grossly normal cerebral cortex associated with mild to moderate mental retardation. Bond et al. (2002) suggested that genes linked to this condition offer potential insights into the development and evolution of the cerebral cortex. </p><p>Fish et al. (2006) found that Aspm was concentrated at mitotic spindle poles in mouse neuroepithelial cells, the primary stem and progenitor cells of the mammalian brain. Aspm expression was downregulated during the switch from proliferative to neurogenic cell divisions. Upon RNA interference in telencephalic neuroepithelial cells, Aspm mRNA was reduced, mitotic spindle poles lacked Aspm protein, and the cleavage plane was less frequently oriented perpendicular to the ventricular surface of the neuroepithelium. The alteration in the cleavage plane orientation increased the probability that the cells underwent asymmetric division, i.e., the apical plasma membrane was inherited by only 1 of the daughter cells. Concomitant with the resulting increase in abventricular cells in the ventricular zone, a large proportion of neuroepithelial cell progeny was found in the neuronal layer, implying a reduction in the number of neuroepithelial progenitor cells upon Aspm knockdown. Fish et al. (2006) concluded that ASPM is crucial for maintaining a cleavage plane orientation that allows symmetric, proliferative division of neuroepithelial cells during brain development. </p><p>Horvath et al. (2006) identified ASPM as a highly connected 'hub' gene within a module of mitosis/cell cycle genes that are coexpressed in glioblastoma and breast cancer. They demonstrated ASPM overexpression in glioblastoma compared to normal tissues. Aspm expression was also high in fetal murine neural stem/progenitor cells, and its expression decreased during differentiation. Knockdown of ASPM by small interfering RNA inhibited proliferation in both a human glioblastoma cell line and murine neural stem/progenitor cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</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>Bond et al. (2002) determined that the ASPM gene contains 28 exons and spans 62 kb of genomic sequence. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By positional cloning, Bond et al. (2002) identified the ASPM gene within the MCPH5 critical region on 1q31. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In each of 4 consanguineous northern Pakistani families with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found a homozygous truncating mutation in the ASPM gene (605481.0001). Bond et al. (2002) were unable to distinguish phenotypically between the 4 families in which these mutations were found. </p><p>Bond et al. (2003) performed a comprehensive mutation screen of the 10.4-kb ASPM gene, identifying 19 mutations in a cohort of 23 consanguineous families. The mutations occurred throughout the ASPM gene and were all predicted to be protein truncating. Phenotypic variation in the 51 affected individuals occurred in the degree of microcephaly (5 to 11 SDs below normal) and of mental retardation (mild to severe), but appeared to be independent of mutation position in the gene. </p><p>In affected members of 3 of 9 consanguineous Indian families with primary microcephaly, Kumar et al. (2004) identified 3 different truncating mutations in the ASPM gene (605481.0005-605481.0007). Kumar et al. (2004) stated that 24 mutations in the ASPM gene had been reported in families from Pakistan, Turkey, the Netherlands, Jordan, Saudi Arabia, Yemen, and India (their patients). </p><p>Shen et al. (2005) described a mutation (605481.0008) of the ASPM gene in affected members of a family in which epilepsy was associated with primary microcephaly. They suggested that a history of seizures should not preclude the diagnosis of primary microcephaly. </p><p>Gul et al. (2006) identified 6 different mutations in the ASPM gene in affected members of 9 unrelated consanguineous Pakistani families with primary microcephaly. </p><p>Desir et al. (2008) identified a homozygous mutation in the ASPM gene (605481.0009) in 2 sibs with MCPH5 (608716). Brain MRI showed a simplified gyral pattern. </p><p>Nicholas et al. (2009) sequenced the ASPM gene in 3 cohorts of microcephalic children. Pathogenic ASPM mutations were identified in 39% of 99 consanguineous MCPH families, and in 11 (40%) of 27 nonconsanguineous predominantly Caucasian families with a strict diagnosis of MCPH. In contrast, only 3 (7%) of 45 families with a less restricted phenotype, including microcephaly and mental retardation, had an ASPM mutation. Overall, the report identified 27 novel mutations in the ASPM gene, which almost doubled the number of MCPH-associated ASPM mutations. All but 1 of the mutations resulted in premature termination. There were no definitive missense mutations and no genotype/phenotype correlations. Nicholas et al. (2009) concluded that ASPM mutations are the most common cause of strict MCPH. </p><p>Passemard et al. (2009) identified homozygous or compound heterozygous mutations in the ASPM