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- *601545 - PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE, ISOFORM 1B, ALPHA SUBUNIT; PAFAH1B1
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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">*601545</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="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/601545">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div 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=ENSG00000007168;t=ENST00000397195" 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=5048" 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=601545" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
|
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000007168;t=ENST00000397195" 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_000430,XM_011523901,XM_011523902,XM_011523903,XM_017024701,XM_017024703,XM_047436162,XM_047436163,XM_047436164" 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_000430" 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=601545" 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=03329&isoform_id=03329_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/PAFAH1B1" 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/349824,349826,349828,1170794,4557741,15217063,17056921,17056923,31874274,40352755,119610942,189053652,194375910,194381154,767992241,767992243,767992245,1034599946,1034599950,2217312198,2217312200,2217312203,2217494823,2462555629,2462555631,2462555633,2462555635,2462555637,2462555639,2462555641" 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/P43034" 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=5048" 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=ENSG00000007168;t=ENST00000397195" 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=PAFAH1B1" 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=PAFAH1B1" 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+5048" 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/PAFAH1B1" 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:5048" 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/5048" 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=chr17&hgg_gene=ENST00000397195.10&hgg_start=2593183&hgg_end=2685615&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:8574" 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://medlineplus.gov/genetics/gene/pafah1b1" 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=601545[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=601545[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/PAFAH1B1/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/ENSG00000007168" 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=PAFAH1B1" 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=PAFAH1B1" 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=PAFAH1B1" 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=PAFAH1B1&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/PA32905" 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:8574" 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/FBgn0015754.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:109520" 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/PAFAH1B1#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:109520" 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/5048/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5048" 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=WBGene00003047;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-040116-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5048" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=PAFAH1B1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 253147000<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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601545
|
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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>
|
|
<h3>
|
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<span class="mim-font">
|
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PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE, ISOFORM 1B, ALPHA SUBUNIT; PAFAH1B1
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
LIS1 GENE; LIS1
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PAFAH1B1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PAFAH1B1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/17/50?start=-3&limit=10&highlight=50">17p13.3</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:2593183-2685615&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'})">17:2,593,183-2,685,615</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/50?start=-3&limit=10&highlight=50">
|
|
17p13.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Lissencephaly 1
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607432"> 607432 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Subcortical laminar heterotopia
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/607432"> 607432 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p>Platelet-activating factor acetylhydrolase (PAFAH) catalyzes the removal of the acetyl group at the sn-2 position of the glycerol backbone of platelet-activating factor (PAF), producing biologically inactive lyso-PAF. Isoform 1B of PAFAH consists of 3 subunits: alpha (PAFAH1B1), beta (PAFAH1B2; <a href="/entry/602508">602508</a>), and gamma (PAFAH1B3; <a href="/entry/603074">603074</a>). The catalytic activity of the enzyme resides in the beta and gamma subunits, whereas the alpha subunit has regulatory activity (summary by <a href="#1" class="mim-tip-reference" title="Adachi, H., Tsujimoto, M., Hattori, M., Arai, H., Inoue, K. <strong>cDNA cloning of human cytosolic platelet-activating factor acetylhydrolase gamma-subunit and its mRNA expression in human tissues.</strong> Biochem. Biophys. Res. Commun. 214: 180-187, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7669037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7669037</a>] [<a href="https://doi.org/10.1006/bbrc.1995.2272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7669037">Adachi et al., 1995</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7669037" 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>The search for the gene involved in Miller-Dieker lissencephaly syndrome (MDLS; <a href="/entry/247200">247200</a>), a disorder of neural development characterized by agyria and facial abnormalities, and classic lissencephaly (type I, LIS1; <a href="/entry/601545">601545</a>), a disorder of isolated agyria, resulted in the identification and characterization of the PAFAH1B1 (LIS1) gene. <a href="#23" class="mim-tip-reference" title="Ledbetter, S. A., Kuwano, A., Dobyns, W. B., Ledbetter, D. H. <strong>Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly.</strong> Am. J. Hum. Genet. 50: 182-189, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1346078/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1346078</a>]" pmid="1346078">Ledbetter et al. (1992)</a> noted that about 90% of patients with MDLS have deletions of 17p13.3 and demonstrated that some patients with isolated lissencephaly had smaller deletions in that chromosomal region. <a href="#32" class="mim-tip-reference" title="Reiner, O., Carrozzo, R., Shen, Y., Wehnert, M., Faustinella, F., Dobyns, W. B., Caskey, C. T., Ledbetter, D. H. <strong>Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.</strong> Nature 364: 717-721, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355785</a>] [<a href="https://doi.org/10.1038/364717a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8355785">Reiner et al. (1993)</a> used degenerate PCR primers designed for conserved beta-transducin-like repeats to screen a human fetal brain cDNA library. Using the amplification product to screen the same library, they identified a cDNA encoding a deduced 411-amino acid protein with 8 WD40 repeats characteristic of heterotrimeric G proteins. Northern blot analysis of human tissues revealed transcripts of at least 4 different sizes (2.2-7.5 kb). Expression was detected in all tissues tested but was most pronounced in brain, heart, and skeletal muscle. After mapping the cDNA to chromosome 17p, <a href="#32" class="mim-tip-reference" title="Reiner, O., Carrozzo, R., Shen, Y., Wehnert, M., Faustinella, F., Dobyns, W. B., Caskey, C. T., Ledbetter, D. H. <strong>Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.</strong> Nature 364: 717-721, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355785</a>] [<a href="https://doi.org/10.1038/364717a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8355785">Reiner et al. (1993)</a> analyzed the cDNA in somatic cell hybrids containing chromosome 17 from patients with MDLS. Nonoverlapping deletions involving either the 5-prime or the 3-prime end of the gene were found in 2 MDLS patients, identifying the gene, which they called LIS1 (lissencephaly-1), as the disease gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8355785+1346078" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Neer, E. J., Schmidt, C. J., Smith, T. <strong>LIS is more.</strong> Nature Genet. 5: 3-4, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8220419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8220419</a>] [<a href="https://doi.org/10.1038/ng0993-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8220419">Neer et al. (1993)</a> commented on the nature of the LIS1 gene and the usefulness of identifying families of genes and the proteins they encode. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8220419" 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>Platelet-activating factor (PAF) is involved in a variety of biologic and pathologic processes (<a href="#15" class="mim-tip-reference" title="Hanahan, D. J. A. <strong>Platelet activating factor: a biologically active phosphoglyceride.</strong> Annu. Rev. Biochem. 55: 483-509, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3017194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3017194</a>] [<a href="https://doi.org/10.1146/annurev.bi.55.070186.002411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3017194">Hanahan, 1986</a>). PAF acetylhydrolase, which inactivates PAF by removing the acetyl group at the sn-2 position, is widely distributed in plasma and tissue cytosols. One isoform of PAF acetylhydrolase present in bovine brain cortex is a heterotrimer comprising subunits with relative molecular masses of 45, 30 (PAFAH1B2; <a href="/entry/602508">602508</a>), and 29 kD (PAFAH1B3; <a href="/entry/603074">603074</a>) (<a href="#17" class="mim-tip-reference" title="Hattori, M., Arai, H., Inoue, K. <strong>Purification and characterization of bovine brain platelet-activating factor acetylhydrolase.</strong> J. Biol. Chem. 268: 18748-18753, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8360169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8360169</a>]" pmid="8360169">Hattori et al., 1993</a>). <a href="#16" class="mim-tip-reference" title="Hattori, M., Adachi, H., Tsujimoto, M., Arai, H., Inoue, K. <strong>Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase.</strong> Nature 370: 216-218, 1994. Note: Erratum: Nature 370: 391 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8028668/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8028668</a>] [<a href="https://doi.org/10.1038/370216a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8028668">Hattori et al. (1994)</a> isolated the cDNA for the 45-kD subunit. Sequence analysis revealed 99% identity with the LIS1 gene, indicating that the LIS1 gene product is a human homolog of the 45-kD subunit of intracellular PAF acetylhydrolase. The results raised the possibility that PAF and PAF acetylhydrolase are important in the formation of the brain cortex during differentiation and development. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8028668+8360169+3017194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong> Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996."None>Chong et al. (1996)</a> and <a href="#26" class="mim-tip-reference" title="Lo Nigro, C., Chong, S. S., Smith, A. C. M., Dobyns, W. B., Carrozzo, R., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.</strong> Hum. Molec. Genet. 6: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063735</a>] [<a href="https://doi.org/10.1093/hmg/6.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063735">Lo Nigro et al. (1997)</a> characterized the LIS1 gene, demonstrating the presence of 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063735" 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="#9" class="mim-tip-reference" title="Chong, S. S., Pack, S. D., Roschke, A. V., Tanigami, A., Carrozzo, R., Smith, A. C. M., Dobyns, W. B., Ledbetter, D. H. <strong>A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3.</strong> Hum. Molec. Genet. 6: 147-155, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063734</a>] [<a href="https://doi.org/10.1093/hmg/6.2.147" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063734">Chong et al. (1997)</a> corrected the positioning of the 5-prime end of the LIS1 gene, constructed a genomic contig of approximately 500 kb encompassing LIS1, and estimated the LIS1 gene extent to be 80 kb. Fluorescence in situ hybridization (FISH) analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localized the lissencephaly minimal critical region to a 100-kb region centromeric to D17S379 and telomeric to D17S1566, within the LIS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Pseudogenes</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="Reiner, O., Bar-Am, I., Sapir, T., Shmueli, O., Carrozzo, R., Lindsay, E. A., Baldini, A., Ledbetter, D. H., Cahana, A. <strong>LIS2, gene and pseudogene, homologous to LIS1 (lissencephaly 1), located on the short and long arms of chromosome 2.</strong> Genomics 30: 251-256, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8586424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8586424</a>] [<a href="https://doi.org/10.1006/geno.1995.9880" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8586424">Reiner et al. (1995)</a> identified 2 genes on chromosome 2 showing high homology to the LIS1 gene. One, designated LIS2, at 2p was considered a potential candidate for a form of lissencephaly; the other, designated LIS2P, at 2q, was determined to be a pseudogene. By sequencing genomic clones that were mapped by means of 2p- and 2q-only hybrids, <a href="#13" class="mim-tip-reference" title="Fogli, A., Giglio, S., Arrigo, G., Lo Nigro, C., Zollo, M., Viggiano, L., Rocchi, M., Archidiacono, N., Zuffardi, O., Carrozzo, R. <strong>Identification of two paralogous regions mapping to the short and long arms of human chromosome 2 comprising LIS1 pseudogenes.</strong> Cytogenet. Cell Genet. 86: 225-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10575211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10575211</a>] [<a href="https://doi.org/10.1159/000015344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10575211">Fogli et al. (1999)</a> determined that both genes are LIS1 processed pseudogenes mapping to 2p11.2 (PAFAH1P1) and 2q13 (PAFAH1P2). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10575211+8586424" 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="#32" class="mim-tip-reference" title="Reiner, O., Carrozzo, R., Shen, Y., Wehnert, M., Faustinella, F., Dobyns, W. B., Caskey, C. T., Ledbetter, D. H. <strong>Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.</strong> Nature 364: 717-721, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8355785/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8355785</a>] [<a href="https://doi.org/10.1038/364717a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8355785">Reiner et al. (1993)</a> suggested that the LIS1 gene may be involved in a signal transduction pathway crucial for cerebral development. Since haploinsufficiency appears to lead to the lissencephaly syndrome, half the normal dosage of the gene product is apparently inadequate for normal development. They speculated that improper proportions of beta and gamma subunits of a G protein disturb formation of the normal protein complex, as in hemoglobin H disease, which is caused by an imbalance in the ratio of alpha- to beta-globin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8355785" 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="#37" class="mim-tip-reference" title="Smith, D. S., Niethammer, M., Ayala, R., Zhou, Y., Gambello, M. J., Wynshaw-Boris, A., Tsai, L.-H. <strong>Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1.</strong> Nature Cell Biol. 2: 767-775, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11056530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11056530</a>] [<a href="https://doi.org/10.1038/35041000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11056530">Smith et al. (2000)</a> showed that LIS1 in mammals is enriched in neurons relative to levels in other cell types, and that LIS1 interacts with the microtubule motor cytoplasmic dynein (see <a href="/entry/600112">600112</a>). Production of more LIS1 in nonneuronal cells increases retrograde movement of cytoplasmic dynein and leads to peripheral accumulation of microtubules. These changes may reflect neuron-like dynein behaviors induced by abundant LIS1. LIS1 deficiency produced the opposite phenotype. The results indicated that abundance of LIS1 in neurons may stimulate specific dynein functions that are involved in neuronal migration and axon growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11056530" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Caspi, M., Atlas, R., Kantor, A., Sapir, T., Reiner, O. <strong>Interaction between LIS1 and doublecortin, two lissencephaly gene products.</strong> Hum. Molec. Genet. 9: 2205-2213, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001923/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001923</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018911" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001923">Caspi et al. (2000)</a> demonstrated an interaction of LIS1 with doublecortin (DCX; <a href="/entry/300121">300121</a>) by coimmunoprecipitation, both in transiently transfected cells and in embryonic brain extracts. Immunofluorescence studies revealed that the 2 protein products colocalized in transfected cells and in primary neuronal cells. LIS1 and DCX enhanced tubulin polymerization in an additive fashion, as measured by a light-scattering assay in vitro. The authors hypothesized that the interaction of LIS1 and DCX is important to proper microtubule function in the developing cerebral cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001923" 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="Faulkner, N. E., Dujardin, D. L., Tai, C.-Y., Vaughan, K. T., O'Connell, C. B., Wang, Y., Vallee, R. B. <strong>A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function.