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<title>
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Entry
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- *602529 - TUBULIN, ALPHA-1A; TUBA1A
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- OMIM
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</ul>
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</div>
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</nav>
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<div id="mimSearch" class="hidden-print">
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<div class="container">
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<form method="get" action="/search" id="mimEntrySearchForm" name="entrySearchForm" class="form-horizontal">
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchStart" name="start" value="1" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="hidden" id="mimSearchSort" name="sort" value="score desc, prefix_sort desc" />
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<div class="row">
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<div class="col-lg-8 col-md-8 col-sm-8 col-xs-8">
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<div class="form-group">
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<div class="input-group">
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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<div class="input-group-btn">
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<button type="submit" id="mimEntrySearchSubmit" class="btn btn-default" style="width: 5em;"><span class="glyphicon glyphicon-search"></span></button>
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<button type="button" class="btn btn-default dropdown-toggle" data-toggle="dropdown"> Options <span class="caret"></span></button>
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<ul class="dropdown-menu dropdown-menu-right">
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<li class="dropdown-header">
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Advanced Search
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/entry"> OMIM </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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</li>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/geneMap"> Gene Map </a>
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<li role="separator" class="divider"></li>
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<li>
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<a href="/history"> Search History </a>
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</ul>
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</form>
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<div class="row">
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<p />
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</div>
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*602529</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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</li>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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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="#geneFamily">Gene Family</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#nomenclature">Nomenclature</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
|
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<a href="/allelicVariants/602529">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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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=ENSG00000167552;t=ENST00000301071" 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=7846" 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=602529" 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=ENSG00000167552;t=ENST00000301071" 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_001270399,NM_001270400,NM_006009" 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_006009" 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=602529" 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=03959&isoform_id=03959_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/TUBA1A" 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/37492,340019,4929134,4929136,13623683,17986283,29791746,55977864,119578456,119578457,119578458,119578459,158259989,194385120,194387512,393715091,393715095" 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/Q71U36" 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=7846" 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=ENSG00000167552;t=ENST00000301071" 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=TUBA1A" 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=TUBA1A" 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+7846" 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/TUBA1A" 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:7846" 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/7846" 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=chr12&hgg_gene=ENST00000301071.12&hgg_start=49184795&hgg_end=49189080&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:20766" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:20766" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/tuba1a" 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=602529[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=602529[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/TUBA1A/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/ENSG00000167552" 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=TUBA1A" 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=TUBA1A" 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=TUBA1A" 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=TUBA1A&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/PA162407319" 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:20766" 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/FBgn0003884.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:98869" 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/TUBA1A#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:98869" 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/7846/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=7846" 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=WBGene00003175;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-090507-4" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7846" 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=TUBA1A&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> 718759003<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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602529
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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TUBULIN, ALPHA-1A; TUBA1A
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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TUBULIN, ALPHA, BRAIN-SPECIFIC<br />
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B-ALPHA-1<br />
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TUBA3
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=TUBA1A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TUBA1A</a></em></strong>
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</span>
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/12/352?start=-3&limit=10&highlight=352">12q13.12</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:49184795-49189080&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'})">12:49,184,795-49,189,080</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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Lissencephaly 3
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PheneGene Graphics <span class="caret"></span>
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<li><a href="/graph/linear/602529" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>Microtubules tend to be functionally distinct and are involved in mitosis, cell movement, intracellular movement, and other biologic processes. The main components of microtubules are different isoforms of alpha and beta tubulins, which are often cell-type specific.</p><p><a href="#10" class="mim-tip-reference" title="Lewis, S. A., Cowan, N. J. <strong>Tubulin genes: structure, expression, and regulation.In: Avila, J. (ed.) : Microtubule proteins.</strong> Boca Raton: CRC Press, Inc. 1990. Pp. 37-66."None>Lewis and Cowan (1990)</a> reviewed the alpha-tubulin gene family. In humans, this family consists of 15 to 20 dispersed genes, many of which are processed pseudogenes. The positions of the first 3 introns are identical between members of the human and rat gene families; in addition, some human alpha-tubulin genes have a fourth intron, also at an identical position. Within a vertebrate species, the genes can be distinguished by their 3-prime untranslated regions (UTRs). Since a large proportion of the diversity of alpha-tubulins is clustered at the C-terminal region and is conserved across species, alpha-tubulin genes can be classified based on homology of their encoded C-terminal motifs to those of mouse alpha-tubulin genes.</p>