gene in 11 (22%) of 52 probands with MCPH. Sixteen novel mutations were identified, and all 18 mutations were truncating or nonsense mutations. The findings of this study expanded the phenotypic spectrum of MCPH5 to include a decrease in OFC with age and mild structural brain imaging anomalies, including simplified gyral pattern, enlarged ventricles, and partial agenesis of the corpus callosum. Two patients had evidence of cortical dysplasia. The anomalies found in these patients suggested that ASPM may be involved not only in mitosis control, but also as an accessory factor in other developmental processes such as migration and cortical layering. </p><p>Among 112 consanguineous Iranian families with primary microcephaly, Darvish et al. (2010) found that 13 (14.1%) showed linkage to the MCPH5 locus. However, homozygous mutations in the ASPM gene were found in only 11 of the families. One of the mutations had been previously reported by Nicholas et al. (2009), and 10 mutations were novel, 9 of which were predicted to result in a truncated protein. </p><p>Sajid Hussain et al. (2013) found linkage to 5 different MCPH disease loci in 34 of 57 consanguineous Pakistani families with autosomal recessive primary microcephaly. Pathogenic mutations were found in 27 of the 34 families. Eighteen families showed linkage to the ASPM gene, and pathogenic mutations were found in 17 families. ASPM was the most commonly mutated gene: the homozygous W1326X mutation (605481.0006) was present in 8 families, suggesting a founder effect. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</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>Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including ASPM, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development. </p><p>Mekel-Bobrov et al. (2005) showed that one genetic variant of ASPM in humans arose nearly about 5,800 years ago and has since swept to high frequency under strong positive selection. They sequenced the entire 62.1-kb genomic region of ASPM in samples from 90 ethnically diverse individuals obtained through the Coriell Institute and from a common chimpanzee. Mekel-Bobrov et al. (2005) showed that haplotype 63 had an unusually high frequency of 21%, whereas the other haplotypes ranged from 0.56 to 3.3%. Haplotype 63 differed consistently from the others at multiple polymorphic sites, 2 of which were nonsynonymous, both in exon 18, and are denoted A44871G and C45126A (the numbers indicate genetic positions from the start codon, and letters at the beginning and end indicate ancestral and derived alleles, respectively). These 2 sites reside in a region of open reading frame that was shown to have experienced particularly strong positive selection in the lineage leading to humans (Evans et al., 2004). These findings, especially the remarkably young age of the positively selected variant, suggested that the human brain is still undergoing rapid adaptive evolution. </p><p>Currat et al. (2006) commented on the paper by Mekel-Bobrov et al. (2005), stating that they had developed models of human history including both population growth and spatial structure that could generate the observed pattern of ASPM haplotypes without selection. Mekel-Bobrov et al. (2006) responded that the demographic models adopted by Currat et al. (2006) strongly contradicted a decade of empirical research on human demographic history and did not account for the critical features of the data on which Mekel-Bobrov et al. (2006) had developed their argument for selection. </p><p>Yu et al. (2007) did further studies based on the conclusions of Mekel-Bobrov et al. (2005). Yu et al. (2007) compared ASPM empirically to a large number of other loci and found that its variation is not unusual and does not support selection. </p><p>In a study of 5 independent population-based samples comprising 2,393 individuals, Mekel-Bobrov et al. (2007) did not find a detectable association between the recent adaptive evolution of either the ASPM or microcephalin (MCPH1; 607117) genes and normal variation in IQ. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Pulvers et al. (2010) developed a line of mice expressing truncated forms of Aspm similar to those causing microcephaly in humans. Heterozygous Aspm mutant mice were indistinguishable from wildtype, but homozygous Aspm mutant mice showed mild microcephaly associated with reduced relative brain weight and cortical thickness. Microcephaly in mutant mice appeared to be due to reduced neural stem cells, since cortical layering appeared normal. In embryonic day-11.5 telencephalon, mutant Aspm localized to spindle poles in metaphase, but it failed to localize to the midbody in telophase. Truncated Aspm proteins also caused massive loss of germ cells, resulting in reduced testis and ovary size accompanied by reduced fertility. </p><p>Johnson et al. (2018) used genome editing to create a germline knockout of Aspm in the ferret (Mustela putorius furo), a species with a larger, gyrified cortex and greater neural progenitor