</strong> Nature Cell Biol. 2: 784-791, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11056532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11056532</a>] [<a href="https://doi.org/10.1038/35041020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11056532">Faulkner et al. (2000)</a> showed that LIS1 protein coimmunoprecipitates with cytoplasmic dynein and dynactin (<a href="/entry/601143">601143</a>), and localizes to the cell cortex and to mitotic kinetochores, which are known sites for binding of cytoplasmic dynein. Overexpression of LIS1 in cultured mammalian cells interfered with mitotic progression and led to spindle misorientation. Injection of anti-LIS1 antibodies interfered with attachment of chromosomes to the metaphase plate, and led to chromosome loss. <a href="#12" class="mim-tip-reference" title="Faulkner, N. E., Dujardin, D. L., Tai, C.-Y., Vaughan, K. T., O'Connell, C. B., Wang, Y., Vallee, R. B. <strong>A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function.</strong> Nature Cell Biol. 2: 784-791, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11056532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11056532</a>] [<a href="https://doi.org/10.1038/35041020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11056532">Faulkner et al. (2000)</a> concluded that LIS1 participates in a subset of dynein functions and may regulate the division of neuronal progenitor cells in the developing brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11056532" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using database mining and protein structural prediction programs, <a href="#11" class="mim-tip-reference" title="Emes, R. D., Ponting, C. P. <strong>A new sequence motif linking lissencephaly, Treacher Collins and oral-facial-digital type 1 syndromes, microtubule dynamics and cell migration.</strong> Hum. Molec. Genet. 10: 2813-2820, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11734546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11734546</a>] [<a href="https://doi.org/10.1093/hmg/10.24.2813" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11734546">Emes and Ponting (2001)</a> identified a sequence motif in the products of genes mutated in MDLS, Treacher Collins syndrome (TCOF1, treacle; <a href="/entry/606847">606847</a>), oral-facial-digital syndrome type I (CXORF5; <a href="/entry/300170">300170</a>), and ocular albinism with late-onset sensorineural deafness (TBL1X; <a href="/entry/300196">300196</a>). Over 100 eukaryotic intracellular proteins were found to possess a LIS1 homology motif, including several katanin p60 (<a href="/entry/606696">606696</a>) subunits, muskelin (<a href="/entry/605623">605623</a>), Nopp140 (<a href="/entry/602394">602394</a>), the plant proteins tonneau and LEUNIG, slime mold protein aimless, and numerous WD repeat-containing beta-propeller proteins. The authors suggested that LIS1 homology motifs may contribute to the regulation of microtubule dynamics, either by mediating dimerization, or by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LIS1 homology motifs, and their occurrence in homologs of G-beta beta-propeller subunits, suggests that they are analogs of G-gamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LIS1 homology motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11734546" 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="Kitagawa, M., Umezu, M., Aoki, J., Koizumi, H., Arai, H., Inoue, K. <strong>Direct association of LIS1, the lissencephaly gene product, with a mammalian homologue of a fungal nuclear distribution protein, rNUDE.</strong> FEBS Lett. 479: 57-62, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10940388/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10940388</a>] [<a href="https://doi.org/10.1016/s0014-5793(00)01856-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10940388">Kitagawa et al. (2000)</a> found that rat Nude (NDE1; <a href="/entry/609449">609449</a>) and the catalytic subunits of Pafah interacted with Pafah1b1 in a competitive manner. They suggested that PAFAH1B1 functions in nuclear migration by interacting with multiple intracellular proteins, including NUDE. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10940388" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analysis of crystalline structures of murine proteins, <a href="#38" class="mim-tip-reference" title="Tarricone, C., Perrina, F., Monzani, S., Massimiliano, L., Kim, M.-H., Derewenda, Z. S., Knapp, S., Tsai, L.-H., Musacchio, A. <strong>Coupling PAF signaling to dynein regulation: structure of LIS1 in complex with PAF-acetylhydrolase.</strong> Neuron 44: 809-821, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15572112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15572112</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.11.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15572112">Tarricone et al. (2004)</a> determined that a Lis1 homodimer binds with either a homodimer of Pafah1b2 (<a href="/entry/602508">602508</a>) or Ndel1 (<a href="/entry/607538">607538</a>) to form a tetramer. Ndel1 competes with the Pafah1b2 homodimer for Lis1, but the interaction is complex and requires both the N- and C-terminal domains of Lis1. The data suggested that the Lis1 molecule undergoes major conformational changes when switching from a complex with the acetylhydrolase subunit to that with Ndel1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15572112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RNA interference (RNAi) with cultured cell lines and mouse embryonic day-15 cortical neurons, <a href="#35" class="mim-tip-reference" title="Shu, T., Ayala, R., Nguyen, M.-D., Xie, Z., Gleeson, J. G., Tsai, L.-H. <strong>Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning.</strong> Neuron 44: 263-277, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15473966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15473966</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.09.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15473966">Shu et al. (2004)</a> determined that Ndel1 regulates dynein activity by facilitating the interaction between Lis1 and dynein. Loss of Ndel1, Lis1, or dynein function in developing neocortex impaired neuronal positioning and caused the uncoupling of centrosomes and nuclei. Overexpression of Lis1 partially rescued the positioning defect caused by Ndel1 RNAi but not that caused by dynein RNAi, whereas overexpression of Ndel1 did not rescue the phenotype induced by Lis1 RNAi. <a href="#35" class="mim-tip-reference" title="Shu, T., Ayala, R., Nguyen, M.-D., Xie, Z., Gleeson, J. G., Tsai, L.-H. <strong>Ndel1 operates in a common pathway with LIS1 and cytoplasmic dynein to regulate cortical neuronal positioning.</strong> Neuron 44: 263-277, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15473966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15473966</a>] [<a href="https://doi.org/10.1016/j.neuron.2004.09.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15473966">Shu et al. (2004)</a> concluded that NDEL1 interacts with LIS1 to sustain the function of dynein, which in turn impacts microtubule organization, nuclear translocation, and neuronal positioning. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15473966" 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="#44" class="mim-tip-reference" title="Zhu, X.-J., Liu, X., Jin, Q., Cai, Y., Yang, Y., Zhou, T. <strong>The L279P mutation of nuclear distribution gene C (NudC) influences its chaperone activity and lissencephaly protein 1 (LIS1) stability.</strong> J. Biol. Chem. 285: 29903-29910, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20675372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20675372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20675372[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/10.1074/jbc.M110.105494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20675372">Zhu et al. (2010)</a> showed that NUDC (<a href="/entry/610325">610325</a>) and HSP90-alpha (HSP90AA1; <a href="/entry/140571">140571</a>) formed an ATPase-dependent chaperone complex with LIS1. An inactivating mutation in NUDC or pharmacologic inhibition of HSP90-alpha resulted in LIS1 destabilization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20675372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#8" class="mim-tip-reference" title="Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong> Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996."None>Chong et al. (1996)</a> performed SSCP analysis of individual exons in 19 patients with isolated lissencephaly sequence (LIS1; <a href="/entry/607432">607432</a>) who showed no deletions detectable by FISH. In 3 of these patients, point mutations were identified: an A-to-G transition in exon 6 resulting in a his149-to-arg missense mutation (<a href="#0001">601545.0001</a>), a C-to-T transition in exon 8 causing an arg247-to-ter nonsense mutation (<a href="/entry/610545#0002">610545.0002</a>), and a 22-bp deletion at the exon 9-intron 9 junction predicted to result in a splicing error (<a href="#0003">601545.0003</a>). <a href="#26" class="mim-tip-reference" title="Lo Nigro, C., Chong, S. S., Smith, A. C. M., Dobyns, W. B., Carrozzo, R., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.</strong> Hum. Molec. Genet. 6: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063735</a>] [<a href="https://doi.org/10.1093/hmg/6.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063735">Lo Nigro et al. (1997)</a> stated that these data confirmed mutations of LIS1 as the cause of the lissencephaly phenotype in LIS and in the Miller-Dieker syndrome. Together with the results of deletion analysis for other LIS and Miller-Dieker syndrome patients, these data were also consistent with the previous suggestion that additional genes distal to LIS1 are responsible for the facial dysmorphism and other anomalies in MDLS patients, thus supporting the original concept of MDLS as a contiguous gene deletion syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063735" 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="Kurahashi, H., Sakamoto, M., Ono, J., Honda, A., Okada, S., Nakamura, Y. <strong>Molecular cloning of the chromosomal breakpoint in the LIS1 gene of a patient with isolated lissencephaly and balanced t(8;17).</strong> Hum. Genet. 103: 189-192, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9760204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9760204</a>] [<a href="https://doi.org/10.1007/s004390050805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9760204">Kurahashi et al. (1998)</a> reported the case of a Japanese patient with isolated lissencephaly sequence who carried a balanced chromosomal translocation that disrupted the 5-prime untranslated region of the LIS1 gene. <a href="#34" class="mim-tip-reference" title="Sakamoto, M., Ono, J., Okada, S., Masuno, M., Nakamura, Y., Kurahashi, H. <strong>Alteration of the LIS1 gene in Japanese patients with isolated lissencephaly sequence or Miller-Dieker syndrome.</strong> Hum. Genet. 103: 586-589, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9860301/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9860301</a>] [<a href="https://doi.org/10.1007/s004390050873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9860301">Sakamoto et al. (1998)</a> examined the LIS1 gene in 8 additional Japanese LIS patients and 4 MDS patients. FISH analysis showed deletion of part of the LIS1 gene or of the chromosomal region surrounding it in 3 of the LIS cases and in 3 of the MDS cases. In 1 of the remaining 5 LIS cases, SSCP analysis and subsequent sequencing identified a 1-bp deletion in exon 4, which would be expected to result in premature termination of the gene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9860301+9760204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Cardoso, C., Leventer, R. J., Matsumoto, N., Kuc, J. A., Ramocki, M. B., Mewborn, S. K., Dudlicek, L. L., May, L. F., Mills, P. L., Das, S., Pilz, D. T., Dobyns, W. B., Ledbetter, D. H. <strong>The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene.</strong> Hum. Molec. Genet. 9: 3019-3028, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11115846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11115846</a>] [<a href="https://doi.org/10.1093/hmg/9.20.3019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11115846">Cardoso et al. (2000)</a> analyzed 29 nondeletion LIS patients carrying an LIS1 mutation and reported 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P less than 0.001). Using a spectrum of LIS patients, the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function was confirmed. The authors suggested that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes, and hypothesized that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11115846" 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="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> described in detail 5 patients with missense mutations in the LIS1 gene (<a href="#0001">601545.0001</a>, <a href="#0004">601545.0004</a>-<a href="#0007">601545.0007</a>) and noted that the mild and highly variable spectrum of cortical malformations and clinical sequelae are likely due to suboptimal function of a mutant LIS1 protein rather than to complete loss of function of the protein. The authors suggested that patients with LIS1 missense mutations are underrecognized and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than previously appreciated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502906" 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 an investigation of 220 children with lissencephaly or subcortical band heterotopia, <a href="#5" class="mim-tip-reference" title="Cardoso, C., Leventer, R. J., Dowling, J. J., Ward, H. L., Chung, J., Petras, K. S., Roseberry, J. A., Weiss, A. M., Das, S., Martin, C. L., Pilz, D. T., Dobyns, W. B., Ledbetter, D. H. <strong>Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1).</strong> Hum. Mutat. 19: 4-15, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11754098/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11754098</a>] [<a href="https://doi.org/10.1002/humu.10028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11754098">Cardoso et al. (2002)</a> found 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including 4 not previously reported. All intragenic mutations were de novo, and there were no familial recurrences. In 88% (36 of 41) of the mutations a truncated or internally deleted protein resulted; missense mutations were found in only 12% (5 of 41). Mutations occurred throughout the gene except for exon 7, with clustering of 3 of the 5 missense mutations in exon 6. Only 5 intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11754098" 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="#27" class="mim-tip-reference" title="Mei, D., Lewis, R., Parrini, E., Lazarou, L. P., Marini, C., Pilz, D. T., Guerrini, R. <strong>High frequency of genomic deletions--and a duplication --in the LIS1 gene in lissencephaly: implications for molecular diagnosis.</strong> J. Med. Genet. 45: 355-361, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285425</a>] [<a href="https://doi.org/10.1136/jmg.2007.056507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285425">Mei et al. (2008)</a> identified mutations in the LIS1 gene in 20 (44%) of 45 patients with isolated lissencephaly showing a posterior to anterior gradient. In 19 (76%) of 25 patients in whom FISH and direct sequencing had failed to detect mutations, MLPA analysis identified 18 small genomic deletions and 1 duplication. Overall, small genomic deletions/duplications represented 49% of all LIS1 alterations identified, and LIS1 involvement was demonstrated in 39 (87%) of 45 patients. Breakpoint characterization in 5 patients suggested that Alu-mediated recombination is a major molecular mechanism underlying LIS1 deletions. <a href="#27" class="mim-tip-reference" title="Mei, D., Lewis, R., Parrini, E., Lazarou, L. P., Marini, C., Pilz, D. T., Guerrini, R. <strong>High frequency of genomic deletions--and a duplication --in the LIS1 gene in lissencephaly: implications for molecular diagnosis.</strong> J. Med. Genet. 45: 355-361, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18285425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18285425</a>] [<a href="https://doi.org/10.1136/jmg.2007.056507" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18285425">Mei et al. (2008)</a> noted the high diagnostic yield with MLPA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18285425" 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 63 patients with posterior predominant lissencephaly, <a href="#33" class="mim-tip-reference" title="Saillour, Y., Carion, N., Quelin, C., Leger, P.-L., Boddaert, N., Elie, C., Toutain, A., Mercier, S., Barthez, M. A., Milh, M., Joriot, S., des Portes, V., and 11 others. <strong>LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity.</strong> Arch. Neurol. 66: 1007-1015, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19667223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19667223</a>] [<a href="https://doi.org/10.1001/archneurol.2009.149" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19667223">Saillour et al. (2009)</a> identified 40 with LIS1 gene defects. There were 8 small deletions and 31 heterozygous LIS1 mutations, including 12 nonsense, 8 frameshift, 6 missense, and 5 splicing defects. The mutations were found scattered throughout the gene, except in exons 3 and 9, and all were confirmed to be de novo. One patient had a somatic truncating mutation present in 30% of the blood, but other tissues were not available for testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19667223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using multiplex ligation-dependent probe amplification (MLPA) analysis, <a href="#18" class="mim-tip-reference" title="Haverfield, E. V., Whited, A. J., Petras, K. S., Dobyns, W. B., Das, S. <strong>Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia.</strong> Europ. J. Hum. Genet. 17: 911-918, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050731</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050731[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050731">Haverfield et al. (2009)</a> identified 12 deletions and 6 duplications involving the LIS1 gene in 18 (35%) of 52 patients with an anterior-to-posterior lissencephaly gradient in whom no molecular defect had previously been identified. The majority of patients with LIS1 deletions or duplications had grade 3 lissencephaly. Most deletions and duplications were scattered within the gene, but several deletions included genes flanking LIS1, such as HIC1 (<a href="/entry/603825">603825</a>), or only included noncoding putative upstream regulatory elements of LIS1. <a href="#18" class="mim-tip-reference" title="Haverfield, E. V., Whited, A. J., Petras, K. S., Dobyns, W. B., Das, S. <strong>Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia.</strong> Europ. J. Hum. Genet. 