3863 lines
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Entry
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- *602662 - TUBULIN, BETA-4A; TUBB4A
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- OMIM
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<p>
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<span class="h4">*602662</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<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="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/602662">Table View</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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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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<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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<h4 class="panel-title">
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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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<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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<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=ENSG00000104833;t=ENST00000264071" 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=10382" 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=602662" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000104833;t=ENST00000264071" 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_001289123,NM_001289127,NM_001289129,NM_001289130,NM_001289131,NM_006087" 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_006087" 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=602662" 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=04045&isoform_id=04045_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/TUBB4A" 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/35959,15489150,16306901,21361322,45503808,93141323,119589484,119589485,193786783,194373785,194376582,194381502,574584803,574584811,574584816,574584818,574584820" 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/P04350" 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 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=10382" 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=ENSG00000104833;t=ENST00000264071" 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=TUBB4A" 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=TUBB4A" 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+10382" 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/TUBB4A" 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:10382" 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/10382" 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=chr19&hgg_gene=ENST00000264071.7&hgg_start=6494319&hgg_end=6502848&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 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:20774" 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:20774" 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/tubb4a" 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=602662[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=602662[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/TUBB4A/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/ENSG00000104833" 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=TUBB4A" 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=TUBB4A" 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=TUBB4A" 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=TUBB4A&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/PA134949465" 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:20774" 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/FBgn0284243.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:107848" 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/TUBB4A#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:107848" 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/10382/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=10382" 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="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00000248;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00000248 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003171;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003171 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006536;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006536 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006538;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006538 </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 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:10382" 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=TUBB4A&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> 724283004<br />
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<strong>ICD10CM:</strong> G23.3<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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602662
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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, BETA-4A; TUBB4A
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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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TUBB4<br />
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TUBULIN, BETA, CLASS IVA
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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=TUBB4A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">TUBB4A</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/19/185?start=-3&limit=10&highlight=185">19p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:6494319-6502848&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'})">19:6,494,319-6,502,848</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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Location
|
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</th>
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<th>
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|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=128101,612438" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
</th>
|
|
<th>
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|
Phenotype <br /> MIM number
|
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</th>
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<th>
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Inheritance
|
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</th>
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<th>
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Phenotype <br /> mapping key
|
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</th>
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/19/185?start=-3&limit=10&highlight=185">
|
|
19p13.3
|
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</a>
|
|
</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Dystonia 4, torsion, autosomal dominant
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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|
|
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<a href="/entry/128101"> 128101 </a>
|
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Leukodystrophy, hypomyelinating, 6
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
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|
<a href="/entry/612438"> 612438 </a>
|
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<p>Microtubules are dynamic polymeric structures consisting of heterodimers of alpha-tubulins (see <a href="/entry/602529">602529</a>) and beta-tubulins that are continuously incorporated and released. Microtubules are an essential component of the cytoskeleton that function in mitosis, intracellular transport, neuron morphology, and ciliary and flagellar motility (<a href="#8" class="mim-tip-reference" title="Leandro-Garcia, L. J., Leskela, S., Landa, I., Montero-Conde, C., Lopez-Jimenez, E., Leton, R., Cascon, A., Robledo, M., Rodriguez-Antona, C. <strong>Tumoral and tissue-specific expression of the major human beta-tubulin isotypes.</strong> Cytoskeleton 67: 214-223, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20191564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20191564</a>] [<a href="https://doi.org/10.1002/cm.20436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20191564">Leandro-Garcia et al., 2010</a>). The TUBB4A gene encodes a brain-specific member of the beta-tubulin family that is most highly expressed in the cerebellum, putamen, and white matter (summary by <a href="#7" class="mim-tip-reference" title="Kancheva, D., Chamova, T., Guergueltcheva, V., Mitev, V., Azmanov, D. N., Kalaydjieva, L., Tournev, I., Jordanova, A. <strong>Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia.</strong> Mov. Disord. 30: 854-858, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25772097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25772097</a>] [<a href="https://doi.org/10.1002/mds.26196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25772097">Kancheva et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=25772097+20191564" 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="#4" class="mim-tip-reference" title="Hall, J. L., Dudley, L., Dobner, P. R., Lewis, S. A., Cowan, N. J. <strong>Identification of two human beta-tubulin isotypes.</strong> Molec. Cell. Biol. 3: 854-862, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6865944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6865944</a>] [<a href="https://doi.org/10.1128/mcb.3.5.854-862.1983" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6865944">Hall et al. (1983)</a> identified the TUBB4A gene, which they designated 5-beta. The 5-beta gene was expressed as a 2.6-kb transcript on Northern blots of HeLa cell mRNA. <a href="#9" class="mim-tip-reference" title="Lee, M. G.-S., Loomis, C., Cowan, N. J. <strong>Sequence of an expressed human beta-tubulin gene containing ten Alu family members.</strong> Nucleic Acids Res. 12: 5823-5836, 1984.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6462917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6462917</a>] [<a href="https://doi.org/10.1093/nar/12.14.5823" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6462917">Lee et al. (1984)</a> reported that the 5-beta sequence encodes a predicted 445-amino acid protein. Using Northern analysis, they determined that 5-beta is expressed in fetal brain, but not in cell lines derived from various other tissues. <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> stated that the mouse homolog of 5-beta, M-beta-4, is expressed specifically in brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=6462917+6865944" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using database analysis, <a href="#8" class="mim-tip-reference" title="Leandro-Garcia, L. J., Leskela, S., Landa, I., Montero-Conde, C., Lopez-Jimenez, E., Leton, R., Cascon, A., Robledo, M., Rodriguez-Antona, C. <strong>Tumoral and tissue-specific expression of the major human beta-tubulin isotypes.