cell diversity than mice, and closer protein sequence homology to the human ASPM protein. Aspm knockout ferrets exhibit severe microcephaly (25 to 40% decreases in brain weight), reflecting reduced cortical surface area without significant change in cortical thickness, as has been found in human patients, suggesting that loss of 'cortical units' has occurred. The cortex of fetal Aspm knockout ferrets displayed a very large premature displacement of ventricular radial glial cells to the outer subventricular zone, where many resemble outer radial glia, a subtype of neural progenitor cells that are essentially absent in mice and have been implicated in cerebral cortical expansion in primates. These data suggested an evolutionary mechanism by which ASPM regulates cortical expansion by controlling the affinity of ventricular radial glial cells for the ventricular surface, thus modulating the ratio of ventricular radial glial cells, the most undifferentiated cell type, to outer radial glia, a more differentiated progenitor. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
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|
</span>
|
|
<strong>11 Selected Examples):</strong>
|
|
</span>
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</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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|
ASPM, 2-BP DEL, 719CT
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<br />
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SNP: rs199422135,
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gnomAD: rs199422135,
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ClinVar: RCV000005244
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</span>
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</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In a consanguineous northern Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) identified a homozygous 2-bp deletion in exon 3 of the ASPM gene, 719-720delCT, causing a frameshift leading to premature termination 15 codons downstream. </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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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
ASPM, 7-BP DEL, NT1258
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|
|
|
<br />
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|
|
|
SNP: rs199422139,
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|
|
|
|
|
ClinVar: RCV000020742
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found that affected members were homozygous for a 7-bp deletion of the ASPM gene, 1258-1264delTCTCAAG, in exon 3, causing a frameshift leading to premature termination 31 codons downstream. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ASPM, 7761T-G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs189678019,
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|
|
|
|
gnomAD: rs189678019,
|
|
|
|
|
|
ClinVar: RCV000005246
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found that affected individuals were homozygous for a nonsense mutation resulting from a 7761T-G transversion in exon 18 of the ASPM gene, producing immediate truncation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ASPM, 1-BP DEL, 9159A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs199422184,
|
|
|
|
|
|
gnomAD: rs199422184,
|
|
|
|
|
|
ClinVar: RCV000005247
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous Pakistani family with primary microcephaly-5 (MCPH5; 608716), Bond et al. (2002) found a 1-bp deletion, 9159delA, in exon 21 of the ASPM gene, causing a frameshift leading to premature termination 4 codons downstream. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ASPM, GLN3060TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852994,
|
|
|
|
|
|
gnomAD: rs137852994,
|
|
|
|
|
|
ClinVar: RCV000005248, RCV000214564, RCV001193347, RCV004955250
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with primary microcephaly-5 (MCPH5; 608716), Kumar et al. (2004) identified a homozygous 9178C-T transition in exon 21 of the ASPM gene, resulting in a gln3060-to-ter (Q3060X) substitution. The family was from southern India, and the parents were related. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ASPM, TRP1326TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852995,
|
|
|
|
|
|
gnomAD: rs137852995,
|
|
|
|
|
|
ClinVar: RCV000005249, RCV002512801
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a child with primary microcephaly-5 (MCPH5; 608716), born of consanguineous parents from southern India, Kumar et al. (2004) identified a homozygous 3978G-A transition in exon 17 of the ASPM gene, resulting in a trp1326-to-ter (W1326X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ASPM, ARG117TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852996,
|
|
|
|
|
|
gnomAD: rs137852996,
|
|
|
|
|
|
ClinVar: RCV000005250