17: 911-918, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19050731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19050731</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19050731[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2008.213" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19050731">Haverfield et al. (2009)</a> suggested that genetic testing for isolated lissencephaly should include both mutation and deletion/duplication analysis of the LIS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19050731" 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="#20" class="mim-tip-reference" title="Jamuar, S. S., Lam, A. N., Kircher, M., D'Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., and 20 others. <strong>Somatic mutations in cerebral cortical malformations.</strong> New Eng. J. Med. 371: 733-743, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25140959/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25140959</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25140959[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/10.1056/NEJMoa1314432" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25140959">Jamuar et al. (2014)</a> used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. Eight of these individuals carried somatic mutations; 6 of these 8 individuals had double cortex syndrome (<a href="/entry/300067">300067</a>), with 3 of the 6 carrying mutations in DCX (<a href="/entry/300121">300121</a>) and the other 3 in LIS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25140959" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#40" class="mim-tip-reference" title="Uyanik, G., Morris-Rosendahl, D. J., Stiegler, J., Klapecki, J., Gross, C., Berman, Y., Martin, P., Dey, L., Spranger, S., Korenke, G. C., Schreyer, I., Hertzberg, C., and 25 others. <strong>Location and type of mutation in the LIS1 gene do not predict phenotypic severity.</strong> Neurology 69: 442-447, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17664403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17664403</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266629.98503.d0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17664403">Uyanik et al. (2007)</a> identified 14 novel and 7 previously described LIS1 mutations in 21 unrelated patients, including 18 with type 1 lissencephaly, 1 with subcortical band heterotopia, and 2 with lissencephaly with cerebellar hypoplasia. There were 9 truncating mutations, 6 splice site mutations, 5 missense mutations, and an in-frame deletion. Somatic mosaicism was assumed in 3 patients with partial subcortical band heterotopia or mild pachygyria. <a href="#40" class="mim-tip-reference" title="Uyanik, G., Morris-Rosendahl, D. J., Stiegler, J., Klapecki, J., Gross, C., Berman, Y., Martin, P., Dey, L., Spranger, S., Korenke, G. C., Schreyer, I., Hertzberg, C., and 25 others. <strong>Location and type of mutation in the LIS1 gene do not predict phenotypic severity.</strong> Neurology 69: 442-447, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17664403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17664403</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266629.98503.d0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17664403">Uyanik et al. (2007)</a> concluded that the severity of the phenotype is independent of the type of mutation and its site within the coding region of the LIS1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17664403" 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="Bi, W., Sapir, T., Shchelochkov, O. A., Zhang, F., Withers, M. A., Hunter, J. V., Levy, T., Shinder, V., Peiffer, D. A., Gunderson, K. L., Nezarati, M. M., Shotts, V. A., and 13 others. <strong>Increased LIS1 expression affects human and mouse brain development.</strong> Nature Genet. 41: 168-177, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136950">Bi et al. (2009)</a> reported 7 unrelated individuals with different submicroscopic duplications of chromosome 17p13.3 (<a href="/entry/613215">613215</a>) involving the LIS1 and/or the YWHAE (<a href="/entry/605066">605066</a>) gene. Four individuals had a duplication of YWHAE but not LIS1, and 1 had a duplication of LIS1 but not YWHAE. A sixth patient had a triplication of LIS1, and a seventh had duplication of both genes. Analysis of the clinical features for each individual indicated that individuals with LIS1 duplications had subtle brain defects, including microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay. Transgenic mice overexpressing Lis1 showed decreased brain size and distorted cellular organization in the ventricular zone. <a href="#3" class="mim-tip-reference" title="Bi, W., Sapir, T., Shchelochkov, O. A., Zhang, F., Withers, M. A., Hunter, J. V., Levy, T., Shinder, V., Peiffer, D. A., Gunderson, K. L., Nezarati, M. M., Shotts, V. A., and 13 others. <strong>Increased LIS1 expression affects human and mouse brain development.</strong> Nature Genet. 41: 168-177, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19136950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19136950</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19136950[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19136950">Bi et al. (2009)</a> concluded that variations in dosage of LIS1 play a role in the development of brain anomalies in humans and mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19136950" 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="#10" 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 PAFAH1B1, 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="#10" 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>
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<p>To understand further the function of platelet-activating factor acetylhydrolase, <a href="#19" class="mim-tip-reference" title="Hirotsune, S., Fleck, M. W., Gambello, M. J., Bix, G. J., Chen, A., Clark, G. D., Ledbetter, D. H., McBain, C. J., Wynshaw-Boris, A. <strong>Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality.</strong> Nature Genet. 19: 333-339, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9697693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9697693</a>] [<a href="https://doi.org/10.1038/1221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9697693">Hirotsune et al. (1998)</a> produced 3 different mutant alleles in the mouse Pafah1b1 gene. Homozygous-null mice died early in embryogenesis soon after implantation. Mice with 1 inactive allele displayed cortical, hippocampal, and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. Mice with further reduction of Pafah1b1 activity displayed more severe brain disorganization as well as cerebellar defects. The results demonstrated an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed were distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9697693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To study the function of the LIS1 gene, <a href="#4" class="mim-tip-reference" title="Cahana, A., Escamez, T., Nowakowski, R. S., Hayes, N. L., Giacobini, M., von Holst, A., Shmueli, O., Sapir, T., McConnell, S. K., Wurst, W., Martinez, S., Reiner, O. <strong>Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization.</strong> Proc. Nat. Acad. Sci. 98: 6429-6434, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11344260/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11344260</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11344260[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.101122598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11344260">Cahana et al. (2001)</a> deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein that initiated from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimicked a mutation described in 1 lissencephaly patient with a milder phenotype (<a href="#13" class="mim-tip-reference" title="Fogli, A., Giglio, S., Arrigo, G., Lo Nigro, C., Zollo, M., Viggiano, L., Rocchi, M., Archidiacono, N., Zuffardi, O., Carrozzo, R. <strong>Identification of two paralogous regions mapping to the short and long arms of human chromosome 2 comprising LIS1 pseudogenes.</strong> Cytogenet. Cell Genet. 86: 225-232, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10575211/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10575211</a>] [<a href="https://doi.org/10.1159/000015344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10575211">Fogli et al., 1999</a>). Homozygotes were early lethal, although heterozygotes were viable and fertile. The morphology of cortical neurons and radial glia was aberrant in the developing cortex, and the neurons migrated more slowly. This was the first demonstration of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalamocortical innervation were also abnormal. Biochemically, the mutant protein was not capable of dimerization, and enzymatic activity was elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of platelet-activating factor acetylhydrolase. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10575211+11344260" 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>Reduced LIS1 activity in both humans and mice results in a neuronal migration defect. <a href="#25" class="mim-tip-reference" title="Liu, Z., Steward, R., Luo, L. <strong>Drosophila Lis1 is required for neuroblast proliferation, dendritic elaboration and axonal transport.</strong> Nature Cell Biol. 2: 776-783, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11056531/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11056531</a>] [<a href="https://doi.org/10.1038/35041011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11056531">Liu et al. (2000)</a> showed that Drosophila Lis1 is highly expressed in the nervous system. It is, furthermore, essential for neuroblast proliferation and axonal transport, as shown by a mosaic analysis using a Lis1-null mutation. Analogous mosaic analysis showed that neurons containing a mutated cytoplasmic dynein heavy chain exhibited phenotypes similar to Lis1 mutants. These results implicated LIS1 as a regulator of the microtubule cytoskeleton and showed that it is important for diverse physiologic functions in the nervous system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11056531" 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="#43" class="mim-tip-reference" title="Yan, W., Assadi, A. H., Wynshaw-Boris, A., Eichele, G., Matzuk, M. M., Clark, G. D. <strong>Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis.</strong> Proc. Nat. Acad. Sci. 100: 7189-7194, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12775763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12775763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12775763[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.1236145100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12775763">Yan et al. (2003)</a> noted that PAF had been shown to affect sperm motility and acrosomal function, thereby altering fertility. PAFAH1B hydrolyzes PAF and is composed of 3 subunits--the LIS1 protein and PAFAH1B2 and PAFAH1B3, which they called alpha-2 and alpha-1, respectively--and structurally resembles a GTP-hydrolyzing protein. In addition to the brain, transcripts for LIS1, alpha-1, and alpha-2 are localized to meiotic and early haploid germ cells. <a href="#43" class="mim-tip-reference" title="Yan, W., Assadi, A. H., Wynshaw-Boris, A., Eichele, G., Matzuk, M. M., Clark, G. D. <strong>Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis.</strong> Proc. Nat. Acad. Sci. 100: 7189-7194, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12775763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12775763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12775763[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.1236145100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12775763">Yan et al. (2003)</a> disrupted the alpha-2 and alpha-1 genes in mice. Male mice homozygous-null for alpha-2 were infertile and spermatogenesis was disrupted at mid- or late pachytene stages of meiosis or early spermiogenesis. Whereas mice homozygous mutant for alpha-1 had normal fertility and normal spermatogenesis, those with disruption of both alpha-1 and alpha-2 manifested an earlier disturbance of spermatogenesis with an onset at preleptotene or leptotene stages of meiosis. Testicular Lis1 protein levels were upregulated in the alpha-2-null and alpha-1/alpha-2 double-null mice. Lowering Lis1 levels by inactivating 1 allele of Lis1 in alpha-2-null or alpha-1/alpha-2-null genetic backgrounds restored spermatogenesis and male fertility. The data provided evidence for unique roles of the PAFAH1B complex, particularly the LIS1 protein, in spermatogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12775763" 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="Assadi, A. H., Zhang, G., Beffert, U., McNeil, R. S., Renfro, A. L., Niu, S., Quattrocchi, C. C., Antalffy, B. A., Sheldon, M., Armstrong, D. D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G. D. <strong>Interaction of reelin signaling and Lis1 in brain development.</strong> Nature Genet. 35: 270-276, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14578885/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14578885</a>] [<a href="https://doi.org/10.1038/ng1257" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14578885">Assadi et al. (2003)</a> investigated interactions between the reelin (Reln; <a href="/entry/600514">600514</a>) signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous mutations in the Pafah1b1 gene had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. The Dab1 (<a href="/entry/603448">603448</a>) signaling molecule and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicated genetic and biochemical interaction between the reelin signaling pathway and LIS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14578885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Williams, S. N., Locke, C. J., Braden, A. L., Caldwell, K. A., Caldwell, G. A. <strong>Epileptic-like convulsions associated with LIS-1 in the cytoskeletal control of neurotransmitter signaling in Caenorhabditis elegans.</strong> Hum. Molec. Genet. 13: 2043-2059, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254012</a>] [<a href="https://doi.org/10.1093/hmg/ddh209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15254012">Williams et al. (2004)</a> showed that convulsions mimicking epilepsy can be induced by a mutation in a C. elegans lis1 allele (pnm1), in combination with a chemical antagonist of gamma-aminobutyric acid (GABA) neurotransmitter signaling. Identical convulsions were obtained using C. elegans mutants defective in GABA transmission, whereas mutations or GABA antagonist alone did not cause convulsions, indicating a threshold was exceeded in response to this combination. Crosses between pnm1 worms and fluorescent-marker strains, which are designed to exclusively illuminate either the processes of GABAergic neurons or synaptic vesicles, showed no deviations in neuronal architecture, but presynaptic defects in GABAergic vesicle distribution were clearly evident and could be phenocopied by RNAi directed against cytoplasmic dynein (see <a href="/entry/600112">600112</a>), a known LIS1 interactor. Mutations in unc104 (ATSV; <a href="/entry/601255">601255</a>) and snb1 (VAMP1; <a href="/entry/185880">185880</a>) exhibited similar convulsion phenotypes following chemical induction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15254012" 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>Interaction between Nde1 (<a href="/entry/609449">609449</a>) and Lis1 is critical in the development of the mouse central nervous system (CNS). <a href="#29" class="mim-tip-reference" title="Pawlisz, A. S., Mutch, C., Wynshaw-Boris, A., Chenn, A., Walsh, C. A., Feng, Y. <strong>Lis1-Nde1-dependent neuronal fate control determines cerebral cortical size and lamination.</strong> Hum. Molec. Genet. 17: 2441-2445, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18469343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18469343</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18469343[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18469343">Pawlisz et al. (2008)</a> analyzed a series of Nde1 and Lis1 double mutations in mice and showed that the Nde1-Lis1 complex was specifically required by the radial glial/neuroepithelial progenitor cells during CNS development. Besides mitotic spindle regulation, Lis1 and Nde1 maintained the morphology and lateral cell-cell contacts of progenitors in the cortical ventricular zone. This cell shape and organization control appeared necessary for symmetrical cell division and the self-renewal of neural progenitors during the early phase of corticogenesis. Loss of Lis1-Nde1 function led to dramatically increased neuronal differentiation at the onset of cortical neurogenesis, resulting in overproduction of the earliest-born preplate and Cajal-Retzius neurons, with consequent loss of the laminar pattern and over 80% mass and surface area of the cerebral cortex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18469343" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#42" class="mim-tip-reference" title="Yamada, M., Yoshida, Y., Mori, D., Takitoh, T., Kengaku, M., Umeshima, H., Takao, H., Miyakawa, T., Sato, M., Sorimachi, H., Wynshaw-Boris, A., Hirotsune, S. <strong>Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.</strong> Nature Med. 15: 1202-1207, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19734909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19734909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19734909[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19734909">Yamada et al. (2009)</a> demonstrated that inhibition or knockdown of calpains (see, e.g., CAPN1; <a href="/entry/114220">114220</a>) protected the Lis1 protein from proteolysis in Lis1 +/- mouse embryonic fibroblasts. Increased protein levels rescued the aberrant distribution of cytoplasmic dynein and mitochondria observed in Lis1 +/- cells, consistent with an improvement in function. Calpain inhibitors also improved neuronal migration of Lis1 +/- cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor to pregnant Lis1 +/- dams rescued apoptotic neuronal cell death and partially rescued neuronal migration defects in Lis1 +/- offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective cortical layering in Lis1+/- mice. <a href="#42" class="mim-tip-reference" title="Yamada, M., Yoshida, Y., Mori, D., Takitoh, T., Kengaku, M., Umeshima, H., Takao, H., Miyakawa, T., Sato, M., Sorimachi, H., Wynshaw-Boris, A., Hirotsune, S. <strong>Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.</strong> Nature Med. 15: 1202-1207, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19734909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19734909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19734909[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nm.2023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19734909">Yamada et al. (2009)</a> suggested that LIS1 is specifically degraded by calpain, and that calpain inhibition could be a potential therapeutic intervention for lissencephaly due to haploinsufficiency of LIS1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19734909" 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="#14" class="mim-tip-reference" title="Greenwood, J. S. F., Wang, Y., Estrada, R. C., Ackerman, L., Ohara, P. T., Baraban, S. C. <strong>Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice.</strong> Ann. Neurol. 66: 644-653, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19938147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19938147</a>] [<a href="https://doi.org/10.1002/ana.21775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19938147">Greenwood et al. (2009)</a> demonstrated that Lis1 +/- mice develop spontaneous seizures. Electrophysiologic studies on hippocampal slices derived from these mice had a nearly 2-fold increase in the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSC) associated with increased glutamate-mediated excitation without a change in receptor patterns. Electron microscopic analysis showed a large increase in presynaptic vesicle number, which corresponded with enhanced excitatory drive. Use of a nonspecific calcium channel blocker restored abnormal paired-pulse facilitation to normal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19938147" 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 patient with lissencephaly 1 (<a href="/entry/607432">607432</a>) in whom no deletions of 17p were detectable by FISH, <a href="#8" class="mim-tip-reference" title="Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong> Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996."None>Chong et al. (1996)</a> identified an A-to-G transition at nucleotide 446 in exon 6 of the PAFAH1B1 gene, resulting in a his149-to-arg substitution. See also <a href="#26" class="mim-tip-reference" title="Lo Nigro, C., Chong, S. S., Smith, A. C. M., Dobyns, W. B., Carrozzo, R., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.</strong> Hum. Molec. Genet. 6: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063735</a>] [<a href="https://doi.org/10.1093/hmg/6.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063735">Lo Nigro et al. (1997)</a>. <a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> described the patient reported by <a href="#8" class="mim-tip-reference" title="Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong> Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996."None>Chong et al. (1996)</a> in greater detail. From infancy, the patient showed developmental delay, myoclonic jerks and spasms, seizures, generalized hypotonia, microcephaly, and dysmorphic facies. Brain MRI revealed moderate agyria in the occipital lobes transitioning to pachygyria anteriorly as well as flattening of the corpus callosum and mild dilation of the posterior horns of the lateral ventricles. The patient developed progressive spasticity and died of sepsis at age 4 years. <a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> noted that this mutation interrupts a highly conserved invariant amino acid and is predicted to change the protein conformation significantly. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11502906+9063735" 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">rs121434483 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434483;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=rs121434483" 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=rs121434483" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with isolated lissencephaly sequence (<a href="/entry/607432">607432</a>) in whom no deletions of 17p were detectable by FISH, <a href="#8" class="mim-tip-reference" title="Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong> Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996."None>Chong et al. (1996)</a> identified a C-to-T transition at nucleotide 817 in exon 8 of the PAFAH1B1 gene, resulting in an arg273-to-ter mutation. See also <a href="#26" class="mim-tip-reference" title="Lo Nigro, C., Chong, S. S., Smith, A. C. M., Dobyns, W. B., Carrozzo, R., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.</strong> Hum. Molec. Genet. 6: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063735</a>] [<a href="https://doi.org/10.1093/hmg/6.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063735">Lo Nigro et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063735" 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">rs1567561137 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1567561137;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=rs1567561137" 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=rs1567561137" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with isolated lissencephaly sequence (<a href="/entry/607432">607432</a>) in whom no deletions of 17p were detectable by FISH, <a href="#8" class="mim-tip-reference" title="Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong> Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996."None>Chong et al. (1996)</a> identified a 22-bp deletion at the exon 9-intron 9 junction of the PAFAH1B1 gene from nucleotide 988 to 1002+7, predicted to result in a splicing error. <a href="#26" class="mim-tip-reference" title="Lo Nigro, C., Chong, S. S., Smith, A. C. M., Dobyns, W. B., Carrozzo, R., Ledbetter, D. H. <strong>Point mutations and an intragenic deletion in LIS1, the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome.</strong> Hum. Molec. Genet. 6: 157-164, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063735</a>] [<a href="https://doi.org/10.1093/hmg/6.2.157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063735">Lo Nigro et al. (1997)</a> noted that the deletion abolished amino acids 301 to 334 of the mature predicted protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063735" 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">rs121434484 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434484;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=rs121434484" 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=rs121434484" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a boy with subcortical band heterotopia (<a href="/entry/607432">607432</a>), <a href="#30" class="mim-tip-reference" title="Pilz, D. T., Kuc, J., Matsumoto, N., Bodurtha, J., Bernadi, B., Tassinari, C. A., Dobyns, W. B., Ledbetter, D. H. <strong>Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1.</strong> Hum. Molec. Genet. 8: 1757-1760, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441340</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441340">Pilz et al. (1999)</a> identified a T-to-C transition at nucleotide 499 in exon 6 of the PAFAH1B1 gene, resulting in a ser169-to-pro substitution. The mutation was not found in the boy's parents. <a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> described the boy reported by <a href="#30" class="mim-tip-reference" title="Pilz, D. T., Kuc, J., Matsumoto, N., Bodurtha, J., Bernadi, B., Tassinari, C. A., Dobyns, W. B., Ledbetter, D. H. <strong>Subcortical band heterotopia in rare affected males can be caused by missense mutations in DCX (XLIS) or LIS1.</strong> Hum. Molec. Genet. 8: 1757-1760, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441340/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441340</a>] [<a href="https://doi.org/10.1093/hmg/8.9.1757" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441340">Pilz et al. (1999)</a> in greater detail. As a child, he had mild global developmental delay and complex partial seizures. MRI showed posterior subcortical band heterotopia and mild dilation of the posterior horns of the lateral ventricles. At age 23 years, he worked as an unskilled manual laborer and enjoyed normal activities, although seizures remained a problem. <a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> suggested that the milder phenotype may be due to somatic mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11502906+10441340" 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">rs121434485 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434485;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=rs121434485" 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=rs121434485" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> reported a patient with generalized hypotonia and poor visual and social interaction who later developed complex partial seizures. MRI revealed moderate pachygyria, consistent with isolated lissencephaly sequence (<a href="/entry/607432">607432</a>), that was most severe in the parietooccipital regions, hypoplasia of the rostral corpus callosum, and mild dilation of the posterior horns of the lateral ventricles. Sequencing of the LIS1 gene showed a 949G-C mutation in exon 9, resulting in an asp317-to-his substitution. At age 4 years, the patient could feed himself and understand simple commands. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502906" 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">rs121434486 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434486;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=rs121434486" 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=rs121434486" 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=RCV000008545" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008545" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008545</a>
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<p><a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> reported a girl with isolated lissencephaly sequence (<a href="/entry/607432">607432</a>) who had global developmental delay and hypotonia and later developed myoclonic jerks, absence seizures, and febrile seizures. Brain MRI showed moderate generalized pachygyria that was most severe in the occipitoparietal regions, hypoplasia of the cerebellar vermis, hypoplasia of the rostral corpus callosum, and mild dilation of the lateral ventricles. Sequencing of the LIS1 gene showed a 92T-C change in exon 3, resulting in a phe31-to-ser substitution, in the N-terminal region outside of the WD repeats which confer correct protein structure and folding. At age 12 years, she walked with assistance, was toilet-trained, and had limited communication skills. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 LISSENCEPHALY 1</strong>
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PAFAH1B1, GLY162SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434487 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434487;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=rs121434487" 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=rs121434487" 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=RCV000008546 OR RCV003555976" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008546, RCV003555976" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008546...</a>
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<p><a href="#24" class="mim-tip-reference" title="Leventer, R. J., Cardoso, C., Ledbetter, D. H., Dobyns, W. B. <strong>LIS1 missense mutations cause milder lissencephaly phenotypes including a child with normal IQ.</strong> Neurology 57: 416-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11502906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11502906</a>] [<a href="https://doi.org/10.1212/wnl.57.3.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11502906">Leventer et al. (2001)</a> reported a boy with speech and walking delay and strabismus who later developed complex partial seizures. Brain MRI showed moderate pachygyria restricted to the occipital and posterior parietal lobes, consistent with isolated lissencephaly sequence (<a href="/entry/607432">607432</a>). Sequencing of the LIS1 gene showed a 484G-A transition in exon 6, resulting in a gly162-to-ser substitution. At age 6 years, the boy attended a developmental preschool, played sports, and was found to have an IQ of 100. The authors noted that this amino acid change has been found as a variant in other WD proteins, which may explain the mild LIS1 phenotype in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11502906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 SUBCORTICAL LAMINAR HETEROTOPIA</strong>
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PAFAH1B1, ARG241PRO
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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> rs121434488 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434488;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/rs121434488?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=rs121434488" 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=rs121434488" 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=RCV000008547 OR RCV001851740" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008547, RCV001851740" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008547...</a>
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<p>In a male patient with subcortical band heterotopia (<a href="/entry/607432">607432</a>), <a href="#36" class="mim-tip-reference" title="Sicca, F., Kelemen, A., Genton, P., Das, S., Mei, D., Moro, F., Dobyns, W. B., Guerrini, R. <strong>Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.</strong> Neurology 61: 1042-1046, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14581661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14581661</a>] [<a href="https://doi.org/10.1212/wnl.61.8.1042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14581661">Sicca et al. (2003)</a> identified somatic mosaicism for a 722G-C transversion in exon 8 of the LIS1 gene, resulting in an arg241-to-pro (R241P) substitution. The mutant allele was present in 18% of lymphocyte DNA and 21% of hair root DNA. The patient had delayed language and motor development as a child, and later showed severe mental retardation, spasticity, and seizures. Brain MRI showed subcortical band heterotopia in posterior regions. <a href="#36" class="mim-tip-reference" title="Sicca, F., Kelemen, A., Genton, P., Das, S., Mei, D., Moro, F., Dobyns, W. B., Guerrini, R. <strong>Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.</strong> Neurology 61: 1042-1046, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14581661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14581661</a>] [<a href="https://doi.org/10.1212/wnl.61.8.1042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14581661">Sicca et al. (2003)</a> noted that the patient had a less severe phenotype than those with lissencephaly, likely due to the somatic mosaicism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14581661" 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="0009" class="mim-anchor"></a>
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<strong>.0009 SUBCORTICAL LAMINAR HETEROTOPIA</strong>
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LISSENCEPHALY 1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434489 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434489;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=rs121434489" 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=rs121434489" 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=RCV000008548 OR RCV000008549 OR RCV001255338 OR RCV001291182 OR RCV001851741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008548, RCV000008549, RCV001255338, RCV001291182, RCV001851741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008548...</a>
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<p>In a male patient with subcortical laminar heterotopia (<a href="/entry/607432">607432</a>), <a href="#36" class="mim-tip-reference" title="Sicca, F., Kelemen, A., Genton, P., Das, S., Mei, D., Moro, F., Dobyns, W. B., Guerrini, R. <strong>Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.</strong> Neurology 61: 1042-1046, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14581661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14581661</a>] [<a href="https://doi.org/10.1212/wnl.61.8.1042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14581661">Sicca et al. (2003)</a> identified somatic mosaicism for a 22C-T transition in exon 2 of the LIS1 gene, resulting in an arg8-to-ter (R8X) mutation. The mutant allele was present in 24% of lymphocyte DNA and 31% of hair root DNA. The patient had seizures and mild mental retardation as well as posterior subcortical laminar heterotopia. The phenotype was relatively mild compared to full-blown lissencephaly. In a male patient with lissencephaly, <a href="#36" class="mim-tip-reference" title="Sicca, F., Kelemen, A., Genton, P., Das, S., Mei, D., Moro, F., Dobyns, W. B., Guerrini, R. <strong>Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.</strong> Neurology 61: 1042-1046, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14581661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14581661</a>] [<a href="https://doi.org/10.1212/wnl.61.8.1042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14581661">Sicca et al. (2003)</a> identified the R8X mutation. The patient did not show somatic mosaicism and had a very severe phenotype. The authors noted that these examples suggested that somatic mosaicism results in a less severe phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14581661" 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 LISSENCEPHALY 1</strong>
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PAFAH1B1, HIS277PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434490 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434490;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=rs121434490" 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=rs121434490" 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=RCV000008550" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008550" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008550</a>
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<p>In a patient with a severe form of isolated lissencephaly sequence (<a href="/entry/607432">607432</a>), <a href="#39" class="mim-tip-reference" title="Torres, F. R., Montenegro, M. A., Marques-de-Faria, A. P., Guerreiro, M. M., Cendes, F., Lopes-Cendes, I. <strong>Mutation screening in a cohort of patients with lissencephaly and subcortical band heterotopia.</strong> Neurology 62: 799-802, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15007136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15007136</a>] [<a href="https://doi.org/10.1212/01.wnl.0000113725.46254.fd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15007136">Torres et al. (2004)</a> identified a 1385A-C transversion in the LIS1 gene, resulting in a his277-to-pro (H277P) substitution in the fifth WD-40 domain of the protein. Sequence alignment showed that the mutated histidine is a conserved amino acid in different organisms, but not when compared to different proteins with WD domains. The authors emphasized that missense mutations in LIS1 are not always associated with milder phenotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15007136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1038/ng.302" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.101122598" target="_blank">Full Text</a>]
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Cardoso, C., Leventer, R. J., Dowling, J. J., Ward, H. L., Chung, J., Petras, K. S., Roseberry, J. A., Weiss, A. M., Das, S., Martin, C. L., Pilz, D. T., Dobyns, W. B., Ledbetter, D. H.