</strong> Cytoskeleton 67: 214-223, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20191564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20191564</a>] [<a href="https://doi.org/10.1002/cm.20436" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20191564">Leandro-Garcia et al. (2010)</a> identified 8 major beta-tubulins, including TUBB4A, which they called TUBB4. Quantitative RT-PCR of 21 normal human tissues detected high TUBB4A expression in brain and much lower expression in testis. Little to no expression was detected in other tissues examined. TUBB4A was the major beta-tubulin isotype in brain, where it represented 46% of all beta-tubulins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20191564" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In human brain, <a href="#6" class="mim-tip-reference" title="Hersheson, J., Mencacci, N. E., Davis, M., MacDonald, N., Trabzuni, D., Ryten, M., Pittman, A., Paudel, R., Kara, E., Fawcett, K., Plagnol, V., Bhatia, K. P., Medlar, A. J., Stanescu, H. C., Hardy, J., Kleta, R., Wood, N. W., Houlden, H. <strong>Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.</strong> Ann. Neurol. 73: 546-553, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23424103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23424103</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23424103[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.23832" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23424103">Hersheson et al. (2013)</a> found highest expression of the TUBB4A gene in the cerebellum, followed by putamen and white matter. The thalamus showed the lowest expression of all brain regions studied. Expression of TUBB4A in other body tissues was very low except for moderate expression in the testes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23424103" 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="Hartz, P. A. <strong>Personal Communication.</strong> Baltimore, Md. 2/28/2013."None>Hartz (2013)</a> mapped the TUBB4A gene to chromosome 19p13.3 based on an alignment of the TUBB4A sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC006570" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC006570</a>) with the genomic sequence (GRCh37).</p>
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<p><strong><em>Dystonia 4</em></strong></p><p>
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In affected members of a large multigenerational family of English and Australian origin with autosomal dominant dystonia-4 (DYT4; <a href="/entry/128101">128101</a>) (<a href="#13" class="mim-tip-reference" title="Parker, N. <strong>Hereditary whispering dysphonia.</strong> J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3156966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3156966</a>] [<a href="https://doi.org/10.1136/jnnp.48.3.218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3156966">Parker, 1985</a>), <a href="#6" class="mim-tip-reference" title="Hersheson, J., Mencacci, N. E., Davis, M., MacDonald, N., Trabzuni, D., Ryten, M., Pittman, A., Paudel, R., Kara, E., Fawcett, K., Plagnol, V., Bhatia, K. P., Medlar, A. J., Stanescu, H. C., Hardy, J., Kleta, R., Wood, N. W., Houlden, H. <strong>Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.</strong> Ann. Neurol. 73: 546-553, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23424103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23424103</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23424103[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.23832" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23424103">Hersheson et al. (2013)</a> identified a heterozygous mutation in the TUBB4A gene (R2G; <a href="#0001">602662.0001</a>), resulting in an arg2-to-gly (R2G) substitution at a highly conserved residue in the autoregulatory MREI domain. The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with the disorder in the family. Previous site-directed mutagenesis studies by <a href="#20" class="mim-tip-reference" title="Yen, T. J., Machlin, P. S., Cleveland, D. W. <strong>Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin.</strong> Nature 334: 580-585, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3405308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3405308</a>] [<a href="https://doi.org/10.1038/334580a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3405308">Yen et al. (1988)</a> had shown that mutations in the MREI domain, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23424103+3405308+3156966" 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>Independently and simultaneously, <a href="#11" class="mim-tip-reference" title="Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., and 17 others. <strong>Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.</strong> Ann. Neurol. 73: 537-545, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23595291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23595291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23595291[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.23829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23595291">Lohmann et al. (2013)</a> identified a heterozygous R2G mutation in the TUBB4A gene in the family with DYT4 originally reported by <a href="#13" class="mim-tip-reference" title="Parker, N. <strong>Hereditary whispering dysphonia.</strong> J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3156966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3156966</a>] [<a href="https://doi.org/10.1136/jnnp.48.3.218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3156966">Parker (1985)</a>. The mutation was found by genomewide linkage analysis and genome sequencing in 2 family members. Cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls. Screening of the TUBB4A gene in 394 unrelated patients with dystonia revealed a different missense variant (A271T; <a href="#0003">602662.0003</a>) in a woman with onset of spasmodic dysphonia at age 60 years. Functional studies of the A271T variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23595291+3156966" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using high-resolution melting and Sanger sequencing, <a href="#18" class="mim-tip-reference" title="Vemula, S. R., Xiao, J., Bastian, R. W., Momcilovic, D., Blitzer, A., LeDoux, M. S. <strong>Pathogenic variants in TUBB4A are not found in primary dystonia.</strong> Neurology 82: 1227-1230, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24598712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24598712</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000294" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24598712">Vemula et al. (2014)</a> did not find any pathogenic variants in the TUBB4A gene in 575 adult individuals with primary laryngeal, segmental, or generalized dystonia. The patients were mainly Caucasians of European descent. The findings suggested that variation in TUBB4A is not a significant cause of primary dystonia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24598712" 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 next-generation sequencing with a dystonia gene panel or whole-exome sequencing in 11 patients from 4 families with DYT4, <a href="#1" class="mim-tip-reference" title="Bally, J. F., Camargos, S., Oliveira Dos Santos, C., Kern, D. S., Lee, T., Pereira da Silva-Junior, F., Puga, R. D., Cardoso, F., Barbosa, E. R., Yadav, R., Ozelius, L. J., de Carvalho Aguiar, P., Lang, A. E. <strong>DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations.</strong> Neurology 96: e1887-e1897, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943487</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32943487[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1212/WNL.0000000000010882" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32943487">Bally et al. (2021)</a> identified 4 novel heterozygous missense variants in the TUBB4A gene (D295N, R46M, Q424H, and R121W). Variants segregated with disease in 3 of the families, with evidence for incomplete penetrance in 2; in the fourth family, 1 affected and 4 unaffected members carried the variant (D295N). All variants changed highly conserved amino acids. No functional studies were performed, but all variants were predicted to be deleterious by in silico analysis. All were confirmed by Sanger sequencing, and none was seen in population databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32943487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Hypomyelinating Leukodystrophy 6</em></strong></p><p>
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In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), <a href="#17" class="mim-tip-reference" title="Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others. <strong>A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.</strong> Am. J. Hum. Genet. 92: 767-773, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23582646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23582646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23582646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23582646">Simons et al. (2013)</a> identified the same de novo heterozygous mutation in the TUBB4A gene (D249N; <a href="#0002">602662.0002</a>). Two affected sibs inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and <a href="#17" class="mim-tip-reference" title="Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others. <strong>A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.</strong> Am. J. Hum. Genet. 92: 767-773, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23582646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23582646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23582646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23582646">Simons et al. (2013)</a> suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed by motor deterioration and extrapyramidal signs. Six patients had cognitive decline and 2 had mild intellectual disability, but 3 had normal cognitive development. All patients except 1 had some type of speech delay and dysarthria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23582646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 9-year-old boy with an attenuated form of HLD6, <a href="#2" class="mim-tip-reference" title="Blumkin, L., Halevy, A., Ben-Ami-Raichman, D., Dahari, D., Haviv, A., Sarit, C., Lev, D., van der Knaap, M. S., Lerman-Sagie, T., Leshinsky-Silver, E. <strong>Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.</strong> Neurogenetics 15: 107-113, 2014. Note: Erratum: Neurogenetics 15: 115 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24526230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24526230</a>] [<a href="https://doi.org/10.1007/s10048-014-0392-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24526230">Blumkin et al. (2014)</a> identified a de novo heterozygous missense mutation in the TUBB4A gene (E410K; <a href="#0004">602662.0004</a>). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24526230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 4-year-old girl with HLD6, <a href="#14" class="mim-tip-reference" title="Purnell, S. M., Bleyl, S. B., Bonkowsky, J. L. <strong>Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy.</strong> Pediat. Neurol. 50: 608-611, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24742798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24742798</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2014.01.051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24742798">Purnell et al. (2014)</a> identified a de novo heterozygous missense mutation in the TUBB4A gene (R156L; <a href="#0005">602662.0005</a>). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24742798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 8 unrelated Japanese patients with HLD6, <a href="#12" class="mim-tip-reference" title="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> identified heterozygous missense mutations in the TUBB4A gene (see, e.g., <a href="#0002">602662.0002</a>; <a href="#0004">602662.0004</a>; <a href="#0006">602662.0006</a>-<a href="#0007">602662.0007</a>). The mutations were found by whole-exome sequencing and occurred de novo in all cases with available parental samples. Structural modeling suggested that the mutations could affect microtubule assembly, structure, or interaction with other proteins, but functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24850488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=602662[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587776983 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776983;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587776983?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776983" 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=rs587776983" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In affected members of a large multigenerational family of English and Australian origin with autosomal dominant dystonia-4 (DYT4; <a href="/entry/128101">128101</a>) (<a href="#13" class="mim-tip-reference" title="Parker, N. <strong>Hereditary whispering dysphonia.</strong> J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3156966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3156966</a>] [<a href="https://doi.org/10.1136/jnnp.48.3.218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3156966">Parker, 1985</a>), <a href="#6" class="mim-tip-reference" title="Hersheson, J., Mencacci, N. E., Davis, M., MacDonald, N., Trabzuni, D., Ryten, M., Pittman, A., Paudel, R., Kara, E., Fawcett, K., Plagnol, V., Bhatia, K. P., Medlar, A. J., Stanescu, H. C., Hardy, J., Kleta, R., Wood, N. W., Houlden, H. <strong>Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.</strong> Ann. Neurol. 73: 546-553, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23424103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23424103</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23424103[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.23832" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23424103">Hersheson et al. (2013)</a> identified a heterozygous c.4C-G transversion in exon 1 of the TUBB4A gene, resulting in an arg2-to-gly (R2G) substitution at a highly conserved residue in the autoregulatory MREI domain. The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with the disorder in the family. Previous site-directed mutagenesis studies by <a href="#20" class="mim-tip-reference" title="Yen, T. J., Machlin, P. S., Cleveland, D. W. <strong>Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin.</strong> Nature 334: 580-585, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3405308/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3405308</a>] [<a href="https://doi.org/10.1038/334580a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3405308">Yen et al. (1988)</a> had shown that mutations in the MREI domain, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23424103+3405308+3156966" 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>Independently and simultaneously, <a href="#11" class="mim-tip-reference" title="Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., and 17 others. <strong>Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.</strong> Ann. Neurol. 73: 537-545, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23595291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23595291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23595291[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.23829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23595291">Lohmann et al. (2013)</a> identified a heterozygous R2G mutation in the TUBB4A gene in affected members of the family with DYT4 originally reported by <a href="#13" class="mim-tip-reference" title="Parker, N. <strong>Hereditary whispering dysphonia.</strong> J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3156966/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3156966</a>] [<a href="https://doi.org/10.1136/jnnp.48.3.218" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3156966">Parker (1985)</a>. The mutation was found by genomewide linkage analysis combined with genome sequencing in 2 family members. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in 1,000 control chromosomes or in the Exome Variant Server database. Primary cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls, suggesting that the pathogenesis involved reduced levels of TUBB4A. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23595291+3156966" 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">rs483352809 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs483352809;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=rs483352809" 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=rs483352809" 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=RCV000043681 OR RCV000255689 OR RCV001249621 OR RCV001814029" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043681, RCV000255689, RCV001249621, RCV001814029" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043681...</a>
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<p>In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), <a href="#17" class="mim-tip-reference" title="Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others. <strong>A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.</strong> Am. J. Hum. Genet. 92: 767-773, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23582646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23582646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23582646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23582646">Simons et al. (2013)</a> identified a de novo heterozygous c.745G-A transition in the TUBB4A gene, resulting in an asp249-to-asn (D249N) substitution at a highly conserved residue in the T7 loop, which interacts with the GTP nucleotide bound to the N-site of the alpha-tubulin and is important for the longitudinal interaction between tubulins. Two sibs with the disorder inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and <a href="#17" class="mim-tip-reference" title="Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others. <strong>A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.</strong> Am. J. Hum. Genet. 92: 767-773, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23582646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23582646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23582646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23582646">Simons et al. (2013)</a> suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed motor deterioration and extrapyramidal signs. Six patients had cognitive decline, 2 had mild intellectual disability, and 3 had normal cognitive development. All patients except 1 had some sort of speech delay and dysarthria. <a href="#17" class="mim-tip-reference" title="Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others. <strong>A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.</strong> Am. J. Hum. Genet. 92: 767-773, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23582646/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23582646</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23582646[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.03.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23582646">Simons et al. (2013)</a> noted that the D249N substitution has been identified in other beta-tubulins as being pathogenic: in the Tubb1 gene (<a href="/entry/612901">612901</a>) in Cavalier King Charles Spaniel dogs with inherited macrothrombocytopenia (<a href="#3" class="mim-tip-reference" title="Davis, B., Toivio-Kinnucan, M., Schuller, S., Boudreaux, M. K. <strong>Mutation in beta-1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels.</strong> J. Vet. Intern. Med. 22: 540-545, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18466252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18466252</a>] [<a href="https://doi.org/10.1111/j.1939-1676.2008.0085.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18466252">Davis et al., 2008</a>), and in a beta-tubulin gene in C. elegans with loss of touch sensitivity (<a href="#16" class="mim-tip-reference" title="Savage, C., Xue, Y., Mitani, S., Hall, D., Zakhary, R., Chalfie, M. <strong>Mutations in the Caenorhabditis elegans beta-tubulin gene mec-7: effects on microtubule assembly and stability and on tubulin autoregulation.</strong> J. Cell Sci. 107: 2165-2175, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7983175/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7983175</a>] [<a href="https://doi.org/10.1242/jcs.107.8.2165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7983175">Savage et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7983175+18466252+23582646" 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="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> identified the D249N mutation in 2 unrelated Japanese patients with HLD6, 1 of whom had previously been reported by <a href="#19" class="mim-tip-reference" title="Wakusawa, K., Haginoya, K., Kitamura, T., Togashi, N., Ishitobi, M., Yokoyama, H., Higano, S., Onuma, A., Nara, T., Iinuma, K. <strong>Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.</strong> Tohoku J. Exp. Med. 209: 163-167, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16707859</a>] [<a href="https://doi.org/10.1620/tjem.209.163" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16707859">Wakusawa et al. (2006)</a>. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The mutation occurred de novo in 1 patient and was absent from the mother's DNA in the second patient; paternal DNA for the second patient was not available. The D249N substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16707859+24850488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777074 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777074;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777074?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777074" 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=rs587777074" 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=RCV000077783 OR RCV004814998" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000077783, RCV004814998" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000077783...</a>