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs with primary microcephaly-5 (MCPH5; 608716), born of consanguineous parents from southern India, Kumar et al. (2004) identified a homozygous 349C-T transition in the ASPM gene, resulting in an arg117-to-ter (R117X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
ASPM, TYR2063TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852997,
|
|
|
|
|
|
|
|
ClinVar: RCV000005251
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
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<p>In 3 sibs with primary microcephaly-5 (MCPH5; 608716) from a consanguineous family from Saudi Arabia, Shen et al. (2005) identified homozygosity for a 6189T-G transversion in exon 18 of the ASPM gene, resulting in a tyr2063-to-ter (Y2063X) substitution. Two of the sibs had seizures, whereas the other did not. </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>.0009 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</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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ASPM, 1-BP INS, 4195A
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<br />
|
|
|
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SNP: rs199422163,
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|
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gnomAD: rs199422163,
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|
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ClinVar: RCV000005252
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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 2 sibs, born of consanguineous Moroccan parents, with primary microcephaly-5 (MCPH5; 608716) and simplified gyration pattern on brain MRI, Desir et al. (2008) identified a homozygous 1-bp insertion (4195insA) in exon 18 of the ASPM gene, resulting in a frameshift and premature termination. The unaffected parents were heterozygous for the mutation. MRI in both patients showed that the simplified gyration was more severe in the anterior cortex. The data indicated that at least 1 form of primary microcephaly is allelic to a form of microcephaly with simplified gyral pattern (603802). However, Desir et al. (2008) noted that prenatal and postnatal brain imaging of patients with microcephaly has rarely been reported, suggesting that the 2 disorders may actually represent a phenotypic continuum. The findings also indicated that neuronal depletion of the ASPM gene predominantly affects the anterior cortex. </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>.0010 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</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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ASPM, ARG797TER
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<br />
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SNP: rs145489194,
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gnomAD: rs145489194,
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ClinVar: RCV000005253, RCV001851664
|
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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 of 5 sibs, born of consanguineous Algerian parents, with primary microcephaly-5 (MCPH5; 608716), Saadi et al. (2009) identified compound heterozygosity for 2 mutations in the ASPM gene: a 2389C-T transition in exon 6, resulting in an arg797-to-ter (R797X) substitution, and a 2-bp deletion in exon 18 (7781delAG; 605481.0011), resulting in a frameshift and premature termination. All 3 sibs had low to low-normal birth weight, variable speech impairment, and mental retardation. Brain MRI showed severe hypoplasia of the frontal lobes, moderate posterior parietal atrophy, an anterior orientation of the insula, a thick corpus callosum, and global gyral simplification. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MICROCEPHALY 5, PRIMARY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
ASPM, 2-BP DEL, 7781AG
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<br />
|
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|
|
SNP: rs199422173,
|
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|
|
gnomAD: rs199422173,
|
|
|
|
|
|
ClinVar: RCV000020796, RCV000365777, RCV000856804, RCV002513150, RCV003421927
|
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|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the 2-bp deletion in the ASPM gene (7781delAG) that was found in compound heterozygous state in sibs with primary microcephaly-5 (MCPH5; 608716) by Saadi et al. (2009), see 605481.0010. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
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<div>
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<p />
|
|
</div>
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<div>
|
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<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Bond, J., Roberts, E., Mochida, G. H., Hampshire, D. J., Scott, S., Askham, J. M., Springell, K., Mahadevan, M., Crow, Y. J., Markham, A. F., Walsh, C. A., Woods, C. G.
|
|
<strong>ASPM is a major determinant of cerebral cortical size.</strong>
|
|
Nature Genet. 32: 316-320, 2002.
