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- *606214 - SPECTRIN, BETA, NONERYTHROCYTIC, 4; SPTBN4
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- OMIM
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<p>
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<span class="h4">*606214</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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="#geneStructure">Gene Structure</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="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/606214">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000160460;t=ENST00000598249" 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=57731" 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=606214" 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 class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<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=ENSG00000160460;t=ENST00000598249" 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_020971,NM_025213,XM_017027049,XM_017027050,XM_017027051,XM_017027052" 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_020971" 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=606214" 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=09372&isoform_id=09372_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/SPTBN4" 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/6453547,10047361,11602836,11602887,11602890,11992162,11992164,17368942,33340563,33340565,115430237,115430239,119577377,119577378,119577379,119577380,119577381,119577382,1034608701,1034608703,1034608706,1034608708,2462566546,2462566548,2462566550,2462566552" 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/Q9H254" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=57731" 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=ENSG00000160460;t=ENST00000598249" 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=SPTBN4" 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=SPTBN4" 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+57731" 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/SPTBN4" 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:57731" 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/57731" 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=ENST00000598249.6&hgg_start=40467001&hgg_end=40576464&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:14896" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606214[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=606214[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://gnomad.broadinstitute.org/gene/ENSG00000160460" 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=SPTBN4" 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=SPTBN4" 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=SPTBN4" 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=SPTBN4&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/PA37918" 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:14896" 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/FBgn0250788.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:1890574" 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/SPTBN4#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:1890574" 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/57731/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA002232/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=57731" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006803;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-081031-8" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:57731" 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=SPTBN4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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606214
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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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SPECTRIN, BETA, NONERYTHROCYTIC, 4; SPTBN4
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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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SPECTRIN, BETA-IV; SPNB4<br />
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QUIVERING, MOUSE, HOMOLOG OF; QV
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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=SPTBN4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SPTBN4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: <a href="/geneMap/19/706?start=-3&limit=10&highlight=706">19q13.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:40467001-40576464&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'})">19:40,467,001-40,576,464</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/19/706?start=-3&limit=10&highlight=706">
|
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19q13.2
|
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</a>
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/617519"> 617519 </a>
|
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|
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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 recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/606214" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/606214" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</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="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
|
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
|
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</span>
|
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</h4>
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<p>The SPTBN4 gene encodes a nonerythrocytic member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle. Spectrins are rod-shaped proteins that were originally identified as part of the lattice-like cytoskeleton under the erythrocyte membrane. Spectrins have also been found in the membranes of intracellular organelles, such as the Golgi, lysosomes, and secretory vesicles. The spectrin molecule is a tetramer consisting of 2 alpha (see, e.g., SPTA1, <a href="/entry/182860">182860</a>) and 2 beta subunits, in which the N terminus of an alpha subunit is tightly connected with the C terminus of a beta subunit to form a heterodimer. Spectrin repeats contain approximately 106 amino acids. Alpha subunits have 20 spectrin repeats, while beta subunits have 17 (summary by <a href="#1" class="mim-tip-reference" title="Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M. <strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong> J. Cell Biol. 151: 985-1001, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.151.5.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086001">Berghs et al., 2000</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11086001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By screening a size-fractionated adult brain cDNA library for cDNAs with the potential to encode large proteins, <a href="#5" class="mim-tip-reference" title="Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 7: 273-281, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>] [<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10997877">Nagase et al. (2000)</a> isolated a partial cDNA encoding SPTBN4, which they called KIAA1642. RT-PCR analysis detected ubiquitous expression of SPTBN4, with relatively high levels in adult and fetal brain, low levels in lung, liver, pancreas, and spleen, and intermediate levels in the other tissues tested and in specific brain regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10997877" 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 a yeast 2-hybrid screen of a brain cDNA library with the cytoplasmic domain of ICA512 (PTPRN; <a href="/entry/601773">601773</a>) as bait, followed by probing a brain cDNA library, PCR, and genomic sequence analysis, <a href="#1" class="mim-tip-reference" title="Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M. <strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong> J. Cell Biol. 151: 985-1001, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.151.5.