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<p>In a 71-year-old woman with torsion dystonia (DYT4; <a href="/entry/128101">128101</a>), <a href="#11" class="mim-tip-reference" title="Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., and 17 others. <strong>Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.</strong> Ann. Neurol. 73: 537-545, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23595291/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23595291</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23595291[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ana.23829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23595291">Lohmann et al. (2013)</a> identified a heterozygous change in the TUBB4A gene, resulting in an ala271-to-thr (A271T) substitution. The patient was ascertained from a cohort of 394 unrelated patients with dystonia who underwent screening for TUBB4A mutations. The patient had onset of spasmodic dysphonia and oromandibular dystonia and dyskinesia at age 60 years. Her mother had had dyskinesia around the mouth from age 70 years, and died at age 76; DNA from the mother was not available. Functional studies of the A271T variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23595291" 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">rs587777428 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777428;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=rs587777428" 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=rs587777428" 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=RCV000122736 OR RCV000763442 OR RCV001542616 OR RCV001563545 OR RCV001795219 OR RCV002463648" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122736, RCV000763442, RCV001542616, RCV001563545, RCV001795219, RCV002463648" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122736...</a>
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<p>In a 9-year-old boy with a slowly progressive form of hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), <a href="#2" class="mim-tip-reference" title="Blumkin, L., Halevy, A., Ben-Ami-Raichman, D., Dahari, D., Haviv, A., Sarit, C., Lev, D., van der Knaap, M. S., Lerman-Sagie, T., Leshinsky-Silver, E. <strong>Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.</strong> Neurogenetics 15: 107-113, 2014. Note: Erratum: Neurogenetics 15: 115 only, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24526230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24526230</a>] [<a href="https://doi.org/10.1007/s10048-014-0392-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24526230">Blumkin et al. (2014)</a> identified a de novo heterozygous c.1218G-A transition in the TUBB4A gene, resulting in a glu410-to-lys (E410K) substitution at a highly conserved residue in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24526230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated Japanese males with a protracted form of HLD6, <a href="#12" class="mim-tip-reference" title="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> identified a de novo heterozygous E410K substitution in the TUBB4A gene, which they stated resulted from a c.1228G-A transition. The patients were previously reported by <a href="#15" class="mim-tip-reference" title="Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N. <strong>Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.</strong> Brain Dev. 31: 582-587, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18851904/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18851904</a>] [<a href="https://doi.org/10.1016/j.braindev.2008.09.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18851904">Sasaki et al. (2009)</a> as patients 2 and 3. The mutations, which were found by whole-exome sequencing, were not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The affected residue is located on the exposed outer surface that mediates interactions with motor proteins and/or microtubule-associated proteins and is crucial for the kinesin microtubule interaction. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18851904+24850488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000122737 OR RCV000623232 OR RCV003982897" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000122737, RCV000623232, RCV003982897" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000122737...</a>
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<p>In a 4-year-old girl with hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), <a href="#14" class="mim-tip-reference" title="Purnell, S. M., Bleyl, S. B., Bonkowsky, J. L. <strong>Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy.</strong> Pediat. Neurol. 50: 608-611, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24742798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24742798</a>] [<a href="https://doi.org/10.1016/j.pediatrneurol.2014.01.051" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24742798">Purnell et al. (2014)</a> identified a de novo heterozygous c.467G-T transversion in exon 4 of the TUBB4A gene, resulting in an arg156-to-leu (R156L) substitution at a highly conserved residue in the alpha-helix-4 domain. The mutation was found by whole-exome sequencing; functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24742798" 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>.0006 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs587777467 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777467;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs587777467?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587777467" 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=rs587777467" 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=RCV000128409 OR RCV000350313" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128409, RCV000350313" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128409...</a>
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<p>In a 15-year-old Japanese girl with hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), <a href="#12" class="mim-tip-reference" title="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> identified a heterozygous c.5G-A transition in the TUBB4A gene, resulting in an arg2-to-gln (R2Q) substitution at a highly conserved residue in the MREI motif involved in autoregulatory mechanisms for beta-tubulin stability. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Parental DNA was not available. Structural modeling showed that the R2Q substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. The patient had a severe disorder, with onset of symptoms at 1.5 months of age. She had severe mental retardation with no head control, spasticity, rigidity, choreoathetosis, and dystonia. Brain MRI showed hypomyelination and atrophy of the cerebellum, basal ganglia, and corpus callosum. <a href="#12" class="mim-tip-reference" title="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> noted that a mutation at the same residue (R2G; <a href="#0001">602662.0001</a>) had been reported in a single large family with a much milder and different phenotype (DYT4; <a href="/entry/128101">128101</a>), and <a href="#12" class="mim-tip-reference" title="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> suggested that the large DYT4 family may have another modifying factor that protects against white matter abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24850488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587777468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587777468;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=rs587777468" 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=rs587777468" 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=RCV000128410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000128410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000128410</a>
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<p>In a 4-year-old Japanese boy with hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), <a href="#12" class="mim-tip-reference" title="Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H. <strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong> Neurology 82: 2230-2237, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24850488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24850488</a>] [<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24850488">Miyatake et al. (2014)</a> identified a de novo heterozygous c.533C-G transversion in the TUBB4A gene, resulting in a thr178-to-arg (T178R) substitution at a highly conserved residue at a longitudinal interheterodimer interface, suggesting that the mutation may affect the tubulin dimerization process. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24850488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
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TUBB4A, HIS190TYR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs761635539 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761635539;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs761635539?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs761635539" 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=rs761635539" 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=RCV000173012" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000173012" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000173012</a>
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<p>In 5 sibs with hypomyelinating leukodystrophy-6 (HLD6; <a href="/entry/612438">612438</a>), born of consanguineous Roma Gypsy parents from Bulgaria, <a href="#7" class="mim-tip-reference" title="Kancheva, D., Chamova, T., Guergueltcheva, V., Mitev, V., Azmanov, D. N., Kalaydjieva, L., Tournev, I., Jordanova, A. <strong>Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia.</strong> Mov. Disord. 30: 854-858, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25772097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25772097</a>] [<a href="https://doi.org/10.1002/mds.26196" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25772097">Kancheva et al. (2015)</a> identified a heterozygous c.568C-T transition (c.568C-T, NM_006087.1) in the TUBB4A gene, resulting in a his190-to-tyr (H190Y) substitution at a conserved residue in the H5 helix at the interface involved in contacts between microtubule protofilaments. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was also found in the mosaic state in the unaffected mother (10% of her blood cells carried the mutant allele). The variant was not found in 72 ethnically matched controls. Functional studies of the variant were not performed. The patients presented with early-onset complicated spastic paraplegia without basal ganglia involvement, dystonia, or cognitive dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25772097" 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 id="Bally2021" class="mim-anchor"></a>
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Bally, J. F., Camargos, S., Oliveira Dos Santos, C., Kern, D. S., Lee, T., Pereira da Silva-Junior, F., Puga, R. D., Cardoso, F., Barbosa, E. R., Yadav, R., Ozelius, L. J., de Carvalho Aguiar, P., Lang, A. E.