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|
[PubMed: 12355089]
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[Full Text: https://doi.org/10.1038/ng995]
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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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|
Bond, J., Scott, S., Hampshire, D. J., Springell, K., Corry, P., Abramowicz, M. J., Mochida, G. H., Hennekam, R. C. M., Maher, E. R., Fryns, J.-P., Alswaid, A., Jafri, H., Rashid, Y., Mubaidin, A., Walsh, C. A., Roberts, E., Woods, C. G.
|
|
<strong>Protein-truncating mutations in ASPM cause variable reduction in brain size.</strong>
|
|
Am. J. Hum. Genet. 73: 1170-1177, 2003.
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[PubMed: 14574646]
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[Full Text: https://doi.org/10.1086/379085]
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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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|
Currat, M., Excoffier, L., Maddison, W., Otto, S. P., Ray, N., Whitlock, M. C., Yeaman, S.
|
|
<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
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|
Science 313: 172 only, 2006.
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[PubMed: 16840683]
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[Full Text: https://doi.org/10.1126/science.1122822]
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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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|
Darvish, H., Esmaeeli-Nieh, S., Monajemi, G. B., Mohseni, M., Ghasemi-Firouzabadi, S., Abedini, S. S., Bahman, I., Jamali, P., Azimi, S., Mojahedi, F., Dehghan, A., Shafeghati, Y., and 14 others.
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|
<strong>A clinical and molecular genetic study of 112 Iranian families with primary microcephaly.</strong>
|
|
J. Med. Genet. 47: 823-828, 2010. Note: Erratum: J. Med. Genet. 51: 70 only, 2014.
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[PubMed: 20978018]
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[Full Text: https://doi.org/10.1136/jmg.2009.076398]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Desir, J., Cassart, M., David, P., Van Bogaert, P., Abramowicz, M.
|
|
<strong>Primary microcephaly with ASPM mutation shows simplified cortical gyration with antero-posterior gradient pre- and post-natally.</strong>
|
|
Am. J. Med. Genet. 146A: 1439-1443, 2008.
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[PubMed: 18452193]
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[Full Text: https://doi.org/10.1002/ajmg.a.32312]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dorus, S., Vallender, E. J., Evans, P. D., Anderson, J. R., Gilbert, S. L., Mahowald, M., Wyckoff, G. J., Malcom, C. M., Lahn, B. T.
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|
<strong>Accelerated evolution of nervous system genes in the origin of Homo sapiens.</strong>
|
|
Cell 119: 1027-1040, 2004.
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[PubMed: 15620360]
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[Full Text: https://doi.org/10.1016/j.cell.2004.11.040]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Evans, P. D., Anderson, J. R., Vallender, E. J., Gilbert, S. L., Malcom, C. M., Dorus, S., Lahn, B. T.
|
|
<strong>Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans.</strong>
|
|
Hum. Molec. Genet. 13: 489-494, 2004.
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|
|
[PubMed: 14722158]
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[Full Text: https://doi.org/10.1093/hmg/ddh055]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fish, J. L., Kosodo, Y., Enard, W., Paabo, S., Huttner, W. B.
|
|
<strong>Aspm specifically maintains symmetric proliferative divisions of neuroepithelial cells.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 10438-10443, 2006.
|
|
|
|
|
|
[PubMed: 16798874]
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[Full Text: https://doi.org/10.1073/pnas.0604066103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gul, A., Hassan, M. J., Mahmood, S., Chen, W., Rahmani, S., Naseer, M. I., Dellefave, L., Muhammad, N., Rafiq, M. A., Ansar, M., Chishti, M. S., Ali, G., Siddique, T., Ahmad, W.
|
|
<strong>Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: novel sequence variants in ASPM gene.</strong>
|
|
Neurogenetics 7: 105-110, 2006.
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|
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|
|
|
[PubMed: 16673149]
|
|
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|
|
[Full Text: https://doi.org/10.1007/s10048-006-0042-4]
|
|
|
|
|
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Horvath, S., Zhang, B., Carlson, M., Lu, K. V., Zhu, S., Felciano, R. M., Laurance, M. F., Zhao, W., Qi, S., Chen, Z., Lee, Y., Scheck, A. C., Liau, L. M., Wu, H., Geschwind, D. H., Febbo, P. G., Kornblum, H. I., Cloughesy, T. F., Nelson, S. F., Mischel, P. S.
|
|
<strong>Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 17402-17407, 2006.
|
|
|
|
|
|
[PubMed: 17090670]
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|
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[Full Text: https://doi.org/10.1073/pnas.0608396103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Johnson, M. B., Sun, X., Kodani, A., Borges-Monroy, R., Girskis, K. M., Ryu, S. C., Wang, P. P., Patel, K., Gonzalez, D. M., Woo, Y. M., Yan, Z., Liang, B., and 13 others.