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086001">Berghs et al. (2000)</a> isolated cDNAs encoding SPTBN4 and several splice variants. Sequence analysis predicted that the full-length 2,559-amino acid SPTBN4 protein, designated sigma-1, contains 2 N-terminal calponin homology domains, which mediate interactions with actin; 16 complete spectrin repeats; 1 partial spectrin repeat; a unique proline-rich, basic domain containing 4 ERQES repeats; numerous SH3 binding sites; and a C-terminal pleckstrin homology domain. An insertion in exon 17 termed exon 17b yields a 1,302-residue splice variant, sigma-2, which terminates in spectrin repeat 9, and another variant, sigma-3, which begins at exon 17b to generate a 1,307-amino acid protein. Variant sigma-4 has an insertion in exon 30 termed exon 30b that introduces 42 amino acids and a stop codon, resulting in a 2,149-amino acid protein that lacks the ERQES and pleckstrin homology domains. Binding analysis indicated that the C terminus of SPTBN4 binds to PTPRN and only weakly to an active tyrosine phosphatase mutant of PTPRN and to PHOGRIN (<a href="/entry/601698">601698</a>). Northern blot analysis revealed expression of 9.0-, 5.1-, and 3.1-kb SPTBN4 transcripts that were predominantly expressed in brain. Western blot analysis showed expression of 250- and 160-kD proteins in rat brain and human pancreatic islets, as well as a 140-kD protein in rat brain only. Phosphatase treatment indicated that the 160-kD protein is phosphorylated, probably in the ERQES domain, which modifies its interaction with cytoskeletal and membrane proteins. Immunocytochemistry and confocal microscopy demonstrated coexpression of PTPRN and SPTBN4 in both insulin-secreting beta cells and glucagon-secreting alpha cells. In situ hybridization and immunocytochemistry suggested coexpression of SPTBN4 and ankyrin-G (ANK3; <a href="/entry/600465">600465</a>) in rat brain. The protein localized to axon initial segments (AIS) and nodes of Ranvier in the central and peripheral nervous system of the rat. <a href="#1" class="mim-tip-reference" title="Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M. <strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong> J. Cell Biol. 151: 985-1001, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.151.5.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086001">Berghs et al. (2000)</a> postulated that SPTBN4 may be required for the anchoring of voltage-gated Na+ channels and cell adhesion molecules to the actin cytoskeleton and may play an important role in nerve conduction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11086001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E. <strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong> J. Biol. Chem. 276: 23974-23985, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294830</a>] [<a href="https://doi.org/10.1074/jbc.M009307200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11294830">Tse et al. (2001)</a> cloned SPTBN4, which they termed SPTBN3, as well as a splice variant, sigma-5, encoding a 678-amino acid protein. Whole-mount in situ hybridization analysis revealed Sptbn4 expression that was restricted to forebrain, hindbrain, and developing eye in postcoital day-9.5 mice. Western blot analysis with polyclonal antibodies detected expression of a predominant 72-kD protein, close to the expected size of the sigma-5 variant. Immunofluorescence microscopy demonstrated colocalization of SPTBN4 with PML (<a href="/entry/102578">102578</a>) and with SUMO1 (UBL1; <a href="/entry/601912">601912</a>) in the cytoplasm and nucleus. The authors showed that both the N- and C-terminal helical coils of sigma-5 are needed to form nuclear dots and are associated with the nuclear matrix. <a href="#7" class="mim-tip-reference" title="Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E. <strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong> J. Biol. Chem. 276: 23974-23985, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294830</a>] [<a href="https://doi.org/10.1074/jbc.M009307200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11294830">Tse et al. (2001)</a> proposed that a spectrin-based skeleton may be important for the structure of the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11294830" 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 muscle, <a href="#4" class="mim-tip-reference" title="Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M. <strong>A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.</strong> Hum. Genet. 136: 903-910, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28540413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28540413</a>] [<a href="https://doi.org/10.1007/s00439-017-1814-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28540413">Knierim et al. (2017)</a> found expression of SPTBN4 at the sarcolemma and in the muscle capillaries. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28540413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By genomic sequence analysis, <a href="#1" class="mim-tip-reference" title="Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M. <strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong> J. Cell Biol. 151: 985-1001, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.151.5.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086001">Berghs et al. (2000)</a> determined that the SPTBN4 gene contains 36 exons. <a href="#7" class="mim-tip-reference" title="Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E. <strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong> J. Biol. Chem. 276: 23974-23985, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294830</a>] [<a href="https://doi.org/10.1074/jbc.M009307200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11294830">Tse et al. (2001)</a> determined that the SPTBN4 gene spans over 145 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11294830+11086001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By radiation hybrid analysis, <a href="#5" class="mim-tip-reference" title="Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 7: 273-281, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>] [<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10997877">Nagase et al. (2000)</a> mapped the SPTBN4 gene to chromosome 19. <a href="#1" class="mim-tip-reference" title="Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M. <strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong> J. Cell Biol. 151: 985-1001, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.151.5.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086001">Berghs et al. (2000)</a> localized the gene to 19q13.13 by FISH. They identified a highly related gene that resides on chromosome 16. <a href="#7" class="mim-tip-reference" title="Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E. <strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong> J. Biol. Chem. 276: 23974-23985, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294830</a>] [<a href="https://doi.org/10.1074/jbc.M009307200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11294830">Tse et al. (2001)</a> mapped the SPTBN4 gene to 19q13.13-q13.2 by radiation hybrid analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11294830+11086001+10997877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M. <strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong> J. Cell Biol. 151: 985-1001, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1083/jcb.151.5.985" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11086001">Berghs et al. (2000)</a> and <a href="#7" class="mim-tip-reference" title="Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E. <strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong> J. Biol. Chem. 276: 23974-23985, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294830</a>] [<a href="https://doi.org/10.1074/jbc.M009307200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11294830">Tse et al. (2001)</a> mapped the mouse Sptnb4 gene to chromosome 7b2. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11294830+11086001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy, born of consanguineous Kurdish parents, with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>), <a href="#4" class="mim-tip-reference" title="Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M. <strong>A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.