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<p>See <a href="#8" class="mim-tip-reference" title="Khodiyar, V. K., Maltais, L. J., Ruef, B. J., Sneddon, K. M. B., Smith, J. R., Shimoyama, M., Cabral, F., Dumontet, C., Dutcher, S. K., Harvey, R. J., Lafanechere, L., Murray, J. M., Nogales, E., Piquemal, D., Stanchi, F., Povey, S., Lovering, R. C. <strong>A revised nomenclature for the human and rodent alpha-tubulin gene family.</strong> Genomics 90: 285-289, 2007. Note: Erratum: Genomics 93: 397 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17543498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17543498</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17543498">Khodiyar et al. (2007)</a> for a revised nomenclature of the alpha-tubulin gene family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17543498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Cloning and Expression</strong>
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<p>The b-alpha-1 gene, cloned from a human fetal brain cDNA library by <a href="#3" class="mim-tip-reference" title="Cowan, N. J., Dobner, P. R., Fuchs, E. V., Cleveland, D. W. <strong>Expression of human alpha-tubulin genes: interspecies conservation of 3-prime untranslated regions.</strong> Molec. Cell. Biol. 3: 1738-1745, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6646120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6646120</a>] [<a href="https://doi.org/10.1128/mcb.3.10.1738-1745.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6646120">Cowan et al. (1983)</a>, is the human counterpart of mouse M-alpha-1. By Northern blot analysis, <a href="#3" class="mim-tip-reference" title="Cowan, N. J., Dobner, P. R., Fuchs, E. V., Cleveland, D. W. <strong>Expression of human alpha-tubulin genes: interspecies conservation of 3-prime untranslated regions.</strong> Molec. Cell. Biol. 3: 1738-1745, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6646120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6646120</a>] [<a href="https://doi.org/10.1128/mcb.3.10.1738-1745.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6646120">Cowan et al. (1983)</a> showed that b-alpha-1 mRNA is expressed only in brain. They found that the 3-prime UTR of b-alpha-1 is more than 80% homologous to the UTR of the rat brain alpha-tubulin gene, IL-alpha-T1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6646120" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Hall, J. L., Cowan, N. J. <strong>Structural features and restricted expression of a human alpha-tubulin gene.</strong> Nucleic Acids Res. 13: 207-223, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3839072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3839072</a>] [<a href="https://doi.org/10.1093/nar/13.1.207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3839072">Hall and Cowan (1985)</a> screened a human genomic library with the 3-prime UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene. B-alpha-1 encodes a predicted 451-amino acid protein that is 100% identical to the rat homolog and differs by only 2 and 3 amino acids from the pig and chicken homologs, respectively. Furthermore, they observed that the first and largest intron of the b-alpha-1 gene is homologous to that of the rat gene. Northern blotting showed that b-alpha-1 expression was restricted to morphologically differentiated neurologic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3839072" 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 Northern blot analysis and in situ hybridization, <a href="#11" class="mim-tip-reference" title="Miller, F. D., Naus, C. C. G., Durand, M., Bloom, F. E., Milner, R. J. <strong>Isotypes of alpha-tubulin are differentially regulated during neuronal maturation.</strong> J. Cell Biol. 105: 3065-3073, 1987.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3693406/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3693406</a>] [<a href="https://doi.org/10.1083/jcb.105.6.3065" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3693406">Miller et al. (1987)</a> found that the rat homolog of b-alpha-1, which they called T-alpha-1, is expressed at high levels during the extension of neuronal processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3693406" 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="#4" class="mim-tip-reference" title="Crabtree, D. V., Ojima, I., Geng, X., Adler, A. J. <strong>Tubulins in the primate retina: evidence that xanthophylls may be endogenous ligands for the paclitaxel-binding site.</strong> Bioorg. Med. Chem. 9: 1967-1976, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11504633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11504633</a>] [<a href="https://doi.org/10.1016/s0968-0896(01)00103-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11504633">Crabtree et al. (2001)</a> cloned alpha-tubulin variants from a human retina cDNA library. One variant had the same sequence as the clone isolated by <a href="#3" class="mim-tip-reference" title="Cowan, N. J., Dobner, P. R., Fuchs, E. V., Cleveland, D. W. <strong>Expression of human alpha-tubulin genes: interspecies conservation of 3-prime untranslated regions.</strong> Molec. Cell. Biol. 3: 1738-1745, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6646120/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6646120</a>] [<a href="https://doi.org/10.1128/mcb.3.10.1738-1745.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6646120">Cowan et al. (1983)</a> from fetal brain, and the other had the same sequence as the brain-specific alpha-tubulin clone isolated by <a href="#5" class="mim-tip-reference" title="Hall, J. L., Cowan, N. J. <strong>Structural features and restricted expression of a human alpha-tubulin gene.</strong> Nucleic Acids Res. 13: 207-223, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3839072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3839072</a>] [<a href="https://doi.org/10.1093/nar/13.1.207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3839072">Hall and Cowan (1985)</a>, suggesting that this alpha-tubulin gene is expressed in both brain and retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6646120+11504633+3839072" 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="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> detected high expression of the TUBA1A gene in human fetal brain. Detailed study of mouse embryos showed expression in the cortex, hippocampus, cerebellum, brainstem, and rostral migratory stream. Tuba1a expression was decreased in most neurons at later postnatal stages and in adulthood. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17584854" 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="#5" class="mim-tip-reference" title="Hall, J. L., Cowan, N. J. <strong>Structural features and restricted expression of a human alpha-tubulin gene.</strong> Nucleic Acids Res. 13: 207-223, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3839072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3839072</a>] [<a href="https://doi.org/10.1093/nar/13.1.207" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3839072">Hall and Cowan (1985)</a> determined that the b-alpha-1 gene contains 4 exons and spans less than 4 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3839072" 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="#14" class="mim-tip-reference" title="Scott, A. F. <strong>Personal Communication.</strong> Baltimore, Md. 10/3/2001."None>Scott (2001)</a> mapped the TUBA1A gene to human chromosome 12 based on sequence similarity between the TUBA1A sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF141347" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF141347</a>) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AC016125" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AC016125</a> and GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AC010173" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AC010173</a>).</p><p><a href="#8" class="mim-tip-reference" title="Khodiyar, V. K., Maltais, L. J., Ruef, B. J., Sneddon, K. M. B., Smith, J. R., Shimoyama, M., Cabral, F., Dumontet, C., Dutcher, S. K., Harvey, R. J., Lafanechere, L., Murray, J. M., Nogales, E., Piquemal, D., Stanchi, F., Povey, S., Lovering, R. C. <strong>A revised nomenclature for the human and rodent alpha-tubulin gene family.</strong> Genomics 90: 285-289, 2007. Note: Erratum: Genomics 93: 397 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17543498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17543498</a>] [<a href="https://doi.org/10.1016/j.ygeno.2007.04.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17543498">Khodiyar et al. (2007)</a> stated that the TUBA1A gene maps to human chromosome 12q13.12 and mouse chromosome 15F1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17543498" 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 2 unrelated patients with lissencephaly (LIS3; <a href="/entry/611603">611603</a>), <a href="#7" class="mim-tip-reference" title="Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. <strong>Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.</strong> Cell 128: 45-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17218254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2006.12.