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<strong>Aspm knockout ferret reveals an evolutionary mechanism governing cerebral cortical size.</strong>
|
|
Nature 556: 370-375, 2018.
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[PubMed: 29643508]
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[Full Text: https://doi.org/10.1038/s41586-018-0035-0]
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kouprina, N., Pavlicek, A., Collins, N. K., Nakano, M., Noskov, V. N., Ohzeki, J.-I., Mochida, G. H., Risinger, J. I., Goldsmith, P., Gunsior, M., Solomon, G., Gersch, W., Kim, J.-H., Barrett, J. C., Walsh, C. A., Jurka, J., Masumoto, H., Larionov, V.
|
|
<strong>The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein.</strong>
|
|
Hum. Molec. Genet. 14: 2155-2165, 2005.
|
|
|
|
|
|
[PubMed: 15972725]
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|
|
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|
[Full Text: https://doi.org/10.1093/hmg/ddi220]
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|
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kumar, A., Blanton, S. H., Babu, M., Markandaya, M., Girimaji, S. C.
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|
<strong>Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations.</strong>
|
|
Clin. Genet. 66: 341-348, 2004.
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|
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[PubMed: 15355437]
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|
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|
[Full Text: https://doi.org/10.1111/j.1399-0004.2004.00304.x]
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|
|
|
|
</p>
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|
</li>
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<li>
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<p class="mim-text-font">
|
|
Mekel-Bobrov, N., Evans, P. D., Gilbert, S. L., Vallender, E. J., Hudson, R. R., Lahn, B. T.
|
|
<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens' and 'microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.' (Abstract)</strong>
|
|
Science 313: 172 only, 2006.
|
|
|
|
|
|
[PubMed: 16840683]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1122822]
|
|
|
|
|
|
</p>
|
|
</li>
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|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mekel-Bobrov, N., Gilbert, S. L., Evans, P. D., Vallender, E. J., Anderson, J. R., Hudson, R. R., Tishkoff, S. A., Lahn, B. T.
|
|
<strong>Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.</strong>
|
|
Science 309: 1720-1722, 2005.
|
|
|
|
|
|
[PubMed: 16151010]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1116815]
|
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|
|
|
</p>
|
|
</li>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Mekel-Bobrov, N., Posthuma, D., Gilbert, S. L., Lind, P., Gosso, M. F., Luciano, M., Harris, S. E., Bates, T. C., Polderman, T. J. C., Whalley, L. J., Fox, H., Starr, J. M., and 10 others.
|
|
<strong>The ongoing adaptive evolution of ASPM and microcephalin is not explained by increased intelligence.</strong>
|
|
Hum. Molec. Genet. 16: 600-608, 2007.
|
|
|
|
|
|
[PubMed: 17220170]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddl487]
|
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|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nicholas, A. K., Swanson, E. A., Cox, J. J., Karbani, G., Malik, S., Springell, K., Hampshire, D., Ahmed, M., Bond, J., Di Benedetto, D., Fichera, M., Romano, C., Dobyns, W. B., Woods, C. G.
|
|
<strong>The molecular landscape of ASPM mutations in primary microcephaly.</strong>
|
|
J. Med. Genet. 46: 249-253, 2009.
|
|
|
|
|
|
[PubMed: 19028728]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1136/jmg.2008.062380]
|
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Passemard, S., Titomanlio, L., Elmaleh, M., Afenjar, A., Alessandri, J.-L., Andria, G., Billette de Villemeur, T., Boespflug-Tanguy, O., Burglen, L., Del Giudice, E., Guimiot, F., Hyon, C., and 11 others.