</strong> Hum. Genet. 136: 903-910, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28540413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28540413</a>] [<a href="https://doi.org/10.1007/s00439-017-1814-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28540413">Knierim et al. (2017)</a> identified a homozygous truncating mutation in the SPTBN4 gene (Q533X; <a href="#0001">606214.0001</a>). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed absence of the SPTBN4 protein, and immunostaining of patient muscle sample showed absence of SPTBN4 at the sarcolemma. The phenotype was similar to that of the 'quivering' mouse, which results from a homozygous loss-of-function mutation in the Sptnb4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28540413" 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 6 patients from 5 unrelated families with NEDHND, <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a> identified homozygous or compound heterozygous mutations in the SPTBN4 gene (see, e.g., <a href="#0002">606214.0002</a>-<a href="#0006">606214.0006</a>). The mutations were found by exome sequencing; confirmed segregation of the mutations with the disorder was only possible in 1 family (family A). All patients except 1 (patient from family C) carried biallelic nonsense or frameshift mutations predicted to result in a complete loss of function. The patient from family C carried compound heterozygous missense mutations (R504Q, <a href="#0004">606214.0004</a> and R2435C, <a href="#0005">606214.0005</a>). Five of the 7 variants were located N-terminal to SR10 and were predicted to affect only the longer sigma-1 splice variant; SR15 mediates the interaction with ankyrin-G (ANK3; <a href="/entry/600465">600465</a>). The equivalent human variants in mouse Sptbn4 were expressed in cultured rat hippocampal neurons. Most of the truncating variants failed to localize to the AIS due to inability to interact with ANK3, whereas the 2 missense variants and 1 C-terminal frameshift mutation (c.7453delG; <a href="#0006">606214.0006</a>) were able to interact with ANK3 and localized properly to the AIS. The c.7453delG mutant was abnormally present in small intracellular puncta rather than normal diffuse distribution, suggesting that the mutation disrupted the PH domain and altered the distribution of SPTBN4 in membrane compartments. The mutant protein was also unable to bind phosphoinositides, further demonstrating an adverse effect on PH domain function. Examination of the nodes of Ranvier was possible for 2 patients. Sural nerve biopsy from the patient with a homozygous truncating mutation (W903X; <a href="#0003">606214.0003</a>) that only affected the sigma-1 variant showed significantly reduced neurofascin labeling at the nodes of Ranvier as well as decreased immunostaining for certain sodium and potassium channels and nearly undetectable nodal immunoreactivity for the shorter SPTBN4 isoform (sigma-6). The findings indicated that sigma-6 is not sufficient to rescue nodal abnormalities. Sural nerve biopsy from the patient with compound heterozygous missense mutations showed fairly normal structure at the nodes of Ranvier, with a small reduction in potassium channels. <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a> concluded that SPTBN4 mutations disrupt the cytoskeletal machinery that controls proper localization of ion channels and function of axonal domains mainly at the AIS and the nodes of Ranvier, resulting in severe neurologic dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The autosomal recessive mouse mutation 'quivering' (qv), described by <a href="#9" class="mim-tip-reference" title="Yoon, C. H., Les, E. P. <strong>Quivering, a new first chromosome mutation in mice.</strong> J. Hered. 48: 176-180, 1957."None>Yoon and Les (1957)</a>, produces progressive ataxia with hindlimb paralysis, deafness, and tremor. Ear twitch responses (Preyer reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory inflammation, indicating that in contrast to the many mutations causing deafness originating in the cochlea, deafness in qv is central in origin (<a href="#3" class="mim-tip-reference" title="Deol, M. S., Frank, M. P., Steel, K. P., Bock, G. R. <strong>Genetic deafness of central origin.</strong> Brain Res. 258: 177-179, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24010186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24010186</a>] [<a href="https://doi.org/10.1016/0006-8993(83)91248-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24010186">Deol et al., 1983</a>; <a href="#2" class="mim-tip-reference" title="Bock, G. R., Frank, M. P., Steel, K. P., Deol, M. S. <strong>The quivering mutant mouse: hereditary deafness of central origin.</strong> Acta Otolaryng. 96: 371-377, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6637453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6637453</a>] [<a href="https://doi.org/10.3109/00016488309132722" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6637453">Bock et al., 1983</a>). <a href="#6" class="mim-tip-reference" title="Parkinson, N. J., Olsson, C. L., Hallows, J. L., McKee-Johnson, J., Keogh, B. P., Noben-Trauth, K., Kujawa, S. G., Tempel, B. L. <strong>Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice.</strong> Nature Genet. 29: 61-65, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528393</a>] [<a href="https://doi.org/10.1038/ng710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11528393">Parkinson et al. (2001)</a> reported that qv mice carry loss-of-function mutations in the Sptnb4 gene that cause alterations in ion channel localization in myelinated nerves. They concluded that this finding provides a rationale for the auditory and motor neuropathies of these mice. <a href="#4" class="mim-tip-reference" title="Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M. <strong>A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.</strong> Hum. Genet. 136: 903-910, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28540413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28540413</a>] [<a href="https://doi.org/10.1007/s00439-017-1814-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28540413">Knierim et al. (2017)</a> found absence of Sptbn4 immunostaining at the sarcolemma of muscle from the qv mouse, as well as complete absence of type 1 muscle fibers. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11528393+24010186+6637453+28540413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a boy, born of consanguineous Kurdish parents, with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>), <a href="#4" class="mim-tip-reference" title="Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M. <strong>A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.</strong> Hum. Genet. 136: 903-910, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28540413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28540413</a>] [<a href="https://doi.org/10.1007/s00439-017-1814-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28540413">Knierim et al. (2017)</a> identified a homozygous c.1597C-T transition (c.1597C-T, NM_020971.2) in the SPTBN4 gene, resulting in a gln533-to-ter (Q533X) substitution. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database of over 150 exomes. Western blot and PCR analysis of patient fibroblasts showed absence of the SPTBN4 protein and mRNA, consistent with nonsense-mediated mRNA decay. Immunostaining of patient muscle sample showed absence of SPTBN4 at the sarcolemma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28540413" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 sibs (family A) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>), <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a> identified a homozygous c.3820G-T transversion (c.3820G-T, NM_020971.2) in the SPTBN4 gene, resulting in a glu1274-to-ter (E1274X) substitution before SR10 and affecting only the sigma-1 isoform. The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" 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> rs864309618 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs864309618;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/rs864309618?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=rs864309618" 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=rs864309618" 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=RCV000203064 OR RCV000677270" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203064, RCV000677270" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203064...</a>