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218254">Keays et al. (2007)</a> and <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified 2 different de novo heterozygous mutations in the TUBA1A gene (<a href="#0001">602529.0001</a>; <a href="#0002">602529.0002</a>). <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified de novo heterozygous TUBA1A mutations (see, e.g., <a href="#0003">602529.0003</a>-<a href="#0005">602529.0005</a>) in 6 additional patients with a wide spectrum of brain dysgenesis, ranging from agyria to laminar heterotopia. Retrospective examination of brain MRI showed defects in the cerebellum, hippocampus, corpus callosum, and brainstem. Patients who survived showed mental retardation, seizures, motor delay, and microcephaly. In general, gyral malformations were more severe in the posterior than anterior brain regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17584854+17218254" 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="Bahi-Buisson, N., Poirier, K., Boddaert, N., Saillour, Y., Castelnau, L., Philip, N., Buyse, G., Villard, L., Joriot, S., Marret, S., Bourgeois, M., Van Esch, H., Lagae, L., Amiel, J., Hertz-Pannier, L., Roubertie, A., Rivier, F., Pinard, J. M., Beldjord, C., Chelly, J. <strong>Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.</strong> J. Med. Genet. 45: 647-653, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728072</a>] [<a href="https://doi.org/10.1136/jmg.2008.058073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728072">Bahi-Buisson et al. (2008)</a> identified 6 de novo mutations in the TUBA1A gene (see, e.g., <a href="#0006">602529.0006</a>; <a href="#0007">602529.0007</a>) in 6 of 100 patients with lissencephaly who were negative for mutations in other known lissencephaly-associated genes. The phenotype ranged from the less severe perisylvian pachygyria to the more severe posteriorly predominant pachygyria, which was associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A mutations shared a common clinical phenotype consisting of congenital microcephaly, mental retardation and diplegia/tetraplegia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728072" 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="Morris-Rosendahl, D. J., Najm, J., Lachmeijer, A. M. A., Sztriha, L., Martins, M., Kuechler, A., Haug, V., Zeschnigk, C., Martin, P., Santos, M., Vasconcelos, C., Omran, H., Kraus, U., Van der Knaap, M. S., Schuierer, G., Kutsche, K., Uyanik, G. <strong>Refining the phenotype of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly.</strong> Clin. Genet. 74: 425-433, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18954413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18954413</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01093.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18954413">Morris-Rosendahl et al. (2008)</a> identified 4 different TUBA1A mutations (see, e.g., <a href="#0008">602529.0008</a>) in 5 of 46 patients with variable patterns of lissencephaly on brain MRI and no DCX (<a href="/entry/300121">300121</a>) or PAFAH1B1 (<a href="/entry/601545">601545</a>) mutation. Four of the 5 patients had congenital microcephaly, and all had dysgenesis of the corpus callosum, cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18954413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kumar, R. A., Pilz, D. T., Babatz, T. D., Cushion, T. D., Harvey, K., Topf, M., Yates, L., Robb, S., Uyanik, G., Mancini, G. M. S., Rees, M. I., Harvey, R. J., Dobyns, W. B. <strong>TUBA1A mutations cause wide spectrum lissencephaly (smooth brain) and suggest that multiple neuronal migration pathways converge on alpha tubulins.</strong> Hum. Molec. Genet. 19: 2817-2827, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20466733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20466733</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20466733[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/ddq182" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20466733">Kumar et al. (2010)</a> screened a cohort of 125 lissencephaly patients in whom mutations in DCX and PAFAH1B1 had been excluded and identified novel and recurrent TUBA1A mutations in 1% of children with classic lissencephaly and in 30% of children with lissencephaly with cerebellar hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of the corpus callosum and cerebellar hypoplasia without lissencephaly. The authors demonstrated a wider spectrum of phenotypes than had been reported and suggested that lissencephaly-associated mutations of TUBA1A may operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20466733" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J. <strong>Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.</strong> Hum. Molec. Genet. 19: 3599-3613, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603323[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/ddq276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603323">Tian et al. (2010)</a> studied the effects of 9 disease-associated TUBA1A mutations on tubulin folding, heterodimer assembly, microtubule dynamics, and stability. The translational yield of each mutant protein varied across a continuum from an amount similar to that of wildtype for mutant L286F, to slightly reduced formation for mutants I188L (<a href="#0003">602529.0003</a>), I238V, P263T (<a href="#0004">602529.0004</a>), R402H (<a href="#0002">602529.0002</a>) and S419L (<a href="#0005">602529.0005</a>), to significantly diminished amounts for mutants V303G, L397P, and R402C. Studies of GTP-dependent polymerization and depolymerization indicated that all the disease-causing TUBA1A mutations were competent for assembly into microtubules in vitro. However, some of the mutant proteins showed defects in the tubulin heterodimer assembly pathway, with deficiencies in the production of intermediates. Mutants I188L, I238V, L397P and R402C all generated lower yields of intermediates compared to control TUBA1A; in addition, R402C showed a time-dependent decay of intermediates, indicating instability. Some of the mutant proteins (R264C, V303G, and L397P) also showed defective interaction with assembly chaperone protein TBCB (see, e.g., TBCA, <a href="/entry/610058">610058</a>). Tests of heterodimer stability showed that P263T and V303G had reduced stability, whereas L397P and R402C were highly unstable. P263T expression resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, whereas the other mutant proteins did not show defects in microtubule growth. The findings demonstrated that different TUBA1A mutations result in a variety of tubulin defects, but also suggested that the mutations may cause compromised interactions with other interacting proteins essential for proper neuronal migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603323" 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="#1" class="mim-tip-reference" title="Aiken, J., Moore, J. K., Bates, E. A. <strong>TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity.</strong> Hum. Molec. Genet. 28: 1227-1243, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30517687/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30517687</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30517687[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/ddy416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30517687">Aiken et al. (2019)</a> found that expression of human TUBA1A R402C or R402H mutants in mouse brain disrupted cortical neuron migration. Analogous R402 mutant alpha-tubulins in yeast assembled into microtubules, but microtubule polymerization rates were lower and dynein function was perturbed. Impairment of dynein activity scaled with the expression level of the mutant alpha-tubulin in yeast, suggesting a dominant 'poisoning' mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30517687" 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="#7" class="mim-tip-reference" title="Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. <strong>Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.</strong> Cell 128: 45-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17218254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2006.12.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218254">Keays et al. (2007)</a> reported a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex accompanied by impaired neuronal migration. Fine mapping and genomic screening identified an S140G mutation in the Tuba1a gene. Functional studies showed that the mutation resulted in decreased GTP binding and impaired tubulin heterodimer formation. However, heterodimers that did form were able to polymerize and were incorporated into the microtubule network of cultured cells. Abnormal neuronal migration was manifest as perturbations in layers II/III and IV of the visual, auditory, and somatosensory cortices, and a fractured pyramidal cell layer in the hippocampus. Behavioral studies showed that the mutant mice had impaired spatial working memory, reduced anxiety, and abnormal nesting, consistent with a hippocampal deficit. <a href="#7" class="mim-tip-reference" title="Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. <strong>Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.</strong> Cell 128: 45-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17218254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2006.12.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218254">Keays et al. (2007)</a> concluded that pathogenic mutations in the TUBA1A gene interferes with microtubule function, thus impairing neuronal migration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17218254" 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">rs137853043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853043;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=rs137853043" 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=rs137853043" 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=RCV000007486 OR RCV000622693 OR RCV000767404 OR RCV001291302 OR RCV001564937" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007486, RCV000622693, RCV000767404, RCV001291302, RCV001564937" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007486...</a>