|
|
<strong>Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.</strong>
|
|
Neurology 73: 962-969, 2009.
|
|
|
|
|
|
[PubMed: 19770472]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/WNL.0b013e3181b8799a]
|
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|
|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Pulvers, J. N., Bryk, J., Fish, J. L., Wilsch-Brauninger, M., Arai, Y., Schreier, D., Naumann, R., Helppi, J., Habermann, B., Vogt, J., Nitsch, R., Toth, A., Enard, W., Paabo, S., Huttner, W. B.
|
|
<strong>Mutations in mouse Aspm (abnormal spindle-like microcephaly associated) cause not only microcephaly but also major defects in the germline.</strong>
|
|
Proc. Nat. Acad. Sci. 107: 16595-16600, 2010.
|
|
|
|
|
|
[PubMed: 20823249]
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|
|
[Full Text: https://doi.org/10.1073/pnas.1010494107]
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|
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Saadi, A., Borck, G., Boddaert, N., Chekkour, M. C., Imessaoudene, B., Munnich, A., Colleaux, L., Chaouch, M.
|
|
<strong>Compound heterozygous ASPM mutations associated with microcephaly and simplified cortical gyration in a consanguineous Algerian family.</strong>
|
|
Europ. J. Med. Genet. 52: 180-184, 2009.
|
|
|
|
|
|
[PubMed: 19332161]
|
|
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|
|
[Full Text: https://doi.org/10.1016/j.ejmg.2009.03.013]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sajid Hussain, M., Marriam Bakhtiar, S., Farooq, M., Anjum, I., Janzen, E., Reza Toliat, M., Eiberg, H., Kjaer, K. W., Tommerup, N., Noegel, A. A., Nurnberg, P., Baig, S. M., Hansen, L.
|
|
<strong>Genetic heterogeneity in Pakistani microcephaly families.</strong>
|
|
Clin. Genet. 83: 446-451, 2013.
|
|
|
|
|
|
[PubMed: 22775483]
|
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|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2012.01932.x]
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Shen, J., Eyaid, W., Mochida, G. H., Al-Moayyad, F., Bodell, A., Woods, C. G., Walsh, C. A.
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<strong>ASPM mutation identified in patients with primary microcephaly and seizures. (Letter)</strong>
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J. Med. Genet. 42: 725-729, 2005.
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[PubMed: 16141009]
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[Full Text: https://doi.org/10.1136/jmg.2004.027706]
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Yu, F., Hill, R. S., Schaffner, S. F., Sabeti, P. C., Wang, E. T., Mignault, A. A., Ferland, R. J., Moyzis, R. K., Walsh, C. A., Reich, D.
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<strong>Comment on 'Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens.'</strong>
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Science 316: 370 only, 2007.
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[PubMed: 17446375]
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[Full Text: https://doi.org/10.1126/science.316.5823.370a]
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Ada Hamosh - updated : 09/07/2018<br>Cassandra L. Kniffin - updated : 12/17/2013<br>Patricia A. Hartz - updated : 11/5/2012<br>Cassandra L. Kniffin - updated : 2/21/2011<br>Cassandra L. Kniffin - updated : 9/21/2010<br>Cassandra L. Kniffin - updated : 7/12/2010<br>Cassandra L. Kniffin - updated : 5/21/2009<br>George E. Tiller - updated : 11/19/2008<br>Cassandra L. Kniffin - updated : 7/8/2008<br>Ada Hamosh - updated : 5/30/2007<br>Patricia A. Hartz - updated : 12/18/2006<br>Cassandra L. Kniffin - updated : 9/5/2006<br>Patricia A. Hartz - updated : 8/16/2006<br>Ada Hamosh - updated : 8/7/2006<br>Victor A. McKusick - updated : 12/20/2005<br>Ada Hamosh - updated : 9/27/2005<br>Cassandra L. Kniffin - updated : 6/13/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Victor A. McKusick - updated : 12/12/2003<br>Victor A. McKusick - updated : 9/24/2002<br>Victor A. McKusick - updated : 3/12/2001
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Victor A. McKusick : 12/19/2000
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