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<p>In a 5-year-old girl (family B) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>), <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a> identified a homozygous c.2709G-A transition (c.2709G-A, NM_020971.2), resulting in a trp903-to-ter (W903X) substitution before SR10 and affecting only the sigma-1 isoform. Sural nerve biopsy from this patient showed significantly reduced neurofascin labeling at the nodes of Ranvier as well as decreased immunostaining for certain sodium and potassium channels and nearly undetectable levels of the shorter SPTBN4 isoform (sigma-6). The findings indicated that sigma-6 is not sufficient to rescue nodal abnormalities. The c.2709G-A variant was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</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> rs765087147 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs765087147;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/rs765087147?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=rs765087147" 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=rs765087147" 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=RCV000677271 OR RCV002531386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000677271, RCV002531386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000677271...</a>
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<p>In a 3-year-old boy (family C) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>), <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a> identified compound heterozygous missense mutations in the SPTBN4 gene: a c.1511G-A transition (c.1511G-A, NM_020971.2), resulting in an arg504-to-gln (R504Q) substitution at a conserved residue in the SR2 domain, and a c.7303C-T transition, resulting in an arg2435-to-cys (R2435C; <a href="#0005">606214.0005</a>) substitution at a conserved residue in the C-terminal PH domain. Expression of the equivalent mouse Sptbn4 in cultured rat hippocampal neurons showed that both variants retained the ability to interact with ANK3 and localized properly to the AIS, unlike most of the other SPTBN4 variants. The SR2 domain is reported to underlie alpha and beta subunit heterodimer interactions, but coexpression studies showed that the R504Q variant did not disrupt the interaction with alpha-2-spectrin (<a href="/entry/182810">182810</a>). Similarly, the R2435C variant showed diffuse intracellular distribution similar to the wildtype pattern when expressed in HEK293 cells and was able to bind normally to phosphoinositides, suggesting normal function of the PH domain. It was thus unclear how the R504Q and R2435C variants exerted pathogenicity in these studies, but the patient's phenotype was similar to that of patients with other SPTBN4 mutations. Sural nerve biopsy from this patient showed normal neurofascin immunostaining at the nodes of Ranvier as well as near normal labeling of certain sodium channels and only a slight decrease in potassium channels. The R504Q and R2435C variants were present in the gnomAD database at low allele frequencies, 6.887 x 10(-5) and 8.94 x 10(-5), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</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> rs777273785 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs777273785;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/rs777273785?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=rs777273785" 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=rs777273785" 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=RCV000677272" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000677272" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000677272</a>
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<p>For discussion of the c.7303C-T transition (c.7303C-T, NM_020971.2) in the SPTBN4 gene, resulting in an arg2435-to-cys (R2435C) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>) by <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a>, see <a href="#0004">606214.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" 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 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</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">rs1555721549 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555721549;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=rs1555721549" 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=rs1555721549" 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=RCV000677273 OR RCV001266475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000677273, RCV001266475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000677273...</a>
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<p>In a 5-year-old boy (family D) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; <a href="/entry/617519">617519</a>), <a href="#8" class="mim-tip-reference" title="Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N. <strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong> Am. J. Hum. Genet. 102: 1158-1168, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>] [<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29861105">Wang et al. (2018)</a> identified a homozygous 1-bp deletion (c.7453delG, NM_020971.2) in the SPTBN4 gene, resulting in a frameshift and premature termination (Ala2485LeufsTer31) within the PH domain. Expression of the mutation in HEK293 cells showed that the mutant protein was abnormally present in small intracellular puncta rather than normal diffuse distribution, suggesting that the mutation disrupted the PH domain and altered the distribution of SPTBN4 in membrane compartments. The mutant protein was also unable to bind phosphoinositides, further demonstrating an adverse effect on PH domain function. The c.7453delG variant was not present in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" 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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Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M.
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<strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong>
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J. Cell Biol. 151: 985-1001, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11086001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11086001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11086001[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=11086001" 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/10.1083/jcb.151.5.985" target="_blank">Full Text</a>]
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Bock, G. R., Frank, M. P., Steel, K. P., Deol, M. S.
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<strong>The quivering mutant mouse: hereditary deafness of central origin.</strong>
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Acta Otolaryng. 96: 371-377, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6637453/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6637453</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=6637453" 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/10.3109/00016488309132722" target="_blank">Full Text</a>]
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Deol, M. S., Frank, M. P., Steel, K. P., Bock, G. R.
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<strong>Genetic deafness of central origin.</strong>
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Brain Res. 258: 177-179, 1983.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24010186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24010186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24010186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/0006-8993(83)91248-9" target="_blank">Full Text</a>]
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<a id="Knierim2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M.