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<p>In a patient with lissencephaly (LIS3; <a href="/entry/611603">611603</a>), <a href="#7" class="mim-tip-reference" title="Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. <strong>Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.</strong> Cell 128: 45-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17218254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2006.12.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218254">Keays et al. (2007)</a> and <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified a heterozygous de novo 790C-T transition in exon 4 of the TUBA1A gene, resulting in an arg264-to-cys (R264C) substitution in a loop between H8 and S7. The patient had microcephaly, pachygyria, an abnormally shaped corpus callosum, and hypoplasia of the cerebellar vermis and brainstem. Clinical features included severe mental retardation, mild motor delay, and absence of seizures. <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> reported another unrelated patient with a similar phenotype who carried the R264C mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17584854+17218254" 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="Bahi-Buisson, N., Poirier, K., Boddaert, N., Saillour, Y., Castelnau, L., Philip, N., Buyse, G., Villard, L., Joriot, S., Marret, S., Bourgeois, M., Van Esch, H., Lagae, L., Amiel, J., Hertz-Pannier, L., Roubertie, A., Rivier, F., Pinard, J. M., Beldjord, C., Chelly, J. <strong>Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.</strong> J. Med. Genet. 45: 647-653, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728072</a>] [<a href="https://doi.org/10.1136/jmg.2008.058073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728072">Bahi-Buisson et al. (2008)</a> identified the R264C mutation in 2 additional unrelated patients with LIS3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728072" 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">rs137853044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853044;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=rs137853044" 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=rs137853044" 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=RCV000007487 OR RCV000767403 OR RCV001091238 OR RCV001291299 OR RCV001801361" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007487, RCV000767403, RCV001091238, RCV001291299, RCV001801361" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007487...</a>
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<p>In a patient with lissencephaly (LIS3; <a href="/entry/611603">611603</a>), <a href="#7" class="mim-tip-reference" title="Keays, D. A., Tian, G., Poirier, K., Huang, G.-J., Siebold, C., Cleak, J., Oliver, P. L., Fray, M., Harvey, R. J., Molnar, Z., Pinon, M. C., Dear, N., Valdar, W., Brown, S. D. M., Davies, K. E., Rawlins, J. N. P., Cowan, N. J., Nolan, P., Chelly, J., Flint, J. <strong>Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans.</strong> Cell 128: 45-57, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218254/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218254</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17218254[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2006.12.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218254">Keays et al. (2007)</a> and <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified a heterozygous de novo 1205G-A transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his (R402H) substitution at the beginning of the H11-H12 loop near the interface with beta-tubulin (<a href="/entry/191130">191130</a>). The patient had microcephaly, agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. Clinical features included profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17584854+17218254" 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 extensive in vitro functional expression assays, <a href="#15" class="mim-tip-reference" title="Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J. <strong>Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.</strong> Hum. Molec. Genet. 19: 3599-3613, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603323[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/ddq276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603323">Tian et al. (2010)</a> found that mutant R402H performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603323" 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">rs137853045 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853045;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=rs137853045" 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=rs137853045" 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=RCV000007488 OR RCV000767405" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007488, RCV000767405" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007488...</a>
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<p>In a female patient with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified a heterozygous de novo 562A-C transversion in the TUBA1A gene, resulting in an ile188-to-leu (I188L) substitution. She had microcephaly, laminar heterotopia, thin corpus callosum with partial agenesis, and hypoplasia of the brainstem and cerebellar vermis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17584854" 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 extensive in vitro functional expression assays, <a href="#15" class="mim-tip-reference" title="Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J. <strong>Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.</strong> Hum. Molec. Genet. 19: 3599-3613, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603323[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/ddq276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603323">Tian et al. (2010)</a> found that mutant I188L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603323" 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">rs137853046 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853046;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=rs137853046" 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=rs137853046" 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=RCV000007489 OR RCV000767429" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007489, RCV000767429" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007489...</a>
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<p>In a 26-week-old fetus with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified a de novo heterozygous 787C-A transversion in the TUBA1A gene, resulting in a pro263-to-thr (P263T) substitution. Postmortem examination showed agyria, agenesis of the corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17584854" 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 extensive in vitro functional expression assays, <a href="#15" class="mim-tip-reference" title="Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J. <strong>Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.</strong> Hum. Molec. Genet. 19: 3599-3613, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603323[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/ddq276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603323">Tian et al. (2010)</a> found that mutant P263T showed reduced stability and resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, with a damping of the microtubule growth rate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603323" 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">rs137853047 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853047;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=rs137853047" 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=rs137853047" 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=RCV000007490 OR RCV000767406 OR RCV001815163" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007490, RCV000767406, RCV001815163" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007490...</a>