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Cardoso, C., Leventer, R. J., Matsumoto, N., Kuc, J. A., Ramocki, M. B., Mewborn, S. K., Dudlicek, L. L., May, L. F., Mills, P. L., Das, S., Pilz, D. T., Dobyns, W. B., Ledbetter, D. H.
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[<a href="https://doi.org/10.1093/hmg/9.20.3019" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/6.2.147" 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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[<a href="https://doi.org/10.1093/hmg/10.24.2813" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11056532/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11056532</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11056532" 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/10.1038/35041020" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19938147/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19938147</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19938147" 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/10.1038/364717a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/archneurol.2009.149" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s004390050873" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2004.09.030" target="_blank">Full Text</a>]
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<strong>Mosaic mutations of the LIS1 gene cause subcortical band heterotopia.</strong>
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[<a href="https://doi.org/10.1212/wnl.61.8.1042" target="_blank">Full Text</a>]
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Smith, D. S., Niethammer, M., Ayala, R., Zhou, Y., Gambello, M. J., Wynshaw-Boris, A., Tsai, L.-H.
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<strong>Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11056530/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11056530</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11056530" 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/10.1038/35041000" target="_blank">Full Text</a>]
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<strong>Coupling PAF signaling to dynein regulation: structure of LIS1 in complex with PAF-acetylhydrolase.</strong>
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Neuron 44: 809-821, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15572112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15572112</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15572112" 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.neuron.2004.11.019" target="_blank">Full Text</a>]
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<strong>Mutation screening in a cohort of patients with lissencephaly and subcortical band heterotopia.</strong>
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Neurology 62: 799-802, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15007136/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15007136</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15007136" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000113725.46254.fd" target="_blank">Full Text</a>]
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Uyanik, G., Morris-Rosendahl, D. J., Stiegler, J., Klapecki, J., Gross, C., Berman, Y., Martin, P., Dey, L., Spranger, S., Korenke, G. C., Schreyer, I., Hertzberg, C., and 25 others.
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<strong>Location and type of mutation in the LIS1 gene do not predict phenotypic severity.</strong>
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Neurology 69: 442-447, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17664403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17664403</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17664403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000266629.98503.d0" target="_blank">Full Text</a>]
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Williams, S. N., Locke, C. J., Braden, A. L., Caldwell, K. A., Caldwell, G. A.
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<strong>Epileptic-like convulsions associated with LIS-1 in the cytoskeletal control of neurotransmitter signaling in Caenorhabditis elegans.</strong>
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Hum. Molec. Genet. 13: 2043-2059, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15254012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15254012</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15254012" 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/ddh209" target="_blank">Full Text</a>]
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Yamada, M., Yoshida, Y., Mori, D., Takitoh, T., Kengaku, M., Umeshima, H., Takao, H., Miyakawa, T., Sato, M., Sorimachi, H., Wynshaw-Boris, A., Hirotsune, S.
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<strong>Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly.</strong>
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Nature Med. 15: 1202-1207, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19734909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19734909</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19734909[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=19734909" 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/nm.2023" target="_blank">Full Text</a>]
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<strong>Previously uncharacterized roles of platelet-activating factor acetylhydrolase 1b complex in mouse spermatogenesis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12775763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12775763</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12775763[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=12775763" 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.1236145100" target="_blank">Full Text</a>]
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Zhu, X.-J., Liu, X., Jin, Q., Cai, Y., Yang, Y., Zhou, T.
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<strong>The L279P mutation of nuclear distribution gene C (NudC) influences its chaperone activity and lissencephaly protein 1 (LIS1) stability.</strong>
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J. Biol. Chem. 285: 29903-29910, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20675372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20675372</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20675372[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=20675372" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M110.105494" target="_blank">Full Text</a>]
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Ada Hamosh - updated : 09/02/2014
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Patricia A. Hartz - updated : 2/10/2012<br>Cassandra L. Kniffin - updated : 1/28/2011<br>Cassandra L. Kniffin - updated : 7/19/2010<br>Cassandra L. Kniffin - updated : 11/18/2009<br>Patricia A. Hartz - updated : 11/3/2009<br>Cassandra L. Kniffin - updated : 3/10/2009<br>Cassandra L. Kniffin - updated : 10/2/2008<br>Cassandra L. Kniffin - updated : 11/26/2007<br>George E. Tiller - updated : 3/21/2007<br>Patricia A. Hartz - updated : 6/28/2005<br>Patricia A. Hartz - updated : 5/16/2005<br>Cassandra L. Kniffin - updated : 4/5/2005<br>Stylianos E. Antonarakis - updated : 1/10/2005<br>Cassandra L. Kniffin - updated : 9/15/2004<br>Cassandra L. Kniffin - updated : 1/22/2004<br>Victor A. McKusick - updated : 7/14/2003<br>Cassandra L. Kniffin - reorganized : 1/3/2003<br>Cassandra L. Kniffin - updated : 12/10/2002<br>George E. Tiller - updated : 6/11/2002<br>Victor A. McKusick - updated : 1/15/2002<br>Victor A. McKusick - updated : 6/27/2001<br>Carol A. Bocchini - updated : 3/14/2001<br>George E. Tiller - updated : 3/5/2001<br>Victor A. McKusick - updated : 1/12/2001<br>George E. Tiller - updated : 12/14/2000<br>Victor A. McKusick - updated : 10/13/1999<br>Victor A. McKusick - updated : 12/10/1998<br>Victor A. McKusick - updated : 7/27/1998<br>Victor A. McKusick - updated : 4/15/1997<br>Victor A. McKusick - updated : 2/25/1997
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Victor A. McKusick : 12/2/1996
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alopez : 09/02/2014<br>alopez : 3/21/2013<br>mgross : 2/22/2012<br>terry : 2/10/2012<br>wwang : 2/17/2011<br>ckniffin : 1/28/2011<br>wwang : 7/20/2010<br>ckniffin : 7/19/2010<br>carol : 1/12/2010<br>ckniffin : 1/12/2010<br>wwang : 12/1/2009<br>ckniffin : 11/18/2009<br>mgross : 11/3/2009<br>alopez : 3/11/2009<br>ckniffin : 3/10/2009<br>wwang : 10/8/2008<br>ckniffin : 10/2/2008<br>carol : 7/8/2008<br>wwang : 12/14/2007<br>ckniffin : 11/26/2007<br>ckniffin : 11/19/2007<br>wwang : 3/23/2007<br>terry : 3/21/2007<br>mgross : 6/28/2005<br>wwang : 5/20/2005<br>wwang : 5/16/2005<br>terry : 4/5/2005<br>ckniffin : 4/5/2005<br>mgross : 1/10/2005<br>tkritzer : 9/17/2004<br>ckniffin : 9/15/2004<br>tkritzer : 2/10/2004<br>ckniffin : 1/22/2004<br>tkritzer : 11/3/2003<br>tkritzer : 7/23/2003<br>terry : 7/14/2003<br>carol : 1/3/2003<br>ckniffin : 12/27/2002<br>carol : 12/12/2002<br>ckniffin : 12/10/2002<br>cwells : 6/12/2002<br>cwells : 6/11/2002<br>carol : 1/22/2002<br>carol : 1/19/2002<br>mcapotos : 1/16/2002<br>terry : 1/15/2002<br>cwells : 7/12/2001<br>cwells : 7/6/2001<br>terry : 6/27/2001<br>mcapotos : 3/15/2001<br>carol : 3/14/2001<br>cwells : 3/6/2001<br>cwells : 3/5/2001<br>cwells : 3/2/2001<br>cwells : 1/18/2001<br>terry : 1/12/2001<br>carol : 12/23/2000<br>terry : 12/14/2000<br>terry : 12/14/2000<br>carol : 11/1/1999<br>mgross : 10/20/1999<br>mgross : 10/20/1999<br>mgross : 10/19/1999<br>terry : 10/13/1999<br>mgross : 3/17/1999<br>mgross : 3/16/1999<br>carol : 1/25/1999<br>carol : 12/15/1998<br>dkim : 12/15/1998<br>terry : 12/10/1998<br>psherman : 10/1/1998<br>carol : 8/19/1998<br>alopez : 7/31/1998<br>alopez : 7/30/1998<br>alopez : 7/30/1998<br>terry : 7/27/1998<br>dkim : 7/23/1998<br>dholmes : 4/16/1998<br>dholmes : 4/16/1998<br>dholmes : 3/17/1998<br>dholmes : 2/19/1998<br>terry : 7/8/1997<br>jenny : 4/15/1997<br>terry : 4/4/1997<br>mark : 2/25/1997<br>terry : 2/24/1997<br>mark : 12/4/1996
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<span class="mim-font">
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<strong>*</strong> 601545
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<h3>
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PLATELET-ACTIVATING FACTOR ACETYLHYDROLASE, ISOFORM 1B, ALPHA SUBUNIT; PAFAH1B1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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LIS1 GENE; LIS1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PAFAH1B1</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 253147000;
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Cytogenetic location: 17p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:2,593,183-2,685,615 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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17p13.3
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Lissencephaly 1
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607432
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Autosomal dominant
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3
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Subcortical laminar heterotopia
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607432
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Platelet-activating factor acetylhydrolase (PAFAH) catalyzes the removal of the acetyl group at the sn-2 position of the glycerol backbone of platelet-activating factor (PAF), producing biologically inactive lyso-PAF. Isoform 1B of PAFAH consists of 3 subunits: alpha (PAFAH1B1), beta (PAFAH1B2; 602508), and gamma (PAFAH1B3; 603074). The catalytic activity of the enzyme resides in the beta and gamma subunits, whereas the alpha subunit has regulatory activity (summary by Adachi et al., 1995). </p>
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<strong>Cloning and Expression</strong>
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<p>The search for the gene involved in Miller-Dieker lissencephaly syndrome (MDLS; 247200), a disorder of neural development characterized by agyria and facial abnormalities, and classic lissencephaly (type I, LIS1; 601545), a disorder of isolated agyria, resulted in the identification and characterization of the PAFAH1B1 (LIS1) gene. Ledbetter et al. (1992) noted that about 90% of patients with MDLS have deletions of 17p13.3 and demonstrated that some patients with isolated lissencephaly had smaller deletions in that chromosomal region. Reiner et al. (1993) used degenerate PCR primers designed for conserved beta-transducin-like repeats to screen a human fetal brain cDNA library. Using the amplification product to screen the same library, they identified a cDNA encoding a deduced 411-amino acid protein with 8 WD40 repeats characteristic of heterotrimeric G proteins. Northern blot analysis of human tissues revealed transcripts of at least 4 different sizes (2.2-7.5 kb). Expression was detected in all tissues tested but was most pronounced in brain, heart, and skeletal muscle. After mapping the cDNA to chromosome 17p, Reiner et al. (1993) analyzed the cDNA in somatic cell hybrids containing chromosome 17 from patients with MDLS. Nonoverlapping deletions involving either the 5-prime or the 3-prime end of the gene were found in 2 MDLS patients, identifying the gene, which they called LIS1 (lissencephaly-1), as the disease gene. </p><p>Neer et al. (1993) commented on the nature of the LIS1 gene and the usefulness of identifying families of genes and the proteins they encode. </p><p>Platelet-activating factor (PAF) is involved in a variety of biologic and pathologic processes (Hanahan, 1986). PAF acetylhydrolase, which inactivates PAF by removing the acetyl group at the sn-2 position, is widely distributed in plasma and tissue cytosols. One isoform of PAF acetylhydrolase present in bovine brain cortex is a heterotrimer comprising subunits with relative molecular masses of 45, 30 (PAFAH1B2; 602508), and 29 kD (PAFAH1B3; 603074) (Hattori et al., 1993). Hattori et al. (1994) isolated the cDNA for the 45-kD subunit. Sequence analysis revealed 99% identity with the LIS1 gene, indicating that the LIS1 gene product is a human homolog of the 45-kD subunit of intracellular PAF acetylhydrolase. The results raised the possibility that PAF and PAF acetylhydrolase are important in the formation of the brain cortex during differentiation and development. </p>
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<strong>Gene Structure</strong>
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<p>Chong et al. (1996) and Lo Nigro et al. (1997) characterized the LIS1 gene, demonstrating the presence of 11 exons. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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<p>Chong et al. (1997) corrected the positioning of the 5-prime end of the LIS1 gene, constructed a genomic contig of approximately 500 kb encompassing LIS1, and estimated the LIS1 gene extent to be 80 kb. Fluorescence in situ hybridization (FISH) analysis of an ILS patient with a de novo balanced translocation, as well as analysis of several other key MDS and ILS deletion patients, localized the lissencephaly minimal critical region to a 100-kb region centromeric to D17S379 and telomeric to D17S1566, within the LIS1 gene. </p><p><strong><em>Pseudogenes</em></strong></p><p>
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Reiner et al. (1995) identified 2 genes on chromosome 2 showing high homology to the LIS1 gene. One, designated LIS2, at 2p was considered a potential candidate for a form of lissencephaly; the other, designated LIS2P, at 2q, was determined to be a pseudogene. By sequencing genomic clones that were mapped by means of 2p- and 2q-only hybrids, Fogli et al. (1999) determined that both genes are LIS1 processed pseudogenes mapping to 2p11.2 (PAFAH1P1) and 2q13 (PAFAH1P2). </p>
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<strong>Gene Function</strong>