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<strong>A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.</strong>
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Hum. Genet. 136: 903-910, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28540413/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28540413</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28540413" 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/s00439-017-1814-7" target="_blank">Full Text</a>]
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<a id="Nagase2000" class="mim-anchor"></a>
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<p class="mim-text-font">
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Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.
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<strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong>
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DNA Res. 7: 273-281, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10997877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10997877</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10997877" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/dnares/7.4.271" target="_blank">Full Text</a>]
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<a id="Parkinson2001" class="mim-anchor"></a>
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<p class="mim-text-font">
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Parkinson, N. J., Olsson, C. L., Hallows, J. L., McKee-Johnson, J., Keogh, B. P., Noben-Trauth, K., Kujawa, S. G., Tempel, B. L.
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<strong>Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice.</strong>
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Nature Genet. 29: 61-65, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11528393/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11528393</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11528393" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng710" target="_blank">Full Text</a>]
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<a id="Tse2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E.
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<strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong>
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J. Biol. Chem. 276: 23974-23985, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11294830/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11294830</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11294830" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M009307200" target="_blank">Full Text</a>]
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<a id="Wang2018" class="mim-anchor"></a>
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Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N.
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<strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong>
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Am. J. Hum. Genet. 102: 1158-1168, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29861105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29861105</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29861105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2018.04.012" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Yoon1957" class="mim-anchor"></a>
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<p class="mim-text-font">
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Yoon, C. H., Les, E. P.
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<strong>Quivering, a new first chromosome mutation in mice.</strong>
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J. Hered. 48: 176-180, 1957.
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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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Cassandra L. Kniffin - updated : 08/10/2018
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 06/09/2017<br>Victor A. McKusick - updated : 8/23/2001<br>Victor A. McKusick - updated : 8/23/2001
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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Creation Date:
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<span class="mim-text-font">
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Paul J. Converse : 8/21/2001
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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carol : 08/13/2018
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<span class="mim-text-font">
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ckniffin : 08/10/2018<br>carol : 07/10/2017<br>carol : 06/09/2017<br>joanna : 06/09/2017<br>terry : 03/03/2005<br>terry : 6/27/2002<br>mgross : 8/23/2001<br>terry : 8/23/2001<br>mgross : 8/22/2001<br>mgross : 8/21/2001
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<strong>*</strong> 606214
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SPECTRIN, BETA, NONERYTHROCYTIC, 4; SPTBN4
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<br />
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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SPECTRIN, BETA-IV; SPNB4<br />
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QUIVERING, MOUSE, HOMOLOG OF; QV
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SPTBN4</em></strong>
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Cytogenetic location: 19q13.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:40,467,001-40,576,464 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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19q13.2
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<span class="mim-font">
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Neurodevelopmental disorder with hypotonia, neuropathy, and deafness
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<span class="mim-font">
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617519
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<span class="mim-font">
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Autosomal recessive
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The SPTBN4 gene encodes a nonerythrocytic member of the beta-spectrin protein family that is expressed in the brain, peripheral nervous system, pancreas, and skeletal muscle. Spectrins are rod-shaped proteins that were originally identified as part of the lattice-like cytoskeleton under the erythrocyte membrane. Spectrins have also been found in the membranes of intracellular organelles, such as the Golgi, lysosomes, and secretory vesicles. The spectrin molecule is a tetramer consisting of 2 alpha (see, e.g., SPTA1, 182860) and 2 beta subunits, in which the N terminus of an alpha subunit is tightly connected with the C terminus of a beta subunit to form a heterodimer. Spectrin repeats contain approximately 106 amino acids. Alpha subunits have 20 spectrin repeats, while beta subunits have 17 (summary by Berghs et al., 2000). </p>
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<strong>Cloning and Expression</strong>