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<p>In an 18-year-old man with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#13" class="mim-tip-reference" title="Poirier, K., Keays, D. A., Francis, F., Saillour, Y., Bahi, N., Manouvrier, S., Fallet-Bianco, C., Pasquier, L., Toutain, A., Tuy, F. P. D., Bienvenu, T., Joriot, S., and 12 others. <strong>Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A).</strong> Hum. Mutat. 28: 1055-1064, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>] [<a href="https://doi.org/10.1002/humu.20572" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17584854">Poirier et al. (2007)</a> identified a de novo heterozygous 1256C-T transition in the TUBA1A gene, resulting in a ser419-to-leu (S419L) substitution. He had profound mental retardation, spastic tetraplegia, intractable seizures, and pachygyria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17584854" 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 extensive in vitro functional expression assays, <a href="#15" class="mim-tip-reference" title="Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J. <strong>Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.</strong> Hum. Molec. Genet. 19: 3599-3613, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603323[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/ddq276" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603323">Tian et al. (2010)</a> found that mutant S419L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603323" 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">rs137853048 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853048;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=rs137853048" 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=rs137853048" 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=RCV000007491 OR RCV000767468" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007491, RCV000767468" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007491...</a>
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<p>In a 5.5-year-old boy with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#2" class="mim-tip-reference" title="Bahi-Buisson, N., Poirier, K., Boddaert, N., Saillour, Y., Castelnau, L., Philip, N., Buyse, G., Villard, L., Joriot, S., Marret, S., Bourgeois, M., Van Esch, H., Lagae, L., Amiel, J., Hertz-Pannier, L., Roubertie, A., Rivier, F., Pinard, J. M., Beldjord, C., Chelly, J. <strong>Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.</strong> J. Med. Genet. 45: 647-653, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728072</a>] [<a href="https://doi.org/10.1136/jmg.2008.058073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728072">Bahi-Buisson et al. (2008)</a> identified a de novo heterozygous 1190T-C transition in the TUBA1A gene, resulting in a leu397-to-pro (L397P) substitution. The patient had microcephaly, spastic diplegia, and cognitive delay with few words acquired. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and posterior agenesis of the corpus callosum. There was also severe vermian dysplasia of the cerebellum. The mutation was not identified in 360 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728072" 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">rs137853049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853049;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=rs137853049" 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=rs137853049" 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=RCV000007492 OR RCV000432377 OR RCV000622854 OR RCV000767469" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007492, RCV000432377, RCV000622854, RCV000767469" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007492...</a>
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<p>In a 4.5-year-old girl with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#2" class="mim-tip-reference" title="Bahi-Buisson, N., Poirier, K., Boddaert, N., Saillour, Y., Castelnau, L., Philip, N., Buyse, G., Villard, L., Joriot, S., Marret, S., Bourgeois, M., Van Esch, H., Lagae, L., Amiel, J., Hertz-Pannier, L., Roubertie, A., Rivier, F., Pinard, J. M., Beldjord, C., Chelly, J. <strong>Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations.</strong> J. Med. Genet. 45: 647-653, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18728072/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18728072</a>] [<a href="https://doi.org/10.1136/jmg.2008.058073" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18728072">Bahi-Buisson et al. (2008)</a> identified a de novo heterozygous 1264C-T transition in the TUBA1A gene, resulting in an arg422-to-cys (R422C) substitution. The patient had microcephaly, spastic diplegia, and could speak only in short sentences. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and mild hypoplasia of the corpus callosum. There was also mild vermian hypoplasia of the cerebellum. The mutation was not identified in 360 control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18728072" 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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TUBA1A, ARG422HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137853050 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137853050;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=rs137853050" 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=rs137853050" 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=RCV000007493 OR RCV000255074 OR RCV000767410 OR RCV001291201" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000007493, RCV000255074, RCV000767410, RCV001291201" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000007493...</a>
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<p>In 2 unrelated patients with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#12" class="mim-tip-reference" title="Morris-Rosendahl, D. J., Najm, J., Lachmeijer, A. M. A., Sztriha, L., Martins, M., Kuechler, A., Haug, V., Zeschnigk, C., Martin, P., Santos, M., Vasconcelos, C., Omran, H., Kraus, U., Van der Knaap, M. S., Schuierer, G., Kutsche, K., Uyanik, G. <strong>Refining the phenotype of alpha-1a tubulin (TUBA1A) mutation in patients with classical lissencephaly.</strong> Clin. Genet. 74: 425-433, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18954413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18954413</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01093.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18954413">Morris-Rosendahl et al. (2008)</a> identified a heterozygous 1265G-A transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his (R422H) substitution. In addition to the classic features of microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum and cerebellum, both patients had subtle evidence of subcortical band heterotopia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18954413" 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 LISSENCEPHALY 3</strong>
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TUBA1A, ILE5LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906840 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906840;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=rs387906840" 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=rs387906840" 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=RCV000023197 OR RCV000767414" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023197, RCV000767414" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023197...</a>
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<p>In 2 sisters, born of consanguineous Moroccan parents, with lissencephaly-3 (LIS3; <a href="/entry/611603">611603</a>), <a href="#6" class="mim-tip-reference" title="Jansen, A. C., Oostra, A., Desprechins, B., De Vlaeminck, Y., Verhelst, H., Regal, L., Verloo, P., Bockaert, N., Keymolen, K., Seneca, S., De Meirleir, L., Lissens, W. <strong>TUBA1A mutations: from isolated lissencephaly to familial polymicrogyria.</strong> Neurology 76: 988-992, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21403111/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21403111</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821043f5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21403111">Jansen et al. (2011)</a> identified a heterozygous 13A-C transversion in exon 2 of the TUBA1A gene, resulting in an ile5-to-leu (I5L) substitution. The girls had developmental delay, spastic diplegia, and ataxia; one had seizures. Brain MRI showed perisylvian polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with a hooked aspect of the right frontal horn due to abnormally shaped basal ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had optic nerve hypoplasia and mild vermian hypoplasia. The clinically asymptomatic mother was found to be somatic mosaic for the mutation, which was detected in 5.6% of DNA in peripheral blood. Her brain MRI showed a thin corpus callosum, hypoplasia of the superior vermis, and a thin medulla. The report indicated that rare familial recurrence of LIS3 can occur. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21403111" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1212/WNL.0b013e31821043f5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ygeno.2007.04.008" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17584854/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17584854</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17584854" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20572" target="_blank">Full Text</a>]
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</p>
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<a id="14" class="mim-anchor"></a>
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<a id="Scott2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Scott, A. F.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 10/3/2001.