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<strong>DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations.</strong>
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Neurology 96: e1887-e1897, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32943487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32943487</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32943487[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=32943487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000010882" target="_blank">Full Text</a>]
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Blumkin, L., Halevy, A., Ben-Ami-Raichman, D., Dahari, D., Haviv, A., Sarit, C., Lev, D., van der Knaap, M. S., Lerman-Sagie, T., Leshinsky-Silver, E.
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<strong>Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.</strong>
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Neurogenetics 15: 107-113, 2014. Note: Erratum: Neurogenetics 15: 115 only, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24526230/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24526230</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24526230" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-014-0392-2" target="_blank">Full Text</a>]
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<a id="Davis2008" class="mim-anchor"></a>
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Davis, B., Toivio-Kinnucan, M., Schuller, S., Boudreaux, M. K.
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<strong>Mutation in beta-1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels.</strong>
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J. Vet. Intern. Med. 22: 540-545, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18466252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18466252</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18466252" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1939-1676.2008.0085.x" target="_blank">Full Text</a>]
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Hall, J. L., Dudley, L., Dobner, P. R., Lewis, S. A., Cowan, N. J.
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<strong>Identification of two human beta-tubulin isotypes.</strong>
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Molec. Cell. Biol. 3: 854-862, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6865944/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6865944</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6865944" 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/10.1128/mcb.3.5.854-862.1983" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000000535" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Sonja A. Rasmussen - updated : 07/07/2022
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Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 6/19/2014<br>Cassandra L. Kniffin -updated : 6/4/2014<br>Cassandra L. Kniffin - updated : 12/30/2013<br>Cassandra L. Kniffin - updated : 6/10/2013<br>Patricia A. Hartz - updated : 2/28/2013
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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 : 5/27/1998
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 07/08/2022
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<span class="mim-text-font">
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alopez : 07/07/2022<br>carol : 06/22/2015<br>mcolton : 6/17/2015<br>ckniffin : 6/16/2015<br>mgross : 10/30/2014<br>mgross : 10/30/2014<br>mgross : 10/29/2014<br>mcolton : 10/28/2014<br>carol : 6/20/2014<br>mcolton : 6/19/2014<br>ckniffin : 6/19/2014<br>alopez : 6/10/2014<br>mcolton : 6/10/2014<br>ckniffin : 6/4/2014<br>carol : 1/6/2014<br>carol : 1/6/2014<br>ckniffin : 12/30/2013<br>carol : 6/20/2013<br>ckniffin : 6/10/2013<br>mgross : 2/28/2013<br>joanna : 12/14/2004<br>psherman : 6/15/1999<br>alopez : 5/27/1998
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<span class="mim-font">
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<strong>*</strong> 602662
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<h3>
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TUBULIN, BETA-4A; TUBB4A
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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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TUBB4<br />
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TUBULIN, BETA, CLASS IVA
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: TUBB4A</em></strong>
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<strong>SNOMEDCT:</strong> 724283004;
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<strong>ICD10CM:</strong> G23.3;
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<strong>
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<em>
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Cytogenetic location: 19p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:6,494,319-6,502,848 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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<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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<tbody>
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<span class="mim-font">
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19p13.3
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<span class="mim-font">
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Dystonia 4, torsion, autosomal dominant
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<span class="mim-font">
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128101
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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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Leukodystrophy, hypomyelinating, 6
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<span class="mim-font">
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612438
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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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</table>
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Microtubules are dynamic polymeric structures consisting of heterodimers of alpha-tubulins (see 602529) and beta-tubulins that are continuously incorporated and released. Microtubules are an essential component of the cytoskeleton that function in mitosis, intracellular transport, neuron morphology, and ciliary and flagellar motility (Leandro-Garcia et al., 2010). The TUBB4A gene encodes a brain-specific member of the beta-tubulin family that is most highly expressed in the cerebellum, putamen, and white matter (summary by Kancheva et al., 2015). </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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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hall et al. (1983) identified the TUBB4A gene, which they designated 5-beta. The 5-beta gene was expressed as a 2.6-kb transcript on Northern blots of HeLa cell mRNA. Lee et al. (1984) reported that the 5-beta sequence encodes a predicted 445-amino acid protein. Using Northern analysis, they determined that 5-beta is expressed in fetal brain, but not in cell lines derived from various other tissues. Lewis and Cowan (1990) stated that the mouse homolog of 5-beta, M-beta-4, is expressed specifically in brain. </p><p>Using database analysis, Leandro-Garcia et al. (2010) identified 8 major beta-tubulins, including TUBB4A, which they called TUBB4. Quantitative RT-PCR of 21 normal human tissues detected high TUBB4A expression in brain and much lower expression in testis. Little to no expression was detected in other tissues examined. TUBB4A was the major beta-tubulin isotype in brain, where it represented 46% of all beta-tubulins. </p><p>In human brain, Hersheson et al. (2013) found highest expression of the TUBB4A gene in the cerebellum, followed by putamen and white matter. The thalamus showed the lowest expression of all brain regions studied. Expression of TUBB4A in other body tissues was very low except for moderate expression in the testes. </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>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Hartz (2013) mapped the TUBB4A gene to chromosome 19p13.3 based on an alignment of the TUBB4A sequence (GenBank BC006570) with the genomic sequence (GRCh37).</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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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Dystonia 4</em></strong></p><p>