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<p>By screening a size-fractionated adult brain cDNA library for cDNAs with the potential to encode large proteins, Nagase et al. (2000) isolated a partial cDNA encoding SPTBN4, which they called KIAA1642. RT-PCR analysis detected ubiquitous expression of SPTBN4, with relatively high levels in adult and fetal brain, low levels in lung, liver, pancreas, and spleen, and intermediate levels in the other tissues tested and in specific brain regions. </p><p>Using a yeast 2-hybrid screen of a brain cDNA library with the cytoplasmic domain of ICA512 (PTPRN; 601773) as bait, followed by probing a brain cDNA library, PCR, and genomic sequence analysis, Berghs et al. (2000) isolated cDNAs encoding SPTBN4 and several splice variants. Sequence analysis predicted that the full-length 2,559-amino acid SPTBN4 protein, designated sigma-1, contains 2 N-terminal calponin homology domains, which mediate interactions with actin; 16 complete spectrin repeats; 1 partial spectrin repeat; a unique proline-rich, basic domain containing 4 ERQES repeats; numerous SH3 binding sites; and a C-terminal pleckstrin homology domain. An insertion in exon 17 termed exon 17b yields a 1,302-residue splice variant, sigma-2, which terminates in spectrin repeat 9, and another variant, sigma-3, which begins at exon 17b to generate a 1,307-amino acid protein. Variant sigma-4 has an insertion in exon 30 termed exon 30b that introduces 42 amino acids and a stop codon, resulting in a 2,149-amino acid protein that lacks the ERQES and pleckstrin homology domains. Binding analysis indicated that the C terminus of SPTBN4 binds to PTPRN and only weakly to an active tyrosine phosphatase mutant of PTPRN and to PHOGRIN (601698). Northern blot analysis revealed expression of 9.0-, 5.1-, and 3.1-kb SPTBN4 transcripts that were predominantly expressed in brain. Western blot analysis showed expression of 250- and 160-kD proteins in rat brain and human pancreatic islets, as well as a 140-kD protein in rat brain only. Phosphatase treatment indicated that the 160-kD protein is phosphorylated, probably in the ERQES domain, which modifies its interaction with cytoskeletal and membrane proteins. Immunocytochemistry and confocal microscopy demonstrated coexpression of PTPRN and SPTBN4 in both insulin-secreting beta cells and glucagon-secreting alpha cells. In situ hybridization and immunocytochemistry suggested coexpression of SPTBN4 and ankyrin-G (ANK3; 600465) in rat brain. The protein localized to axon initial segments (AIS) and nodes of Ranvier in the central and peripheral nervous system of the rat. Berghs et al. (2000) postulated that SPTBN4 may be required for the anchoring of voltage-gated Na+ channels and cell adhesion molecules to the actin cytoskeleton and may play an important role in nerve conduction. </p><p>Tse et al. (2001) cloned SPTBN4, which they termed SPTBN3, as well as a splice variant, sigma-5, encoding a 678-amino acid protein. Whole-mount in situ hybridization analysis revealed Sptbn4 expression that was restricted to forebrain, hindbrain, and developing eye in postcoital day-9.5 mice. Western blot analysis with polyclonal antibodies detected expression of a predominant 72-kD protein, close to the expected size of the sigma-5 variant. Immunofluorescence microscopy demonstrated colocalization of SPTBN4 with PML (102578) and with SUMO1 (UBL1; 601912) in the cytoplasm and nucleus. The authors showed that both the N- and C-terminal helical coils of sigma-5 are needed to form nuclear dots and are associated with the nuclear matrix. Tse et al. (2001) proposed that a spectrin-based skeleton may be important for the structure of the nucleus. </p><p>In human muscle, Knierim et al. (2017) found expression of SPTBN4 at the sarcolemma and in the muscle capillaries. </p>
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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>Gene Structure</strong>
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</h4>
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<span class="mim-text-font">
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<p>By genomic sequence analysis, Berghs et al. (2000) determined that the SPTBN4 gene contains 36 exons. Tse et al. (2001) determined that the SPTBN4 gene spans over 145 kb. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By radiation hybrid analysis, Nagase et al. (2000) mapped the SPTBN4 gene to chromosome 19. Berghs et al. (2000) localized the gene to 19q13.13 by FISH. They identified a highly related gene that resides on chromosome 16. Tse et al. (2001) mapped the SPTBN4 gene to 19q13.13-q13.2 by radiation hybrid analysis. </p><p>Berghs et al. (2000) and Tse et al. (2001) mapped the mouse Sptnb4 gene to chromosome 7b2. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In a boy, born of consanguineous Kurdish parents, with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519), Knierim et al. (2017) identified a homozygous truncating mutation in the SPTBN4 gene (Q533X; 606214.0001). The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. Western blot analysis of patient fibroblasts showed absence of the SPTBN4 protein, and immunostaining of patient muscle sample showed absence of SPTBN4 at the sarcolemma. The phenotype was similar to that of the 'quivering' mouse, which results from a homozygous loss-of-function mutation in the Sptnb4 gene. </p><p>In 6 patients from 5 unrelated families with NEDHND, Wang et al. (2018) identified homozygous or compound heterozygous mutations in the SPTBN4 gene (see, e.g., 606214.0002-606214.0006). The mutations were found by exome sequencing; confirmed segregation of the mutations with the disorder was only possible in 1 family (family A). All patients except 1 (patient from family C) carried biallelic nonsense or frameshift mutations predicted to result in a complete loss of function. The patient from family C carried compound heterozygous missense mutations (R504Q, 606214.0004 and R2435C, 606214.0005). Five of the 7 variants were located N-terminal to SR10 and were predicted to affect only the longer sigma-1 splice variant; SR15 mediates the interaction with ankyrin-G (ANK3; 600465). The equivalent human variants in mouse Sptbn4 were expressed in cultured rat hippocampal neurons. Most of the truncating variants failed to localize to the AIS due to inability to interact with ANK3, whereas the 2 missense variants and 1 C-terminal frameshift mutation (c.7453delG; 606214.0006) were able to interact with ANK3 and localized properly to the AIS. The c.7453delG mutant was abnormally present in small intracellular puncta rather than normal diffuse distribution, suggesting that the mutation disrupted the PH domain and altered the distribution of SPTBN4 in membrane compartments. The mutant protein was also unable to bind phosphoinositides, further demonstrating an adverse effect on PH domain function. Examination of the nodes of Ranvier was possible for 2 patients. Sural nerve biopsy from the patient with a homozygous truncating mutation (W903X; 606214.0003) that only affected the sigma-1 variant showed significantly reduced neurofascin labeling at the nodes of Ranvier as well as decreased immunostaining for certain sodium and potassium channels and nearly undetectable nodal immunoreactivity for the shorter SPTBN4 isoform (sigma-6). The findings indicated that sigma-6 is not sufficient to rescue nodal abnormalities. Sural nerve biopsy from the patient with compound heterozygous missense mutations showed fairly normal structure at the nodes of Ranvier, with a small reduction in potassium channels. Wang et al. (2018) concluded that SPTBN4 mutations disrupt the cytoskeletal machinery that controls proper localization of ion channels and function of axonal domains mainly at the AIS and the nodes of Ranvier, resulting in severe neurologic dysfunction. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The autosomal recessive mouse mutation 'quivering' (qv), described by Yoon and Les (1957), produces progressive ataxia with hindlimb paralysis, deafness, and tremor. Ear twitch responses (Preyer reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory inflammation, indicating that in contrast to the many mutations causing deafness originating in the cochlea, deafness in qv is central in origin (Deol et al., 1983; Bock et al., 1983). Parkinson et al. (2001) reported that qv mice carry loss-of-function mutations in the Sptnb4 gene that cause alterations in ion channel localization in myelinated nerves. They concluded that this finding provides a rationale for the auditory and motor neuropathies of these mice. Knierim et al. (2017) found absence of Sptbn4 immunostaining at the sarcolemma of muscle from the qv mouse, as well as complete absence of type 1 muscle fibers. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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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>6 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">