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</p>
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<a id="15" class="mim-anchor"></a>
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<a id="Tian2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tian, G., Jaglin, X. H., Keays, D. A., Francis, F., Chelly, J., Cowan, N. J.
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<strong>Disease-associated mutations in TUBA1A result in a spectrum of defects in the tubulin folding and heterodimer assembly pathway.</strong>
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Hum. Molec. Genet. 19: 3599-3613, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603323[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=20603323" 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/ddq276" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 09/26/2019
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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George E. Tiller - updated : 9/5/2013<br>Cassandra L. Kniffin - updated : 4/18/2012<br>Cassandra L. Kniffin - updated : 3/3/2009<br>Cassandra L. Kniffin - updated : 2/12/2009<br>Cassandra L. Kniffin - updated : 11/19/2007<br>Patricia A. Hartz - updated : 12/21/2004<br>Alan F. Scott - updated : 10/3/2001
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 4/16/1998
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 10/14/2021
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<span class="mim-text-font">
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mgross : 09/26/2019<br>mgross : 09/26/2019<br>carol : 06/04/2019<br>carol : 03/11/2015<br>alopez : 9/5/2013<br>terry : 11/28/2012<br>carol : 5/3/2012<br>ckniffin : 4/18/2012<br>alopez : 8/18/2011<br>alopez : 8/18/2011<br>ckniffin : 8/3/2011<br>wwang : 3/6/2009<br>ckniffin : 3/3/2009<br>wwang : 2/20/2009<br>ckniffin : 2/12/2009<br>wwang : 12/14/2007<br>ckniffin : 11/19/2007<br>carol : 9/13/2007<br>carol : 9/11/2007<br>alopez : 2/8/2007<br>alopez : 2/8/2007<br>mgross : 1/12/2005<br>terry : 12/21/2004<br>joanna : 10/3/2001<br>alopez : 6/18/1999<br>psherman : 4/20/1998<br>psherman : 4/16/1998
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<span class="mim-font">
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<strong>*</strong> 602529
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<h3>
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TUBULIN, ALPHA-1A; TUBA1A
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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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<span class="mim-font">
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TUBULIN, ALPHA, BRAIN-SPECIFIC<br />
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B-ALPHA-1<br />
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TUBA3
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TUBA1A</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 718759003;
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<strong>
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Cytogenetic location: 12q13.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:49,184,795-49,189,080 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<span class="mim-font">
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12q13.12
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<span class="mim-font">
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Lissencephaly 3
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<span class="mim-font">
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611603
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<span class="mim-font">
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Autosomal dominant
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<strong>Gene Family</strong>
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<span class="mim-text-font">
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<p>Microtubules tend to be functionally distinct and are involved in mitosis, cell movement, intracellular movement, and other biologic processes. The main components of microtubules are different isoforms of alpha and beta tubulins, which are often cell-type specific.</p><p>Lewis and Cowan (1990) reviewed the alpha-tubulin gene family. In humans, this family consists of 15 to 20 dispersed genes, many of which are processed pseudogenes. The positions of the first 3 introns are identical between members of the human and rat gene families; in addition, some human alpha-tubulin genes have a fourth intron, also at an identical position. Within a vertebrate species, the genes can be distinguished by their 3-prime untranslated regions (UTRs). Since a large proportion of the diversity of alpha-tubulins is clustered at the C-terminal region and is conserved across species, alpha-tubulin genes can be classified based on homology of their encoded C-terminal motifs to those of mouse alpha-tubulin genes.</p>
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<strong>Nomenclature</strong>
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<span class="mim-text-font">
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<p>See Khodiyar et al. (2007) for a revised nomenclature of the alpha-tubulin gene family. </p>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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<span class="mim-text-font">
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<p>The b-alpha-1 gene, cloned from a human fetal brain cDNA library by Cowan et al. (1983), is the human counterpart of mouse M-alpha-1. By Northern blot analysis, Cowan et al. (1983) showed that b-alpha-1 mRNA is expressed only in brain. They found that the 3-prime UTR of b-alpha-1 is more than 80% homologous to the UTR of the rat brain alpha-tubulin gene, IL-alpha-T1. </p><p>Hall and Cowan (1985) screened a human genomic library with the 3-prime UTR of b-alpha-1 and isolated the b-alpha-1 gene and a pseudogene. B-alpha-1 encodes a predicted 451-amino acid protein that is 100% identical to the rat homolog and differs by only 2 and 3 amino acids from the pig and chicken homologs, respectively. Furthermore, they observed that the first and largest intron of the b-alpha-1 gene is homologous to that of the rat gene. Northern blotting showed that b-alpha-1 expression was restricted to morphologically differentiated neurologic cells. </p><p>By Northern blot analysis and in situ hybridization, Miller et al. (1987) found that the rat homolog of b-alpha-1, which they called T-alpha-1, is expressed at high levels during the extension of neuronal processes. </p><p>Crabtree et al. (2001) cloned alpha-tubulin variants from a human retina cDNA library. One variant had the same sequence as the clone isolated by Cowan et al. (1983) from fetal brain, and the other had the same sequence as the brain-specific alpha-tubulin clone isolated by Hall and Cowan (1985), suggesting that this alpha-tubulin gene is expressed in both brain and retina. </p><p>Poirier et al. (2007) detected high expression of the TUBA1A gene in human fetal brain. Detailed study of mouse embryos showed expression in the cortex, hippocampus, cerebellum, brainstem, and rostral migratory stream. Tuba1a expression was decreased in most neurons at later postnatal stages and in adulthood. </p>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hall and Cowan (1985) determined that the b-alpha-1 gene contains 4 exons and spans less than 4 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Scott (2001) mapped the TUBA1A gene to human chromosome 12 based on sequence similarity between the TUBA1A sequence (GenBank AF141347) and chromosome 12 clones RP11-234P5 and RP11-977B10, (GenBank AC016125 and GenBank AC010173).