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<p>Reiner et al. (1993) suggested that the LIS1 gene may be involved in a signal transduction pathway crucial for cerebral development. Since haploinsufficiency appears to lead to the lissencephaly syndrome, half the normal dosage of the gene product is apparently inadequate for normal development. They speculated that improper proportions of beta and gamma subunits of a G protein disturb formation of the normal protein complex, as in hemoglobin H disease, which is caused by an imbalance in the ratio of alpha- to beta-globin. </p><p>Smith et al. (2000) showed that LIS1 in mammals is enriched in neurons relative to levels in other cell types, and that LIS1 interacts with the microtubule motor cytoplasmic dynein (see 600112). Production of more LIS1 in nonneuronal cells increases retrograde movement of cytoplasmic dynein and leads to peripheral accumulation of microtubules. These changes may reflect neuron-like dynein behaviors induced by abundant LIS1. LIS1 deficiency produced the opposite phenotype. The results indicated that abundance of LIS1 in neurons may stimulate specific dynein functions that are involved in neuronal migration and axon growth. </p><p>Caspi et al. (2000) demonstrated an interaction of LIS1 with doublecortin (DCX; 300121) by coimmunoprecipitation, both in transiently transfected cells and in embryonic brain extracts. Immunofluorescence studies revealed that the 2 protein products colocalized in transfected cells and in primary neuronal cells. LIS1 and DCX enhanced tubulin polymerization in an additive fashion, as measured by a light-scattering assay in vitro. The authors hypothesized that the interaction of LIS1 and DCX is important to proper microtubule function in the developing cerebral cortex. </p><p>Faulkner et al. (2000) showed that LIS1 protein coimmunoprecipitates with cytoplasmic dynein and dynactin (601143), and localizes to the cell cortex and to mitotic kinetochores, which are known sites for binding of cytoplasmic dynein. Overexpression of LIS1 in cultured mammalian cells interfered with mitotic progression and led to spindle misorientation. Injection of anti-LIS1 antibodies interfered with attachment of chromosomes to the metaphase plate, and led to chromosome loss. Faulkner et al. (2000) concluded that LIS1 participates in a subset of dynein functions and may regulate the division of neuronal progenitor cells in the developing brain. </p><p>Using database mining and protein structural prediction programs, Emes and Ponting (2001) identified a sequence motif in the products of genes mutated in MDLS, Treacher Collins syndrome (TCOF1, treacle; 606847), oral-facial-digital syndrome type I (CXORF5; 300170), and ocular albinism with late-onset sensorineural deafness (TBL1X; 300196). Over 100 eukaryotic intracellular proteins were found to possess a LIS1 homology motif, including several katanin p60 (606696) subunits, muskelin (605623), Nopp140 (602394), the plant proteins tonneau and LEUNIG, slime mold protein aimless, and numerous WD repeat-containing beta-propeller proteins. The authors suggested that LIS1 homology motifs may contribute to the regulation of microtubule dynamics, either by mediating dimerization, or by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LIS1 homology motifs, and their occurrence in homologs of G-beta beta-propeller subunits, suggests that they are analogs of G-gamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LIS1 homology motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. </p><p>Kitagawa et al. (2000) found that rat Nude (NDE1; 609449) and the catalytic subunits of Pafah interacted with Pafah1b1 in a competitive manner. They suggested that PAFAH1B1 functions in nuclear migration by interacting with multiple intracellular proteins, including NUDE. </p><p>By analysis of crystalline structures of murine proteins, Tarricone et al. (2004) determined that a Lis1 homodimer binds with either a homodimer of Pafah1b2 (602508) or Ndel1 (607538) to form a tetramer. Ndel1 competes with the Pafah1b2 homodimer for Lis1, but the interaction is complex and requires both the N- and C-terminal domains of Lis1. The data suggested that the Lis1 molecule undergoes major conformational changes when switching from a complex with the acetylhydrolase subunit to that with Ndel1. </p><p>Using RNA interference (RNAi) with cultured cell lines and mouse embryonic day-15 cortical neurons, Shu et al. (2004) determined that Ndel1 regulates dynein activity by facilitating the interaction between Lis1 and dynein. Loss of Ndel1, Lis1, or dynein function in developing neocortex impaired neuronal positioning and caused the uncoupling of centrosomes and nuclei. Overexpression of Lis1 partially rescued the positioning defect caused by Ndel1 RNAi but not that caused by dynein RNAi, whereas overexpression of Ndel1 did not rescue the phenotype induced by Lis1 RNAi. Shu et al. (2004) concluded that NDEL1 interacts with LIS1 to sustain the function of dynein, which in turn impacts microtubule organization, nuclear translocation, and neuronal positioning. </p><p>Zhu et al. (2010) showed that NUDC (610325) and HSP90-alpha (HSP90AA1; 140571) formed an ATPase-dependent chaperone complex with LIS1. An inactivating mutation in NUDC or pharmacologic inhibition of HSP90-alpha resulted in LIS1 destabilization. </p>
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<strong>Molecular Genetics</strong>
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<p>Chong et al. (1996) performed SSCP analysis of individual exons in 19 patients with isolated lissencephaly sequence (LIS1; 607432) who showed no deletions detectable by FISH. In 3 of these patients, point mutations were identified: an A-to-G transition in exon 6 resulting in a his149-to-arg missense mutation (601545.0001), a C-to-T transition in exon 8 causing an arg247-to-ter nonsense mutation (610545.0002), and a 22-bp deletion at the exon 9-intron 9 junction predicted to result in a splicing error (601545.0003). Lo Nigro et al. (1997) stated that these data confirmed mutations of LIS1 as the cause of the lissencephaly phenotype in LIS and in the Miller-Dieker syndrome. Together with the results of deletion analysis for other LIS and Miller-Dieker syndrome patients, these data were also consistent with the previous suggestion that additional genes distal to LIS1 are responsible for the facial dysmorphism and other anomalies in MDLS patients, thus supporting the original concept of MDLS as a contiguous gene deletion syndrome. </p><p>Kurahashi et al. (1998) reported the case of a Japanese patient with isolated lissencephaly sequence who carried a balanced chromosomal translocation that disrupted the 5-prime untranslated region of the LIS1 gene. Sakamoto et al. (1998) examined the LIS1 gene in 8 additional Japanese LIS patients and 4 MDS patients. FISH analysis showed deletion of part of the LIS1 gene or of the chromosomal region surrounding it in 3 of the LIS cases and in 3 of the MDS cases. In 1 of the remaining 5 LIS cases, SSCP analysis and subsequent sequencing identified a 1-bp deletion in exon 4, which would be expected to result in premature termination of the gene product. </p><p>Cardoso et al. (2000) analyzed 29 nondeletion LIS patients carrying an LIS1 mutation and reported 15 novel mutations. Patients with missense mutations had a milder lissencephaly grade compared with those with mutations leading to a shortened or truncated protein (P = 0.022). Early truncation/deletion mutations in the putative microtubule-binding domain resulted in a more severe lissencephaly than later truncation/deletion mutations (P less than 0.001). Using a spectrum of LIS patients, the importance of specific WD40 repeats and a putative microtubule-binding domain for PAFAH1B1 function was confirmed. The authors suggested that the small number of missense mutations identified may be due to underdiagnosis of milder phenotypes, and hypothesized that the greater lissencephaly severity seen in Miller-Dieker syndrome may be secondary to the loss of another cortical development gene in the deletion of 17p13.3. </p><p>Leventer et al. (2001) described in detail 5 patients with missense mutations in the LIS1 gene (601545.0001, 601545.0004-601545.0007) and noted that the mild and highly variable spectrum of cortical malformations and clinical sequelae are likely due to suboptimal function of a mutant LIS1 protein rather than to complete loss of function of the protein. The authors suggested that patients with LIS1 missense mutations are underrecognized and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than previously appreciated. </p><p>In an investigation of 220 children with lissencephaly or subcortical band heterotopia, Cardoso et al. (2002) found 65 large deletions of the LIS1 gene detected by FISH and 41 intragenic mutations, including 4 not previously reported. All intragenic mutations were de novo, and there were no familial recurrences. In 88% (36 of 41) of the mutations a truncated or internally deleted protein resulted; missense mutations were found in only 12% (5 of 41). Mutations occurred throughout the gene except for exon 7, with clustering of 3 of the 5 missense mutations in exon 6. Only 5 intragenic mutations were recurrent. In general, the most severe LIS phenotype was seen in patients with large deletions of 17p13.3, with milder phenotypes seen with intragenic mutations. Of these, the mildest phenotypes were seen in patients with missense mutations. </p><p>Mei et al. (2008) identified mutations in the LIS1 gene in 20 (44%) of 45 patients with isolated lissencephaly showing a posterior to anterior gradient. In 19 (76%) of 25 patients in whom FISH and direct sequencing had failed to detect mutations, MLPA analysis identified 18 small genomic deletions and 1 duplication. Overall, small genomic deletions/duplications represented 49% of all LIS1 alterations identified, and LIS1 involvement was demonstrated in 39 (87%) of 45 patients. Breakpoint characterization in 5 patients suggested that Alu-mediated recombination is a major molecular mechanism underlying LIS1 deletions. Mei et al. (2008) noted the high diagnostic yield with MLPA. </p><p>Among 63 patients with posterior predominant lissencephaly, Saillour et al. (2009) identified 40 with LIS1 gene defects. There were 8 small deletions and 31 heterozygous LIS1 mutations, including 12 nonsense, 8 frameshift, 6 missense, and 5 splicing defects. The mutations were found scattered throughout the gene, except in exons 3 and 9, and all were confirmed to be de novo. One patient had a somatic truncating mutation present in 30% of the blood, but other tissues were not available for testing. </p><p>Using multiplex ligation-dependent probe amplification (MLPA) analysis, Haverfield et al. (2009) identified 12 deletions and 6 duplications involving the LIS1 gene in 18 (35%) of 52 patients with an anterior-to-posterior lissencephaly gradient in whom no molecular defect had previously been identified. The majority of patients with LIS1 deletions or duplications had grade 3 lissencephaly. Most deletions and duplications were scattered within the gene, but several deletions included genes flanking LIS1, such as HIC1 (603825), or only included noncoding putative upstream regulatory elements of LIS1. Haverfield et al. (2009) suggested that genetic testing for isolated lissencephaly should include both mutation and deletion/duplication analysis of the LIS1 gene. </p><p>Jamuar et al. (2014) used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. Eight of these individuals carried somatic mutations; 6 of these 8 individuals had double cortex syndrome (300067), with 3 of the 6 carrying mutations in DCX (300121) and the other 3 in LIS1. </p>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</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>Uyanik et al. (2007) identified 14 novel and 7 previously described LIS1 mutations in 21 unrelated patients, including 18 with type 1 lissencephaly, 1 with subcortical band heterotopia, and 2 with lissencephaly with cerebellar hypoplasia. There were 9 truncating mutations, 6 splice site mutations, 5 missense mutations, and an in-frame deletion. Somatic mosaicism was assumed in 3 patients with partial subcortical band heterotopia or mild pachygyria. Uyanik et al. (2007) concluded that the severity of the phenotype is independent of the type of mutation and its site within the coding region of the LIS1 gene. </p><p>Bi et al. (2009) reported 7 unrelated individuals with different submicroscopic duplications of chromosome 17p13.3 (613215) involving the LIS1 and/or the YWHAE (605066) gene. Four individuals had a duplication of YWHAE but not LIS1, and 1 had a duplication of LIS1 but not YWHAE. A sixth patient had a triplication of LIS1, and a seventh had duplication of both genes. Analysis of the clinical features for each individual indicated that individuals with LIS1 duplications had subtle brain defects, including microcephaly, dysgenesis of the corpus callosum, and cerebellar atrophy, as well as neurobehavioral disorders, including delayed development, mental retardation, and attention deficit-hyperactivity disorder. Patients with duplications of YWHAE tended to have macrosomia, facial dysmorphism, and mild developmental delay. Transgenic mice overexpressing Lis1 showed decreased brain size and distorted cellular organization in the ventricular zone. Bi et al. (2009) concluded that variations in dosage of LIS1 play a role in the development of brain anomalies in humans and mice. </p>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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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 PAFAH1B1, 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>
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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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<p>To understand further the function of platelet-activating factor acetylhydrolase, Hirotsune et al. (1998) produced 3 different mutant alleles in the mouse Pafah1b1 gene. Homozygous-null mice died early in embryogenesis soon after implantation. Mice with 1 inactive allele displayed cortical, hippocampal, and olfactory bulb disorganization resulting from delayed neuronal migration by a cell-autonomous neuronal pathway. Mice with further reduction of Pafah1b1 activity displayed more severe brain disorganization as well as cerebellar defects. The results demonstrated an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development. The phenotypes observed were distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration. </p><p>To study the function of the LIS1 gene, Cahana et al. (2001) deleted the first coding exon from the mouse Lis1 gene. The deletion resulted in a shorter protein that initiated from the second methionine, a unique situation because most LIS1 mutations result in a null allele. This mutation mimicked a mutation described in 1 lissencephaly patient with a milder phenotype (Fogli et al., 1999). Homozygotes were early lethal, although heterozygotes were viable and fertile. The morphology of cortical neurons and radial glia was aberrant in the developing cortex, and the neurons migrated more slowly. This was the first demonstration of a cellular abnormality in the migrating neurons after Lis1 mutation. Moreover, cortical plate splitting and thalamocortical innervation were also abnormal. Biochemically, the mutant protein was not capable of dimerization, and enzymatic activity was elevated in the embryos, thus a demonstration of the in vivo role of LIS1 as a subunit of platelet-activating factor acetylhydrolase. </p><p>Reduced LIS1 activity in both humans and mice results in a neuronal migration defect. Liu et al. (2000) showed that Drosophila Lis1 is highly expressed in the nervous system. It is, furthermore, essential for neuroblast proliferation and axonal transport, as shown by a mosaic analysis using a Lis1-null mutation. Analogous mosaic analysis showed that neurons containing a mutated cytoplasmic dynein heavy chain exhibited phenotypes similar to Lis1 mutants. These results implicated LIS1 as a regulator of the microtubule cytoskeleton and showed that it is important for diverse physiologic functions in the nervous system. </p><p>Yan et al. (2003) noted that PAF had been shown to affect sperm motility and acrosomal function, thereby altering fertility. PAFAH1B hydrolyzes PAF and is composed of 3 subunits--the LIS1 protein and PAFAH1B2 and PAFAH1B3, which they called alpha-2 and alpha-1, respectively--and structurally resembles a GTP-hydrolyzing protein. In addition to the brain, transcripts for LIS1, alpha-1, and alpha-2 are localized to meiotic and early haploid germ cells. Yan et al. (2003) disrupted the alpha-2 and alpha-1 genes in mice. Male mice homozygous-null for alpha-2 were infertile and spermatogenesis was disrupted at mid- or late pachytene stages of meiosis or early spermiogenesis. Whereas mice homozygous mutant for