|
|
<strong>.0001 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</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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SPTBN4, GLN533TER
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<br />
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SNP: rs1114167445,
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gnomAD: rs1114167445,
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ClinVar: RCV000490799, RCV000498686
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a boy, born of consanguineous Kurdish parents, with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519), Knierim et al. (2017) identified a homozygous c.1597C-T transition (c.1597C-T, NM_020971.2) in the SPTBN4 gene, resulting in a gln533-to-ter (Q533X) substitution. The mutation, which was found by a combination of autozygosity mapping and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in an in-house database of over 150 exomes. Western blot and PCR analysis of patient fibroblasts showed absence of the SPTBN4 protein and mRNA, consistent with nonsense-mediated mRNA decay. Immunostaining of patient muscle sample showed absence of SPTBN4 at the sarcolemma. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</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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SPTBN4, GLU1274TER
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<br />
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SNP: rs1555818396,
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ClinVar: RCV000677269, RCV000760610
|
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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 2 sibs (family A) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519), Wang et al. (2018) identified a homozygous c.3820G-T transversion (c.3820G-T, NM_020971.2) in the SPTBN4 gene, resulting in a glu1274-to-ter (E1274X) substitution before SR10 and affecting only the sigma-1 isoform. The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the gnomAD database. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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SPTBN4, TRP903TER
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<br />
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|
|
SNP: rs864309618,
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|
|
gnomAD: rs864309618,
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|
|
|
|
|
ClinVar: RCV000203064, RCV000677270
|
|
|
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|
|
</span>
|
|
</div>
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old girl (family B) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519), Wang et al. (2018) identified a homozygous c.2709G-A transition (c.2709G-A, NM_020971.2), resulting in a trp903-to-ter (W903X) substitution before SR10 and affecting only the sigma-1 isoform. Sural nerve biopsy from this patient showed significantly reduced neurofascin labeling at the nodes of Ranvier as well as decreased immunostaining for certain sodium and potassium channels and nearly undetectable levels of the shorter SPTBN4 isoform (sigma-6). The findings indicated that sigma-6 is not sufficient to rescue nodal abnormalities. The c.2709G-A variant was not found in the gnomAD database. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SPTBN4, ARG504GLN
|
|
|
|
|
|
<br />
|
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|
|
SNP: rs765087147,
|
|
|
|
|
|
gnomAD: rs765087147,
|
|
|
|
|
|
ClinVar: RCV000677271, RCV002531386
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old boy (family C) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519), Wang et al. (2018) identified compound heterozygous missense mutations in the SPTBN4 gene: a c.1511G-A transition (c.1511G-A, NM_020971.2), resulting in an arg504-to-gln (R504Q) substitution at a conserved residue in the SR2 domain, and a c.7303C-T transition, resulting in an arg2435-to-cys (R2435C; 606214.0005) substitution at a conserved residue in the C-terminal PH domain. Expression of the equivalent mouse Sptbn4 in cultured rat hippocampal neurons showed that both variants retained the ability to interact with ANK3 and localized properly to the AIS, unlike most of the other SPTBN4 variants. The SR2 domain is reported to underlie alpha and beta subunit heterodimer interactions, but coexpression studies showed that the R504Q variant did not disrupt the interaction with alpha-2-spectrin (182810). Similarly, the R2435C variant showed diffuse intracellular distribution similar to the wildtype pattern when expressed in HEK293 cells and was able to bind normally to phosphoinositides, suggesting normal function of the PH domain. It was thus unclear how the R504Q and R2435C variants exerted pathogenicity in these studies, but the patient's phenotype was similar to that of patients with other SPTBN4 mutations. Sural nerve biopsy from this patient showed normal neurofascin immunostaining at the nodes of Ranvier as well as near normal labeling of certain sodium channels and only a slight decrease in potassium channels. The R504Q and R2435C variants were present in the gnomAD database at low allele frequencies, 6.887 x 10(-5) and 8.94 x 10(-5), respectively. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SPTBN4, ARG2435CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs777273785,
|
|
|
|
|
|
gnomAD: rs777273785,
|
|
|
|
|
|
ClinVar: RCV000677272
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the c.7303C-T transition (c.7303C-T, NM_020971.2) in the SPTBN4 gene, resulting in an arg2435-to-cys (R2435C) substitution, that was found in compound heterozygous state in a patient with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519) by Wang et al. (2018), see 606214.0004. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA, NEUROPATHY, AND DEAFNESS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SPTBN4, 1-BP DEL, 7453G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555721549,
|
|
|
|
|
|
|
|
ClinVar: RCV000677273, RCV001266475
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 5-year-old boy (family D) with neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND; 617519), Wang et al. (2018) identified a homozygous 1-bp deletion (c.7453delG, NM_020971.2) in the SPTBN4 gene, resulting in a frameshift and premature termination (Ala2485LeufsTer31) within the PH domain. Expression of the mutation in HEK293 cells showed that the mutant protein was abnormally present in small intracellular puncta rather than normal diffuse distribution, suggesting that the mutation disrupted the PH domain and altered the distribution of SPTBN4 in membrane compartments. The mutant protein was also unable to bind phosphoinositides, further demonstrating an adverse effect on PH domain function. The c.7453delG variant was not present in the gnomAD database. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
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</div>
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</div>
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</div>
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<div>
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|
<h4>
|
|
<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">
|
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Berghs, S., Aggujaro, D., Dirkx, R., Jr., Maksimova, E., Stabach, P., Hermel, J.-M., Zhang, J.-P., Philbrick, W., Slepnev, V., Ort, T., Slimena, M.