</p><p>Khodiyar et al. (2007) stated that the TUBA1A gene maps to human chromosome 12q13.12 and mouse chromosome 15F1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified 2 different de novo heterozygous mutations in the TUBA1A gene (602529.0001; 602529.0002). Poirier et al. (2007) identified de novo heterozygous TUBA1A mutations (see, e.g., 602529.0003-602529.0005) in 6 additional patients with a wide spectrum of brain dysgenesis, ranging from agyria to laminar heterotopia. Retrospective examination of brain MRI showed defects in the cerebellum, hippocampus, corpus callosum, and brainstem. Patients who survived showed mental retardation, seizures, motor delay, and microcephaly. In general, gyral malformations were more severe in the posterior than anterior brain regions. </p><p>Bahi-Buisson et al. (2008) identified 6 de novo mutations in the TUBA1A gene (see, e.g., 602529.0006; 602529.0007) in 6 of 100 patients with lissencephaly who were negative for mutations in other known lissencephaly-associated genes. The phenotype ranged from the less severe perisylvian pachygyria to the more severe posteriorly predominant pachygyria, which was associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. Patients with TUBA1A mutations shared a common clinical phenotype consisting of congenital microcephaly, mental retardation and diplegia/tetraplegia. </p><p>Morris-Rosendahl et al. (2008) identified 4 different TUBA1A mutations (see, e.g., 602529.0008) in 5 of 46 patients with variable patterns of lissencephaly on brain MRI and no DCX (300121) or PAFAH1B1 (601545) mutation. Four of the 5 patients had congenital microcephaly, and all had dysgenesis of the corpus callosum, cerebellar hypoplasia, and variable cortical malformations, including subtle subcortical band heterotopia and absence or hypoplasia of the anterior limb of the internal capsule. </p><p>Kumar et al. (2010) screened a cohort of 125 lissencephaly patients in whom mutations in DCX and PAFAH1B1 had been excluded and identified novel and recurrent TUBA1A mutations in 1% of children with classic lissencephaly and in 30% of children with lissencephaly with cerebellar hypoplasia. A TUBA1A mutation was also found in 1 child with agenesis of the corpus callosum and cerebellar hypoplasia without lissencephaly. The authors demonstrated a wider spectrum of phenotypes than had been reported and suggested that lissencephaly-associated mutations of TUBA1A may operate via diverse mechanisms that include disruption of binding sites for microtubule-associated proteins. </p><p>Tian et al. (2010) studied the effects of 9 disease-associated TUBA1A mutations on tubulin folding, heterodimer assembly, microtubule dynamics, and stability. The translational yield of each mutant protein varied across a continuum from an amount similar to that of wildtype for mutant L286F, to slightly reduced formation for mutants I188L (602529.0003), I238V, P263T (602529.0004), R402H (602529.0002) and S419L (602529.0005), to significantly diminished amounts for mutants V303G, L397P, and R402C. Studies of GTP-dependent polymerization and depolymerization indicated that all the disease-causing TUBA1A mutations were competent for assembly into microtubules in vitro. However, some of the mutant proteins showed defects in the tubulin heterodimer assembly pathway, with deficiencies in the production of intermediates. Mutants I188L, I238V, L397P and R402C all generated lower yields of intermediates compared to control TUBA1A; in addition, R402C showed a time-dependent decay of intermediates, indicating instability. Some of the mutant proteins (R264C, V303G, and L397P) also showed defective interaction with assembly chaperone protein TBCB (see, e.g., TBCA, 610058). Tests of heterodimer stability showed that P263T and V303G had reduced stability, whereas L397P and R402C were highly unstable. P263T expression resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, whereas the other mutant proteins did not show defects in microtubule growth. The findings demonstrated that different TUBA1A mutations result in a variety of tubulin defects, but also suggested that the mutations may cause compromised interactions with other interacting proteins essential for proper neuronal migration. </p><p>Aiken et al. (2019) found that expression of human TUBA1A R402C or R402H mutants in mouse brain disrupted cortical neuron migration. Analogous R402 mutant alpha-tubulins in yeast assembled into microtubules, but microtubule polymerization rates were lower and dynein function was perturbed. Impairment of dynein activity scaled with the expression level of the mutant alpha-tubulin in yeast, suggesting a dominant 'poisoning' mechanism. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Keays et al. (2007) reported a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex accompanied by impaired neuronal migration. Fine mapping and genomic screening identified an S140G mutation in the Tuba1a gene. Functional studies showed that the mutation resulted in decreased GTP binding and impaired tubulin heterodimer formation. However, heterodimers that did form were able to polymerize and were incorporated into the microtubule network of cultured cells. Abnormal neuronal migration was manifest as perturbations in layers II/III and IV of the visual, auditory, and somatosensory cortices, and a fractured pyramidal cell layer in the hippocampus. Behavioral studies showed that the mutant mice had impaired spatial working memory, reduced anxiety, and abnormal nesting, consistent with a hippocampal deficit. Keays et al. (2007) concluded that pathogenic mutations in the TUBA1A gene interferes with microtubule function, thus impairing neuronal migration. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 LISSENCEPHALY 3</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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TUBA1A, ARG264CYS
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<br />
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SNP: rs137853043,
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ClinVar: RCV000007486, RCV000622693, RCV000767404, RCV001291302, RCV001564937
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</span>
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<span class="mim-text-font">
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<p>In a patient with lissencephaly (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 790C-T transition in exon 4 of the TUBA1A gene, resulting in an arg264-to-cys (R264C) substitution in a loop between H8 and S7. The patient had microcephaly, pachygyria, an abnormally shaped corpus callosum, and hypoplasia of the cerebellar vermis and brainstem. Clinical features included severe mental retardation, mild motor delay, and absence of seizures. Poirier et al. (2007) reported another unrelated patient with a similar phenotype who carried the R264C mutation. </p><p>Bahi-Buisson et al. (2008) identified the R264C mutation in 2 additional unrelated patients with LIS3. </p>
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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 3</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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TUBA1A, ARG402HIS
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<br />
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SNP: rs137853044,
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ClinVar: RCV000007487, RCV000767403, RCV001091238, RCV001291299, RCV001801361
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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 (LIS3; 611603), Keays et al. (2007) and Poirier et al. (2007) identified a heterozygous de novo 1205G-A transition in exon 4 of the TUBA1A gene, resulting in an arg402-to-his (R402H) substitution at the beginning of the H11-H12 loop near the interface with beta-tubulin (191130). The patient had microcephaly, agyria, thin corpus callosum, abnormal hippocampus, and hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. Clinical features included profound mental retardation, spastic tetraplegia, and intractable tonic-clonic seizures. </p><p>By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant R402H performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. </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 3</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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TUBA1A, ILE188LEU