alpha-1 had normal fertility and normal spermatogenesis, those with disruption of both alpha-1 and alpha-2 manifested an earlier disturbance of spermatogenesis with an onset at preleptotene or leptotene stages of meiosis. Testicular Lis1 protein levels were upregulated in the alpha-2-null and alpha-1/alpha-2 double-null mice. Lowering Lis1 levels by inactivating 1 allele of Lis1 in alpha-2-null or alpha-1/alpha-2-null genetic backgrounds restored spermatogenesis and male fertility. The data provided evidence for unique roles of the PAFAH1B complex, particularly the LIS1 protein, in spermatogenesis. </p><p>Assadi et al. (2003) investigated interactions between the reelin (Reln; 600514) signaling pathway and Lis1 in brain development. Compound mutant mice with disruptions in the Reln pathway and heterozygous mutations in the Pafah1b1 gene had a higher incidence of hydrocephalus and enhanced cortical and hippocampal layering defects. The Dab1 (603448) signaling molecule and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicated genetic and biochemical interaction between the reelin signaling pathway and LIS1. </p><p>Williams et al. (2004) showed that convulsions mimicking epilepsy can be induced by a mutation in a C. elegans lis1 allele (pnm1), in combination with a chemical antagonist of gamma-aminobutyric acid (GABA) neurotransmitter signaling. Identical convulsions were obtained using C. elegans mutants defective in GABA transmission, whereas mutations or GABA antagonist alone did not cause convulsions, indicating a threshold was exceeded in response to this combination. Crosses between pnm1 worms and fluorescent-marker strains, which are designed to exclusively illuminate either the processes of GABAergic neurons or synaptic vesicles, showed no deviations in neuronal architecture, but presynaptic defects in GABAergic vesicle distribution were clearly evident and could be phenocopied by RNAi directed against cytoplasmic dynein (see 600112), a known LIS1 interactor. Mutations in unc104 (ATSV; 601255) and snb1 (VAMP1; 185880) exhibited similar convulsion phenotypes following chemical induction. </p><p>Interaction between Nde1 (609449) and Lis1 is critical in the development of the mouse central nervous system (CNS). Pawlisz et al. (2008) analyzed a series of Nde1 and Lis1 double mutations in mice and showed that the Nde1-Lis1 complex was specifically required by the radial glial/neuroepithelial progenitor cells during CNS development. Besides mitotic spindle regulation, Lis1 and Nde1 maintained the morphology and lateral cell-cell contacts of progenitors in the cortical ventricular zone. This cell shape and organization control appeared necessary for symmetrical cell division and the self-renewal of neural progenitors during the early phase of corticogenesis. Loss of Lis1-Nde1 function led to dramatically increased neuronal differentiation at the onset of cortical neurogenesis, resulting in overproduction of the earliest-born preplate and Cajal-Retzius neurons, with consequent loss of the laminar pattern and over 80% mass and surface area of the cerebral cortex. </p><p>Yamada et al. (2009) demonstrated that inhibition or knockdown of calpains (see, e.g., CAPN1; 114220) protected the Lis1 protein from proteolysis in Lis1 +/- mouse embryonic fibroblasts. Increased protein levels rescued the aberrant distribution of cytoplasmic dynein and mitochondria observed in Lis1 +/- cells, consistent with an improvement in function. Calpain inhibitors also improved neuronal migration of Lis1 +/- cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor to pregnant Lis1 +/- dams rescued apoptotic neuronal cell death and partially rescued neuronal migration defects in Lis1 +/- offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective cortical layering in Lis1+/- mice. Yamada et al. (2009) suggested that LIS1 is specifically degraded by calpain, and that calpain inhibition could be a potential therapeutic intervention for lissencephaly due to haploinsufficiency of LIS1. </p><p>Greenwood et al. (2009) demonstrated that Lis1 +/- mice develop spontaneous seizures. Electrophysiologic studies on hippocampal slices derived from these mice had a nearly 2-fold increase in the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSC) associated with increased glutamate-mediated excitation without a change in receptor patterns. Electron microscopic analysis showed a large increase in presynaptic vesicle number, which corresponded with enhanced excitatory drive. Use of a nonspecific calcium channel blocker restored abnormal paired-pulse facilitation to normal. </p>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>10 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 LISSENCEPHALY 1</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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PAFAH1B1, HIS149ARG
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<br />
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SNP: rs121434482,
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ClinVar: RCV000008540, RCV002512912
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with lissencephaly 1 (607432) in whom no deletions of 17p were detectable by FISH, Chong et al. (1996) identified an A-to-G transition at nucleotide 446 in exon 6 of the PAFAH1B1 gene, resulting in a his149-to-arg substitution. See also Lo Nigro et al. (1997). Leventer et al. (2001) described the patient reported by Chong et al. (1996) in greater detail. From infancy, the patient showed developmental delay, myoclonic jerks and spasms, seizures, generalized hypotonia, microcephaly, and dysmorphic facies. Brain MRI revealed moderate agyria in the occipital lobes transitioning to pachygyria anteriorly as well as flattening of the corpus callosum and mild dilation of the posterior horns of the lateral ventricles. The patient developed progressive spasticity and died of sepsis at age 4 years. Leventer et al. (2001) noted that this mutation interrupts a highly conserved invariant amino acid and is predicted to change the protein conformation significantly. </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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<h4>
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<span class="mim-font">
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<strong>.0002 LISSENCEPHALY 1</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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PAFAH1B1, ARG273TER
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<br />
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SNP: rs121434483,
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ClinVar: RCV000008541, RCV000255710
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with isolated lissencephaly sequence (607432) in whom no deletions of 17p were detectable by FISH, Chong et al. (1996) identified a C-to-T transition at nucleotide 817 in exon 8 of the PAFAH1B1 gene, resulting in an arg273-to-ter mutation. See also Lo Nigro et al. (1997). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LISSENCEPHALY 1</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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PAFAH1B1, 22-BP DEL
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<br />
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SNP: rs1567561137,
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ClinVar: RCV000008542
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with isolated lissencephaly sequence (607432) in whom no deletions of 17p were detectable by FISH, Chong et al. (1996) identified a 22-bp deletion at the exon 9-intron 9 junction of the PAFAH1B1 gene from nucleotide 988 to 1002+7, predicted to result in a splicing error. Lo Nigro et al. (1997) noted that the deletion abolished amino acids 301 to 334 of the mature predicted protein. </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 SUBCORTICAL LAMINAR HETEROTOPIA</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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PAFAH1B1, SER169PRO
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<br />
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SNP: rs121434484,
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ClinVar: RCV000008543
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy with subcortical band heterotopia (607432), Pilz et al. (1999) identified a T-to-C transition at nucleotide 499 in exon 6 of the PAFAH1B1 gene, resulting in a ser169-to-pro substitution. The mutation was not found in the boy's parents. Leventer et al. (2001) described the boy reported by Pilz et al. (1999) in greater detail. As a child, he had mild global developmental delay and complex partial seizures. MRI showed posterior subcortical band heterotopia and mild dilation of the posterior horns of the lateral ventricles. At age 23 years, he worked as an unskilled manual laborer and enjoyed normal activities, although seizures remained a problem. Leventer et al. (2001) suggested that the milder phenotype may be due to somatic mosaicism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 LISSENCEPHALY 1</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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PAFAH1B1, ASP317HIS
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<br />
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SNP: rs121434485,
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ClinVar: RCV000008544
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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>Leventer et al. (2001) reported a patient with generalized hypotonia and poor visual and social interaction who later developed complex partial seizures. MRI revealed moderate pachygyria, consistent with isolated lissencephaly sequence (607432), that was most severe in the parietooccipital regions, hypoplasia of the rostral corpus callosum, and mild dilation of the posterior horns of the lateral ventricles. Sequencing of the LIS1 gene showed a 949G-C mutation in exon 9, resulting in an asp317-to-his substitution. At age 4 years, the patient could feed himself and understand simple commands. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 LISSENCEPHALY 1</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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PAFAH1B1, PHE31SER
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<br />
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SNP: rs121434486,
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ClinVar: RCV000008545
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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>Leventer et al. (2001) reported a girl with isolated lissencephaly sequence (607432) who had global developmental delay and hypotonia and later developed myoclonic jerks, absence seizures, and febrile seizures. Brain MRI showed moderate generalized pachygyria that was most severe in the occipitoparietal regions, hypoplasia of the cerebellar vermis, hypoplasia of the rostral corpus callosum, and mild dilation of the lateral ventricles. Sequencing of the LIS1 gene showed a 92T-C change in exon 3, resulting in a phe31-to-ser substitution, in the N-terminal region outside of the WD repeats which confer correct protein structure and folding. At age 12 years, she walked with assistance, was toilet-trained, and had limited communication skills. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 LISSENCEPHALY 1</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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PAFAH1B1, GLY162SER
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<br />
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SNP: rs121434487,
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ClinVar: RCV000008546, RCV003555976
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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>Leventer et al. (2001) reported a boy with speech and walking delay and strabismus who later developed complex partial seizures. Brain MRI showed moderate pachygyria restricted to the occipital and posterior parietal lobes, consistent with isolated lissencephaly sequence (607432). Sequencing of the LIS1 gene showed a 484G-A transition in exon 6, resulting in a gly162-to-ser substitution. At age 6 years, the boy attended a developmental preschool, played sports, and was found to have an IQ of 100. The authors noted that this amino acid change has been found as a variant in other WD proteins, which may explain the mild LIS1 phenotype in this patient. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 SUBCORTICAL LAMINAR HETEROTOPIA</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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PAFAH1B1, ARG241PRO
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<br />
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SNP: rs121434488,
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gnomAD: rs121434488,
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ClinVar: RCV000008547, RCV001851740
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient with subcortical band heterotopia (607432), Sicca et al. (2003) identified somatic mosaicism for a 722G-C transversion in exon 8 of the LIS1 gene, resulting in an arg241-to-pro (R241P) substitution. The mutant allele was present in 18% of lymphocyte DNA and 21% of hair root DNA. The patient had delayed language and motor development as a child, and later showed severe mental retardation, spasticity, and seizures. Brain MRI showed subcortical band heterotopia in posterior regions. Sicca et al. (2003) noted that the patient had a less severe phenotype than those with lissencephaly, likely due to the somatic mosaicism. </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 SUBCORTICAL LAMINAR HETEROTOPIA</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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|
LISSENCEPHALY 1
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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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PAFAH1B1, ARG8TER
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<br />
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SNP: rs121434489,
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ClinVar: RCV000008548, RCV000008549, RCV001255338, RCV001291182, RCV001851741
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a male patient with subcortical laminar heterotopia (607432), Sicca et al. (2003) identified somatic mosaicism for a 22C-T transition in exon 2 of the LIS1 gene, resulting in an arg8-to-ter (R8X) mutation. The mutant allele was present in 24% of lymphocyte DNA and 31% of hair root DNA. The patient had seizures and mild mental retardation as well as posterior subcortical laminar heterotopia. The phenotype was relatively mild compared to full-blown lissencephaly. In a male patient with lissencephaly, Sicca et al. (2003) identified the R8X mutation. The patient did not show somatic mosaicism and had a very severe phenotype. The authors noted that these examples suggested that somatic mosaicism results in a less severe phenotype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 LISSENCEPHALY 1</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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PAFAH1B1, HIS277PRO
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<br />
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|
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SNP: rs121434490,
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|
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ClinVar: RCV000008550
|
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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 patient with a severe form of isolated lissencephaly sequence (607432), Torres et al. (2004) identified a 1385A-C transversion in the LIS1 gene, resulting in a his277-to-pro (H277P) substitution in the fifth WD-40 domain of the protein. Sequence alignment showed that the mutated histidine is a conserved amino acid in different organisms, but not when compared to different proteins with WD domains. The authors emphasized that missense mutations in LIS1 are not always associated with milder phenotypes. </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>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
|
|
<ol>
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Adachi, H., Tsujimoto, M., Hattori, M., Arai, H., Inoue, K.