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In affected members of a large multigenerational family of English and Australian origin with autosomal dominant dystonia-4 (DYT4; 128101) (Parker, 1985), Hersheson et al. (2013) identified a heterozygous mutation in the TUBB4A gene (R2G; 602662.0001), resulting in an arg2-to-gly (R2G) substitution at a highly conserved residue in the autoregulatory MREI domain. The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with the disorder in the family. Previous site-directed mutagenesis studies by Yen et al. (1988) had shown that mutations in the MREI domain, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis. </p><p>Independently and simultaneously, Lohmann et al. (2013) identified a heterozygous R2G mutation in the TUBB4A gene in the family with DYT4 originally reported by Parker (1985). The mutation was found by genomewide linkage analysis and genome sequencing in 2 family members. Cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls. Screening of the TUBB4A gene in 394 unrelated patients with dystonia revealed a different missense variant (A271T; 602662.0003) in a woman with onset of spasmodic dysphonia at age 60 years. Functional studies of the A271T variant were not performed. </p><p>Using high-resolution melting and Sanger sequencing, Vemula et al. (2014) did not find any pathogenic variants in the TUBB4A gene in 575 adult individuals with primary laryngeal, segmental, or generalized dystonia. The patients were mainly Caucasians of European descent. The findings suggested that variation in TUBB4A is not a significant cause of primary dystonia. </p><p>By next-generation sequencing with a dystonia gene panel or whole-exome sequencing in 11 patients from 4 families with DYT4, Bally et al. (2021) identified 4 novel heterozygous missense variants in the TUBB4A gene (D295N, R46M, Q424H, and R121W). Variants segregated with disease in 3 of the families, with evidence for incomplete penetrance in 2; in the fourth family, 1 affected and 4 unaffected members carried the variant (D295N). All variants changed highly conserved amino acids. No functional studies were performed, but all variants were predicted to be deleterious by in silico analysis. All were confirmed by Sanger sequencing, and none was seen in population databases. </p><p><strong><em>Hypomyelinating Leukodystrophy 6</em></strong></p><p>
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In 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; 612438), Simons et al. (2013) identified the same de novo heterozygous mutation in the TUBB4A gene (D249N; 602662.0002). Two affected sibs inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed by motor deterioration and extrapyramidal signs. Six patients had cognitive decline and 2 had mild intellectual disability, but 3 had normal cognitive development. All patients except 1 had some type of speech delay and dysarthria. </p><p>In a 9-year-old boy with an attenuated form of HLD6, Blumkin et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (E410K; 602662.0004). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. </p><p>In a 4-year-old girl with HLD6, Purnell et al. (2014) identified a de novo heterozygous missense mutation in the TUBB4A gene (R156L; 602662.0005). The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. </p><p>In 8 unrelated Japanese patients with HLD6, Miyatake et al. (2014) identified heterozygous missense mutations in the TUBB4A gene (see, e.g., 602662.0002; 602662.0004; 602662.0006-602662.0007). The mutations were found by whole-exome sequencing and occurred de novo in all cases with available parental samples. Structural modeling suggested that the mutations could affect microtubule assembly, structure, or interaction with other proteins, but functional studies were not performed. </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>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 DYSTONIA 4, TORSION, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TUBB4A, ARG2GLY
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<br />
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SNP: rs587776983,
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gnomAD: rs587776983,
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ClinVar: RCV000043680, RCV000258667
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large multigenerational family of English and Australian origin with autosomal dominant dystonia-4 (DYT4; 128101) (Parker, 1985), Hersheson et al. (2013) identified a heterozygous c.4C-G transversion in exon 1 of the TUBB4A gene, resulting in an arg2-to-gly (R2G) substitution at a highly conserved residue in the autoregulatory MREI domain. The mutation, which was found by linkage analysis and exome sequencing, was not found in several large control databases and segregated with the disorder in the family. Previous site-directed mutagenesis studies by Yen et al. (1988) had shown that mutations in the MREI domain, including R2G, abrogate the autoregulatory capability of TUBB4A, which may affect the balance of tubulin subunits and interfere with proper assembly. The findings suggested a role for the cytoskeleton in dystonia pathogenesis. </p><p>Independently and simultaneously, Lohmann et al. (2013) identified a heterozygous R2G mutation in the TUBB4A gene in affected members of the family with DYT4 originally reported by Parker (1985). The mutation was found by genomewide linkage analysis combined with genome sequencing in 2 family members. The mutation, which was confirmed by Sanger sequencing, segregated with the disorder in the family and was not present in 1,000 control chromosomes or in the Exome Variant Server database. Primary cells from 1 of the mutation carriers showed decreased levels of mutant TUBB4A mRNA compared to controls, suggesting that the pathogenesis involved reduced levels of TUBB4A. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TUBB4A, ASP249ASN
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<br />
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SNP: rs483352809,
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ClinVar: RCV000043681, RCV000255689, RCV001249621, RCV001814029
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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 9 unrelated patients with hypomyelinating leukodystrophy-6 (HLD6; 612438), Simons et al. (2013) identified a de novo heterozygous c.745G-A transition in the TUBB4A gene, resulting in an asp249-to-asn (D249N) substitution at a highly conserved residue in the T7 loop, which interacts with the GTP nucleotide bound to the N-site of the alpha-tubulin and is important for the longitudinal interaction between tubulins. Two sibs with the disorder inherited the mutation from their unaffected mother, who was found to be somatic mosaic for the mutation. The D249N mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. TUBB4A is highly expressed in neurons, and Simons et al. (2013) suggested that the mutation may result in a dominant-negative effect on tubulin dimerization, microtubule polymerization, or microtubule stability in neurons with a secondary involvement of glial cells. The phenotype was characterized primarily by onset in the first years of life of delayed motor development or gait instability, followed motor deterioration and extrapyramidal signs. Six patients had cognitive decline, 2 had mild intellectual disability, and 3 had normal cognitive development. All patients except 1 had some sort of speech delay and dysarthria. Simons et al. (2013) noted that the D249N substitution has been identified in other beta-tubulins as being pathogenic: in the Tubb1 gene (612901) in Cavalier King Charles Spaniel dogs with inherited macrothrombocytopenia (Davis et al., 2008), and in a beta-tubulin gene in C. elegans with loss of touch sensitivity (Savage et al., 1994). </p><p>Miyatake et al. (2014) identified the D249N mutation in 2 unrelated Japanese patients with HLD6, 1 of whom had previously been reported by Wakusawa et al. (2006). The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The mutation occurred de novo in 1 patient and was absent from the mother's DNA in the second patient; paternal DNA for the second patient was not available. The D249N substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. </p>
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</span>
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</div>
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<div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 DYSTONIA 4, TORSION, AUTOSOMAL DOMINANT</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TUBB4A, ALA271THR
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<br />
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SNP: rs587777074,
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gnomAD: rs587777074,