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<br />
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SNP: rs137853045,
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ClinVar: RCV000007488, RCV000767405
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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 female patient with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a heterozygous de novo 562A-C transversion in the TUBA1A gene, resulting in an ile188-to-leu (I188L) substitution. She had microcephaly, laminar heterotopia, thin corpus callosum with partial agenesis, and hypoplasia of the brainstem and cerebellar vermis. </p><p>By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant I188L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LISSENCEPHALY 3</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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TUBA1A, PRO263THR
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<br />
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SNP: rs137853046,
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ClinVar: RCV000007489, RCV000767429
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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 26-week-old fetus with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a de novo heterozygous 787C-A transversion in the TUBA1A gene, resulting in a pro263-to-thr (P263T) substitution. Postmortem examination showed agyria, agenesis of the corpus callosum, abnormal hippocampus, hypoplasia of the cerebellar vermis and brainstem, and severe ventricular dilatation. </p><p>By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant P263T showed reduced stability and resulted in the assembly of heterodimers with a deleterious effect on microtubule dynamics, with a damping of the microtubule growth rate. </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 3</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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TUBA1A, SER419LEU
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<br />
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SNP: rs137853047,
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ClinVar: RCV000007490, RCV000767406, RCV001815163
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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 an 18-year-old man with lissencephaly-3 (LIS3; 611603), Poirier et al. (2007) identified a de novo heterozygous 1256C-T transition in the TUBA1A gene, resulting in a ser419-to-leu (S419L) substitution. He had profound mental retardation, spastic tetraplegia, intractable seizures, and pachygyria. </p><p>By extensive in vitro functional expression assays, Tian et al. (2010) found that mutant S419L performed like wildtype, although there was a slight reduction in the amount of protein translated and a slight reduction in the formation of tubulin assembly intermediates. There were no obvious effects on de novo heterodimer assembly or microtubule dynamics, suggesting that the disease phenotype is likely to be caused by an effect on other microtubule-dependent processes such as the binding of associated proteins. </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 3</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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TUBA1A, LEU397PRO
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<br />
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SNP: rs137853048,
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ClinVar: RCV000007491, RCV000767468
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 5.5-year-old boy with lissencephaly-3 (LIS3; 611603), Bahi-Buisson et al. (2008) identified a de novo heterozygous 1190T-C transition in the TUBA1A gene, resulting in a leu397-to-pro (L397P) substitution. The patient had microcephaly, spastic diplegia, and cognitive delay with few words acquired. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and posterior agenesis of the corpus callosum. There was also severe vermian dysplasia of the cerebellum. The mutation was not identified in 360 control individuals. </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 3</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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TUBA1A, ARG422CYS
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<br />
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SNP: rs137853049,
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ClinVar: RCV000007492, RCV000432377, RCV000622854, RCV000767469
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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 4.5-year-old girl with lissencephaly-3 (LIS3; 611603), Bahi-Buisson et al. (2008) identified a de novo heterozygous 1264C-T transition in the TUBA1A gene, resulting in an arg422-to-cys (R422C) substitution. The patient had microcephaly, spastic diplegia, and could speak only in short sentences. MRI scan showed perisylvian pachygyria with dysgenesis of the internal capsule and mild hypoplasia of the corpus callosum. There was also mild vermian hypoplasia of the cerebellum. The mutation was not identified in 360 control individuals. </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 LISSENCEPHALY 3</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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TUBA1A, ARG422HIS
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<br />
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SNP: rs137853050,
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ClinVar: RCV000007493, RCV000255074, RCV000767410, RCV001291201
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients with lissencephaly-3 (LIS3; 611603), Morris-Rosendahl et al. (2008) identified a heterozygous 1265G-A transition in exon 4 of the TUBA1A gene, resulting in an arg422-to-his (R422H) substitution. In addition to the classic features of microcephaly, seizure, pachygyria, and hypoplasia of the corpus callosum and cerebellum, both patients had subtle evidence of subcortical band heterotopia. </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 LISSENCEPHALY 3</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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TUBA1A, ILE5LEU
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<br />
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SNP: rs387906840,
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ClinVar: RCV000023197, RCV000767414
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters, born of consanguineous Moroccan parents, with lissencephaly-3 (LIS3; 611603), Jansen et al. (2011) identified a heterozygous 13A-C transversion in exon 2 of the TUBA1A gene, resulting in an ile5-to-leu (I5L) substitution. The girls had developmental delay, spastic diplegia, and ataxia; one had seizures. Brain MRI showed perisylvian polymicrogyria, gray matter heterotopia, enlarged lateral ventricle with a hooked aspect of the right frontal horn due to abnormally shaped basal ganglia, thin corpus callosum, and hypoplasia of the pons. One girl had optic nerve hypoplasia and mild vermian hypoplasia. The clinically asymptomatic mother was found to be somatic mosaic for the mutation, which was detected in 5.6% of DNA in peripheral blood. Her brain MRI showed a thin corpus callosum, hypoplasia of the superior vermis, and a thin medulla. The report indicated that rare familial recurrence of LIS3 can occur. </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>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Aiken, J., Moore, J. K., Bates, E. A.
|
|
<strong>TUBA1A mutations identified in lissencephaly patients dominantly disrupt neuronal migration and impair dynein activity.</strong>
|
|
Hum. Molec. Genet. 28: 1227-1243, 2019.
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[PubMed: 30517687]
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[Full Text: https://doi.org/10.1093/hmg/ddy416]
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