|
|
<strong>cDNA cloning of human cytosolic platelet-activating factor acetylhydrolase gamma-subunit and its mRNA expression in human tissues.</strong>
|
|
Biochem. Biophys. Res. Commun. 214: 180-187, 1995.
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[PubMed: 7669037]
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[Full Text: https://doi.org/10.1006/bbrc.1995.2272]
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</p>
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|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Assadi, A. H., Zhang, G., Beffert, U., McNeil, R. S., Renfro, A. L., Niu, S., Quattrocchi, C. C., Antalffy, B. A., Sheldon, M., Armstrong, D. D., Wynshaw-Boris, A., Herz, J., D'Arcangelo, G., Clark, G. D.
|
|
<strong>Interaction of reelin signaling and Lis1 in brain development.</strong>
|
|
Nature Genet. 35: 270-276, 2003.
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|
[PubMed: 14578885]
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[Full Text: https://doi.org/10.1038/ng1257]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Bi, W., Sapir, T., Shchelochkov, O. A., Zhang, F., Withers, M. A., Hunter, J. V., Levy, T., Shinder, V., Peiffer, D. A., Gunderson, K. L., Nezarati, M. M., Shotts, V. A., and 13 others.
|
|
<strong>Increased LIS1 expression affects human and mouse brain development.</strong>
|
|
Nature Genet. 41: 168-177, 2009.
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[PubMed: 19136950]
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[Full Text: https://doi.org/10.1038/ng.302]
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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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|
Cahana, A., Escamez, T., Nowakowski, R. S., Hayes, N. L., Giacobini, M., von Holst, A., Shmueli, O., Sapir, T., McConnell, S. K., Wurst, W., Martinez, S., Reiner, O.
|
|
<strong>Targeted mutagenesis of Lis1 disrupts cortical development and LIS1 homodimerization.</strong>
|
|
Proc. Nat. Acad. Sci. 98: 6429-6434, 2001.
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|
|
|
|
[PubMed: 11344260]
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[Full Text: https://doi.org/10.1073/pnas.101122598]
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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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Cardoso, C., Leventer, R. J., Dowling, J. J., Ward, H. L., Chung, J., Petras, K. S., Roseberry, J. A., Weiss, A. M., Das, S., Martin, C. L., Pilz, D. T., Dobyns, W. B., Ledbetter, D. H.
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|
<strong>Clinical and molecular basis of classical lissencephaly: mutations in the LIS1 gene (PAFAH1B1).</strong>
|
|
Hum. Mutat. 19: 4-15, 2002.
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[PubMed: 11754098]
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[Full Text: https://doi.org/10.1002/humu.10028]
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</p>
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<li>
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<p class="mim-text-font">
|
|
Cardoso, C., Leventer, R. J., Matsumoto, N., Kuc, J. A., Ramocki, M. B., Mewborn, S. K., Dudlicek, L. L., May, L. F., Mills, P. L., Das, S., Pilz, D. T., Dobyns, W. B., Ledbetter, D. H.
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<strong>The location and type of mutation predict malformation severity in isolated lissencephaly caused by abnormalities within the LIS1 gene.</strong>
|
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Hum. Molec. Genet. 9: 3019-3028, 2000.
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[PubMed: 11115846]
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[Full Text: https://doi.org/10.1093/hmg/9.20.3019]
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</p>
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<p class="mim-text-font">
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Caspi, M., Atlas, R., Kantor, A., Sapir, T., Reiner, O.
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<strong>Interaction between LIS1 and doublecortin, two lissencephaly gene products.</strong>
|
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Hum. Molec. Genet. 9: 2205-2213, 2000.
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[PubMed: 11001923]
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[Full Text: https://doi.org/10.1093/oxfordjournals.hmg.a018911]
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<li>
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<p class="mim-text-font">
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Chong, S. S., Lo Nigro, C., Roschke, A. V., Tanigami, A., Pack, S. D., Smith, A. C. M., Carrozzo, R., Dobyns, W. B., Ledbetter, D. H.
|
|
<strong>Point mutations and an intragenic deletion in three ILS patients confirm LIS1 as the lissencephaly causative gene in isolated lissencephaly sequence and Miller-Dieker syndrome. (Abstract)</strong>
|
|
Am. J. Hum. Genet. 59 (suppl.): A23 only, 1996.
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<p class="mim-text-font">
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Chong, S. S., Pack, S. D., Roschke, A. V., Tanigami, A., Carrozzo, R., Smith, A. C. M., Dobyns, W. B., Ledbetter, D. H.
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<strong>A revision of the lissencephaly and Miller-Dieker syndrome critical regions in chromosome 17p13.3.</strong>
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Hum. Molec. Genet. 6: 147-155, 1997.
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[PubMed: 9063734]
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[Full Text: https://doi.org/10.1093/hmg/6.2.147]
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<p class="mim-text-font">
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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>
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Cell 119: 1027-1040, 2004.
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<p class="mim-text-font">
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Emes, R. D., Ponting, C. P.
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<strong>A new sequence motif linking lissencephaly, Treacher Collins and oral-facial-digital type 1 syndromes, microtubule dynamics and cell migration.</strong>
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<p class="mim-text-font">
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Faulkner, N. E., Dujardin, D. L., Tai, C.-Y., Vaughan, K. T., O'Connell, C. B., Wang, Y., Vallee, R. B.
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<strong>A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function.</strong>
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Nature Cell Biol. 2: 784-791, 2000.
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[PubMed: 11056532]
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<p class="mim-text-font">
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Fogli, A., Giglio, S., Arrigo, G., Lo Nigro, C., Zollo, M., Viggiano, L., Rocchi, M., Archidiacono, N., Zuffardi, O., Carrozzo, R.
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<strong>Identification of two paralogous regions mapping to the short and long arms of human chromosome 2 comprising LIS1 pseudogenes.</strong>
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<p class="mim-text-font">
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Greenwood, J. S. F., Wang, Y., Estrada, R. C., Ackerman, L., Ohara, P. T., Baraban, S. C.
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<strong>Seizures, enhanced excitation, and increased vesicle number in Lis1 mutant mice.</strong>
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<p class="mim-text-font">
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Hanahan, D. J. A.
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<strong>Platelet activating factor: a biologically active phosphoglyceride.</strong>
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Annu. Rev. Biochem. 55: 483-509, 1986.
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[PubMed: 3017194]
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[Full Text: https://doi.org/10.1146/annurev.bi.55.070186.002411]
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<p class="mim-text-font">
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Hattori, M., Adachi, H., Tsujimoto, M., Arai, H., Inoue, K.
|
|
<strong>Miller-Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase.</strong>
|
|
Nature 370: 216-218, 1994. Note: Erratum: Nature 370: 391 only, 1994.
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[PubMed: 8028668]
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[Full Text: https://doi.org/10.1038/370216a0]
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<p class="mim-text-font">
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Hattori, M., Arai, H., Inoue, K.
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<strong>Purification and characterization of bovine brain platelet-activating factor acetylhydrolase.</strong>
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J. Biol. Chem. 268: 18748-18753, 1993.
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[PubMed: 8360169]
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<p class="mim-text-font">
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Haverfield, E. V., Whited, A. J., Petras, K. S., Dobyns, W. B., Das, S.
|
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<strong>Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia.</strong>
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Europ. J. Hum. Genet. 17: 911-918, 2009.
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[Full Text: https://doi.org/10.1038/ejhg.2008.213]
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<p class="mim-text-font">
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|
Hirotsune, S., Fleck, M. W., Gambello, M. J., Bix, G. J., Chen, A., Clark, G. D., Ledbetter, D. H., McBain, C. J., Wynshaw-Boris, A.
|
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<strong>Graded reduction of Pafah1b1 (Lis1) activity results in neuronal migration defects and early embryonic lethality.</strong>
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Nature Genet. 19: 333-339, 1998.
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[PubMed: 9697693]
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[Full Text: https://doi.org/10.1038/1221]
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<li>
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<p class="mim-text-font">
|
|
Jamuar, S. S., Lam, A. N., Kircher, M., D'Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., and 20 others.
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<strong>Somatic mutations in cerebral cortical malformations.</strong>
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New Eng. J. Med. 371: 733-743, 2014.
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[PubMed: 25140959]
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[Full Text: https://doi.org/10.1056/NEJMoa1314432]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kitagawa, M., Umezu, M., Aoki, J., Koizumi, H., Arai, H., Inoue, K.
|
|
<strong>Direct association of LIS1, the lissencephaly gene product, with a mammalian homologue of a fungal nuclear distribution protein, rNUDE.</strong>
|
|
FEBS Lett. 479: 57-62, 2000.
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|
|
[PubMed: 10940388]
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[Full Text: https://doi.org/10.1016/s0014-5793(00)01856-1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kurahashi, H., Sakamoto, M., Ono, J., Honda, A., Okada, S., Nakamura, Y.
|
|
<strong>Molecular cloning of the chromosomal breakpoint in the LIS1 gene of a patient with isolated lissencephaly and balanced t(8;17).</strong>
|
|
Hum. Genet. 103: 189-192, 1998.
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|
|
[PubMed: 9760204]
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[Full Text: https://doi.org/10.1007/s004390050805]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Ledbetter, S. A., Kuwano, A., Dobyns, W. B., Ledbetter, D. H.
|
|
<strong>Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly.</strong>
|
|
Am. J. Hum. Genet. 50: 182-189, 1992.
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|
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