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ClinVar: RCV000077783, RCV004814998
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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 71-year-old woman with torsion dystonia (DYT4; 128101), Lohmann et al. (2013) identified a heterozygous change in the TUBB4A gene, resulting in an ala271-to-thr (A271T) substitution. The patient was ascertained from a cohort of 394 unrelated patients with dystonia who underwent screening for TUBB4A mutations. The patient had onset of spasmodic dysphonia and oromandibular dystonia and dyskinesia at age 60 years. Her mother had had dyskinesia around the mouth from age 70 years, and died at age 76; DNA from the mother was not available. Functional studies of the A271T variant were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TUBB4A, GLU410LYS
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<br />
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SNP: rs587777428,
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ClinVar: RCV000122736, RCV000763442, RCV001542616, RCV001563545, RCV001795219, RCV002463648
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 9-year-old boy with a slowly progressive form of hypomyelinating leukodystrophy-6 (HLD6; 612438), Blumkin et al. (2014) identified a de novo heterozygous c.1218G-A transition in the TUBB4A gene, resulting in a glu410-to-lys (E410K) substitution at a highly conserved residue in the C-terminal domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases. Functional studies of the variant were not performed. </p><p>In 2 unrelated Japanese males with a protracted form of HLD6, Miyatake et al. (2014) identified a de novo heterozygous E410K substitution in the TUBB4A gene, which they stated resulted from a c.1228G-A transition. The patients were previously reported by Sasaki et al. (2009) as patients 2 and 3. The mutations, which were found by whole-exome sequencing, were not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. The affected residue is located on the exposed outer surface that mediates interactions with motor proteins and/or microtubule-associated proteins and is crucial for the kinesin microtubule interaction. Functional studies of the variant were not performed. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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TUBB4A, ARG156LEU
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<br />
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SNP: rs587777429,
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gnomAD: rs587777429,
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ClinVar: RCV000122737, RCV000623232, RCV003982897
|
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</span>
|
|
</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 4-year-old girl with hypomyelinating leukodystrophy-6 (HLD6; 612438), Purnell et al. (2014) identified a de novo heterozygous c.467G-T transversion in exon 4 of the TUBB4A gene, resulting in an arg156-to-leu (R156L) substitution at a highly conserved residue in the alpha-helix-4 domain. The mutation was found by whole-exome sequencing; functional studies were not performed. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
TUBB4A, ARG2GLN
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<br />
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SNP: rs587777467,
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gnomAD: rs587777467,
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|
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ClinVar: RCV000128409, RCV000350313
|
|
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 15-year-old Japanese girl with hypomyelinating leukodystrophy-6 (HLD6; 612438), Miyatake et al. (2014) identified a heterozygous c.5G-A transition in the TUBB4A gene, resulting in an arg2-to-gln (R2Q) substitution at a highly conserved residue in the MREI motif involved in autoregulatory mechanisms for beta-tubulin stability. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Parental DNA was not available. Structural modeling showed that the R2Q substitution occurs at an intraheterodimer interface, suggesting that the mutation may affect tubulin heterodimerization; however, functional studies were not performed. The patient had a severe disorder, with onset of symptoms at 1.5 months of age. She had severe mental retardation with no head control, spasticity, rigidity, choreoathetosis, and dystonia. Brain MRI showed hypomyelination and atrophy of the cerebellum, basal ganglia, and corpus callosum. Miyatake et al. (2014) noted that a mutation at the same residue (R2G; 602662.0001) had been reported in a single large family with a much milder and different phenotype (DYT4; 128101), and Miyatake et al. (2014) suggested that the large DYT4 family may have another modifying factor that protects against white matter abnormalities. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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TUBB4A, THR178ARG
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<br />
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SNP: rs587777468,
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|
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ClinVar: RCV000128410
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old Japanese boy with hypomyelinating leukodystrophy-6 (HLD6; 612438), Miyatake et al. (2014) identified a de novo heterozygous c.533C-G transversion in the TUBB4A gene, resulting in a thr178-to-arg (T178R) substitution at a highly conserved residue at a longitudinal interheterodimer interface, suggesting that the mutation may affect the tubulin dimerization process. The mutation, which was found by whole-exome sequencing, was not present in the Exome Sequencing Project or 1000 Genomes Project databases, or in 575 in-house control exomes. Functional studies were not performed. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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|
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 LEUKODYSTROPHY, HYPOMYELINATING, 6</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
TUBB4A, HIS190TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs761635539,
|
|
|
|
|
|
gnomAD: rs761635539,
|
|
|
|
|
|
ClinVar: RCV000173012
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 sibs with hypomyelinating leukodystrophy-6 (HLD6; 612438), born of consanguineous Roma Gypsy parents from Bulgaria, Kancheva et al. (2015) identified a heterozygous c.568C-T transition (c.568C-T, NM_006087.1) in the TUBB4A gene, resulting in a his190-to-tyr (H190Y) substitution at a conserved residue in the H5 helix at the interface involved in contacts between microtubule protofilaments. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was also found in the mosaic state in the unaffected mother (10% of her blood cells carried the mutant allele). The variant was not found in 72 ethnically matched controls. Functional studies of the variant were not performed. The patients presented with early-onset complicated spastic paraplegia without basal ganglia involvement, dystonia, or cognitive dysfunction. </p>
|
|
</span>
|
|
</div>
|
|
|
|
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<div>
|
|
<br />
|
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</div>
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|
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</div>
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|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</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">
|
|
Bally, J. F., Camargos, S., Oliveira Dos Santos, C., Kern, D. S., Lee, T., Pereira da Silva-Junior, F., Puga, R. D., Cardoso, F., Barbosa, E. R., Yadav, R., Ozelius, L. J., de Carvalho Aguiar, P., Lang, A. E.
|
|
<strong>DYT-TUBB4A (DYT4 dystonia): new clinical and genetic observations.</strong>
|
|
Neurology 96: e1887-e1897, 2021.
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[PubMed: 32943487]
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[Full Text: https://doi.org/10.1212/WNL.0000000000010882]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Blumkin, L., Halevy, A., Ben-Ami-Raichman, D., Dahari, D., Haviv, A., Sarit, C., Lev, D., van der Knaap, M. S., Lerman-Sagie, T., Leshinsky-Silver, E.
|
|
<strong>Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.</strong>
|
|
Neurogenetics 15: 107-113, 2014. Note: Erratum: Neurogenetics 15: 115 only, 2014.
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[PubMed: 24526230]
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[Full Text: https://doi.org/10.1007/s10048-014-0392-2]
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Davis, B., Toivio-Kinnucan, M., Schuller, S., Boudreaux, M. K.