|
|
<strong>Beta-IV spectrin, a new spectrin localized at axon initial segments and nodes of Ranvier in the central and peripheral nervous system.</strong>
|
|
J. Cell Biol. 151: 985-1001, 2000.
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|
|
[PubMed: 11086001]
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[Full Text: https://doi.org/10.1083/jcb.151.5.985]
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</p>
|
|
</li>
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<li>
|
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<p class="mim-text-font">
|
|
Bock, G. R., Frank, M. P., Steel, K. P., Deol, M. S.
|
|
<strong>The quivering mutant mouse: hereditary deafness of central origin.</strong>
|
|
Acta Otolaryng. 96: 371-377, 1983.
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|
[PubMed: 6637453]
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[Full Text: https://doi.org/10.3109/00016488309132722]
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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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Deol, M. S., Frank, M. P., Steel, K. P., Bock, G. R.
|
|
<strong>Genetic deafness of central origin.</strong>
|
|
Brain Res. 258: 177-179, 1983.
|
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|
|
[PubMed: 24010186]
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[Full Text: https://doi.org/10.1016/0006-8993(83)91248-9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Knierim, E., Gill, E., Seifert, F., Morales-Gonzalez, S., Unudurthi, S. D., Hund, T. J., Stenzel, W., Schuelke, M.
|
|
<strong>A recessive mutation in beta-IV-spectrin (SPTBN4) associates with congenital myopathy, neuropathy, and central deafness.</strong>
|
|
Hum. Genet. 136: 903-910, 2017.
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|
|
[PubMed: 28540413]
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[Full Text: https://doi.org/10.1007/s00439-017-1814-7]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O.
|
|
<strong>Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong>
|
|
DNA Res. 7: 273-281, 2000.
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|
[PubMed: 10997877]
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[Full Text: https://doi.org/10.1093/dnares/7.4.271]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Parkinson, N. J., Olsson, C. L., Hallows, J. L., McKee-Johnson, J., Keogh, B. P., Noben-Trauth, K., Kujawa, S. G., Tempel, B. L.
|
|
<strong>Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice.</strong>
|
|
Nature Genet. 29: 61-65, 2001.
|
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|
|
[PubMed: 11528393]
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|
|
[Full Text: https://doi.org/10.1038/ng710]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Tse, W. T., Tang, J., Jin, O., Korsgren, C., John, K. M., Kung, A. L., Gwynn, B., Peters, L. L., Lux, S. E.
|
|
<strong>A new spectrin, beta-IV, has a major truncated isoform that associates with promyelocytic leukemia protein nuclear bodies and the nuclear matrix.</strong>
|
|
J. Biol. Chem. 276: 23974-23985, 2001.
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|
[PubMed: 11294830]
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[Full Text: https://doi.org/10.1074/jbc.M009307200]
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Wang, C.-C., Ortiz-Gonzalez, S. R., Yum, S. W., Gill, S. M., White, A., Kelter, E., Seaver, L. H., Lee, S., Wiley, G., Gaffney, P. M., Wierenga, K. J., Rasband, M. N.
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<strong>Beta-IV spectrinopathies cause profound intellectual disability, congenital hypotonia, and motor axonal neuropathy.</strong>
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Am. J. Hum. Genet. 102: 1158-1168, 2018.
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[PubMed: 29861105]
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[Full Text: https://doi.org/10.1016/j.ajhg.2018.04.012]
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Yoon, C. H., Les, E. P.
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<strong>Quivering, a new first chromosome mutation in mice.</strong>
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J. Hered. 48: 176-180, 1957.
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Cassandra L. Kniffin - updated : 08/10/2018<br>Cassandra L. Kniffin - updated : 06/09/2017<br>Victor A. McKusick - updated : 8/23/2001<br>Victor A. McKusick - updated : 8/23/2001
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Paul J. Converse : 8/21/2001
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carol : 08/13/2018<br>ckniffin : 08/10/2018<br>carol : 07/10/2017<br>carol : 06/09/2017<br>joanna : 06/09/2017<br>terry : 03/03/2005<br>terry : 6/27/2002<br>mgross : 8/23/2001<br>terry : 8/23/2001<br>mgross : 8/22/2001<br>mgross : 8/21/2001
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