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<strong>Mutation in beta-1-tubulin correlates with macrothrombocytopenia in Cavalier King Charles Spaniels.</strong>
|
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J. Vet. Intern. Med. 22: 540-545, 2008.
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[PubMed: 18466252]
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[Full Text: https://doi.org/10.1111/j.1939-1676.2008.0085.x]
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<li>
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<p class="mim-text-font">
|
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Hall, J. L., Dudley, L., Dobner, P. R., Lewis, S. A., Cowan, N. J.
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<strong>Identification of two human beta-tubulin isotypes.</strong>
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Molec. Cell. Biol. 3: 854-862, 1983.
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[PubMed: 6865944]
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[Full Text: https://doi.org/10.1128/mcb.3.5.854-862.1983]
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</p>
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<li>
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<p class="mim-text-font">
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Hartz, P. A.
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<strong>Personal Communication.</strong>
|
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Baltimore, Md. 2/28/2013.
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</p>
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Hersheson, J., Mencacci, N. E., Davis, M., MacDonald, N., Trabzuni, D., Ryten, M., Pittman, A., Paudel, R., Kara, E., Fawcett, K., Plagnol, V., Bhatia, K. P., Medlar, A. J., Stanescu, H. C., Hardy, J., Kleta, R., Wood, N. W., Houlden, H.
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<strong>Mutations in the autoregulatory domain of beta-tubulin 4a cause hereditary dystonia.</strong>
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Ann. Neurol. 73: 546-553, 2013.
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[PubMed: 23424103]
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[Full Text: https://doi.org/10.1002/ana.23832]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kancheva, D., Chamova, T., Guergueltcheva, V., Mitev, V., Azmanov, D. N., Kalaydjieva, L., Tournev, I., Jordanova, A.
|
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<strong>Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia.</strong>
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Mov. Disord. 30: 854-858, 2015.
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[PubMed: 25772097]
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[Full Text: https://doi.org/10.1002/mds.26196]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Leandro-Garcia, L. J., Leskela, S., Landa, I., Montero-Conde, C., Lopez-Jimenez, E., Leton, R., Cascon, A., Robledo, M., Rodriguez-Antona, C.
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<strong>Tumoral and tissue-specific expression of the major human beta-tubulin isotypes.</strong>
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Cytoskeleton 67: 214-223, 2010.
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[PubMed: 20191564]
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[Full Text: https://doi.org/10.1002/cm.20436]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Lee, M. G.-S., Loomis, C., Cowan, N. J.
|
|
<strong>Sequence of an expressed human beta-tubulin gene containing ten Alu family members.</strong>
|
|
Nucleic Acids Res. 12: 5823-5836, 1984.
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|
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[PubMed: 6462917]
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[Full Text: https://doi.org/10.1093/nar/12.14.5823]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Lewis, S. A., Cowan, N. J.
|
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<strong>Tubulin genes: structure, expression, and regulation.In: Avila, J. (ed.) : Microtubule proteins.</strong>
|
|
Boca Raton: CRC Press, Inc. 1990. Pp. 37-66.
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|
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</p>
|
|
</li>
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<li>
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<p class="mim-text-font">
|
|
Lohmann, K., Wilcox, R. A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.-S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., and 17 others.
|
|
<strong>Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.</strong>
|
|
Ann. Neurol. 73: 537-545, 2013.
|
|
|
|
|
|
[PubMed: 23595291]
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|
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[Full Text: https://doi.org/10.1002/ana.23829]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Miyatake, S., Osaka, H., Shiina, M., Sasaki, M., Takanashi, J., Haginoya, K., Wada, T., Morimoto, M., Ando, N., Ikuta, Y., Nakashima, M., Tsurusaki, Y., Miyake, N., Ogata, K., Matsumoto, N., Saitsu, H.
|
|
<strong>Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.</strong>
|
|
Neurology 82: 2230-2237, 2014.
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|
|
[PubMed: 24850488]
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|
|
[Full Text: https://doi.org/10.1212/WNL.0000000000000535]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Parker, N.
|
|
<strong>Hereditary whispering dysphonia.</strong>
|
|
J. Neurol. Neurosurg. Psychiat. 48: 218-224, 1985.
|
|
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|
|
[PubMed: 3156966]
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|
|
[Full Text: https://doi.org/10.1136/jnnp.48.3.218]
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Purnell, S. M., Bleyl, S. B., Bonkowsky, J. L.
|
|
<strong>Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy.</strong>
|
|
Pediat. Neurol. 50: 608-611, 2014.
|
|
|
|
|
|
[PubMed: 24742798]
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|
|
[Full Text: https://doi.org/10.1016/j.pediatrneurol.2014.01.051]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Sasaki, M., Takanashi, J., Tada, H., Sakuma, H., Furushima, W., Sato, N.
|
|
<strong>Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.</strong>
|
|
Brain Dev. 31: 582-587, 2009.
|
|
|
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|
|
[PubMed: 18851904]
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|
|
[Full Text: https://doi.org/10.1016/j.braindev.2008.09.003]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Savage, C., Xue, Y., Mitani, S., Hall, D., Zakhary, R., Chalfie, M.
|
|
<strong>Mutations in the Caenorhabditis elegans beta-tubulin gene mec-7: effects on microtubule assembly and stability and on tubulin autoregulation.</strong>
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Simons, C., Wolf, N. I., McNeil, N., Caldovic, L., Devaney, J. M., Takanohashi, A., Crawford, J., Ru, K., Grimmond, S. M., Miller, D., Tonduti, D., Schmidt J. L., and 9 others.
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<strong>A de novo mutation in the beta-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.</strong>
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Vemula, S. R., Xiao, J., Bastian, R. W., Momcilovic, D., Blitzer, A., LeDoux, M. S.
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<strong>Pathogenic variants in TUBB4A are not found in primary dystonia.</strong>
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Wakusawa, K., Haginoya, K., Kitamura, T., Togashi, N., Ishitobi, M., Yokoyama, H., Higano, S., Onuma, A., Nara, T., Iinuma, K.
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Yen, T. J., Machlin, P. S., Cleveland, D. W.
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<strong>Autoregulated instability of beta-tubulin mRNAs by recognition of the nascent amino terminus of beta-tubulin.</strong>
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Sonja A. Rasmussen - updated : 07/07/2022<br>Cassandra L. Kniffin - updated : 6/16/2015<br>Cassandra L. Kniffin - updated : 6/19/2014<br>Cassandra L. Kniffin -updated : 6/4/2014<br>Cassandra L. Kniffin - updated : 12/30/2013<br>Cassandra L. Kniffin - updated : 6/10/2013<br>Patricia A. Hartz - updated : 2/28/2013
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