3542 lines
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Entry
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- *600374 - BBS4 GENE; BBS4
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*600374</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/600374">Table View</a>
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</li>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000140463;t=ENST00000268057" 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=585" 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=600374" 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 class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000140463;t=ENST00000268057" 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_001252678,NM_001320665,NM_033028,NR_045565,NR_045566,XM_017022450,XM_017022454,XM_047432911,XM_047432912,XM_047432913,XM_047432914" 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_033028" 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=600374" 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=08982&isoform_id=08982_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/BBS4" 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/14280089,20379692,22761336,25952122,39644705,42374828,119598318,119598319,160359000,189069441,194383438,194386434,221043954,358248275,957948998,957949001,1002623431,1034591436,1034591444,2217302224,2217302227,2217302229,2217302232,2462545359,2462545361,2462545363,2462545365,2462545367,2462545369" 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/Q96RK4" 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=585" 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=ENSG00000140463;t=ENST00000268057" 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=BBS4" 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=BBS4" 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+585" 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/BBS4" 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:585" 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/585" 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=chr15&hgg_gene=ENST00000268057.9&hgg_start=72686207&hgg_end=72738473&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:969" 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=600374[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=600374[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/ENSG00000140463" 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=BBS4" 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=BBS4" 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=BBS4" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www.euro-wabb.org/en/lovd-genetic-variation-database" title="EURO-WABB Project Open Variation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">EURO-WABB Project Open Var…</a></div><div style="margin-left: 0.5em;"><a href="http://www.retina-international.org/files/sci-news/bbs4mut.htm" title="Mutations of the Bardet-Biedl Syndrome Type 4 Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Mutations of the Bardet-Bi…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BBS4&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/PA25278" 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:969" 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/FBgn0033578.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:2143311" 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/BBS4#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:2143311" 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/585/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=585" 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=WBGene00043992;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-060126-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=BBS4&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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600374
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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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BBS4 GENE; BBS4
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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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<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=BBS4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BBS4</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/15/358?start=-3&limit=10&highlight=358">15q24.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:72686207-72738473&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'})">15:72,686,207-72,738,473</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/15/358?start=-3&limit=10&highlight=358">
|
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15q24.1
|
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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">
|
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Bardet-Biedl syndrome 4
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
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<a href="/entry/615982"> 615982 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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<abbr class="mim-tip-hint" title="Autosomal 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/600374" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/600374" 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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<p>BBS4 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (<a href="#15" class="mim-tip-reference" title="Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J., Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F., Sheffield, V. C., Jackson, P. K. <strong>A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.</strong> Cell 129: 1201-1213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17574030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17574030</a>] [<a href="https://doi.org/10.1016/j.cell.2007.03.053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17574030">Nachury et al., 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17574030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> analyzed an EST cluster within the critical mapping region for Bardet-Biedl syndrome-4 (BBS4; see <a href="/entry/209900">209900</a>) on chromosome 15q22 and identified a contig with an open reading frame of 519 codons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381270" 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 microarray analysis, <a href="#18" class="mim-tip-reference" title="Shah, A. S., Farmen, S. L., Moninger, T. O., Businga, T. R., Andrews, M. P., Bugge, K., Searby, C. C., Nishimura, D., Brogden, K. A., Kline, J. N., Sheffield, V. C., Welsh, M. J. <strong>Loss of Bardet-Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia.</strong> Proc. Nat. Acad. Sci. 105: 3380-3385, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18299575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18299575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18299575[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0712327105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18299575">Shah et al. (2008)</a> showed that human airway epithelia expressed all 12 BBS genes. Immunohistochemical analysis localized BBS2 and BBS4 to cellular structures associated with motile cilia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18299575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> found that the BBS4 gene contains 16 exons and spans approximately 52 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381270" 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 sequence analysis, <a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> mapped the BBS4 gene to chromosome 15q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> pointed out that the predicted protein sequence of BBS4 shows strongest homology to O-linked N-acetylglucosamine transferase (OGT; <a href="/entry/300255">300255</a>) from several species, including archaebacteria and plants. The plant OGT is a signal transduction protein involved in a variety of developmental processes in Arabidopsis. In humans, OGT has been implicated in insulin resistance and may play a role in diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Kim, J. C., Badano, J. L., Sibold, S., Esmail, M. A., Hill, J., Hoskins, B. E., Leitch, C. C., Venner, K., Ansley, S. J., Ross, A. J., Leroux, M. R., Katsanis, N., Beales, P. L. <strong>The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.</strong> Nature Genet. 36: 462-470, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15107855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15107855</a>] [<a href="https://doi.org/10.1038/ng1352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15107855">Kim et al. (2004)</a> showed that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery (DCTN1; <a href="/entry/601143">601143</a>) to recruit pericentriolar material-1 protein (PCM1; <a href="/entry/600299">600299</a>) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division, and apoptotic cell death. Expression of 2 truncated forms of BBS4 that are similar to those found in some individuals with Bardet-Biedl syndrome had a similar effect on PCM1 and microtubules. These findings indicated that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes, and retinal degeneration. <a href="#9" class="mim-tip-reference" title="Kim, J. C., Badano, J. L., Sibold, S., Esmail, M. A., Hill, J., Hoskins, B. E., Leitch, C. C., Venner, K., Ansley, S. J., Ross, A. J., Leroux, M. R., Katsanis, N., Beales, P. L. <strong>The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.</strong> Nature Genet. 36: 462-470, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15107855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15107855</a>] [<a href="https://doi.org/10.1038/ng1352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15107855">Kim et al. (2004)</a> commented that Bardet-Biedl syndrome appeared to the first pleiotropic phenotype attributable to pericentriolar dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15107855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J., Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F., Sheffield, V. C., Jackson, P. K. <strong>A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.</strong> Cell 129: 1201-1213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17574030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17574030</a>] [<a href="https://doi.org/10.1016/j.cell.2007.03.053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17574030">Nachury et al. (2007)</a> found that BBS1 (<a href="/entry/209901">209901</a>), BBS2 (<a href="/entry/606151">606151</a>), BBS4, BBS5 (<a href="/entry/603650">603650</a>), BBS7 (<a href="/entry/607590">607590</a>), BBS8 (TTC8; <a href="/entry/608132">608132</a>), and BBS9 (<a href="/entry/607968">607968</a>) copurified in stoichiometric amounts from human retinal pigment epithelium (RPE) cells and from mouse testis. PCM1 and alpha-tubulin (see <a href="/entry/602529">602529</a>)/beta-tubulin (<a href="/entry/191130">191130</a>) copurified in substoichiometric amounts. The apparent molecular mass of the complex, which <a href="#15" class="mim-tip-reference" title="Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J., Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F., Sheffield, V. C., Jackson, P. K. <strong>A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.</strong> Cell 129: 1201-1213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17574030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17574030</a>] [<a href="https://doi.org/10.1016/j.cell.2007.03.053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17574030">Nachury et al. (2007)</a> called the BBSome, was 438 kD, and it had a sedimentation coefficient of 14S. The complex localized with PCM1 to nonmembranous centriolar satellites in the cytoplasm and, in the absence of PCM1, to the ciliary membrane. Cotransfection and immunoprecipitation experiments suggested that BBS9 was the complex-organizing subunit and that BBS5 mediated binding to phospholipids, predominantly phosphatidylinositol 3-phosphate. BBS1 mediated interaction with RABIN8 (RAB3IP; <a href="/entry/608686">608686</a>), the guanine nucleotide exchange factor for the small G protein RAB8 (RAB8A; <a href="/entry/165040">165040</a>). <a href="#15" class="mim-tip-reference" title="Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J., Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F., Sheffield, V. C., Jackson, P. K. <strong>A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.</strong> Cell 129: 1201-1213, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17574030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17574030</a>] [<a href="https://doi.org/10.1016/j.cell.2007.03.053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17574030">Nachury et al. (2007)</a> found that RAB8 promoted ciliary membrane growth through fusion of exocytic vesicles to the base of the ciliary membrane. They concluded that BBS proteins likely function in membrane trafficking to the primary cilium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17574030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Loktev, A. V., Zhang, Q., Beck, J. S., Searby, C. C., Scheetz, T. E., Bazan, J. F., Slusarski, D. C., Sheffield, V. C., Jackson, P. K., Nachury, M. V. <strong>A BBSome subunit links ciliogenesis, microtubule stability, and acetylation.</strong> Dev. Cell 15: 854-865, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19081074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19081074</a>] [<a href="https://doi.org/10.1016/j.devcel.2008.11.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19081074">Loktev et al. (2008)</a> found that BBIP10 (<a href="/entry/613605">613605</a>) copurified and cosedimented with the BBS protein complex from RPE cells. Knockdown of BBIP10 in RPE cells via small interfering RNA compromised assembly of the BBS protein complex and caused failure of ciliogenesis. Knockdown of BBS1, BBS5, or PCM1 resulted in a similar failure of ciliogenesis in RPE cells. Depletion of BBIP10 or BBS8 increased the frequency of centrosome splitting in interphase cells. BBIP10 also had roles in cytoplasmic microtubule stabilization and acetylation that appeared to be independent of its role in assembly of the BBS protein complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19081074" 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 protein pull-down assay with homogenized bovine retina, <a href="#7" class="mim-tip-reference" title="Jin, H., White, S. R., Shida, T., Schulz, S., Aguiar, M., Gygi, S. P., Bazan, J. F., Nachury, M. V. <strong>The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.</strong> Cell 141: 1208-1219, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603001">Jin et al. (2010)</a> showed that ARL6 (<a href="/entry/608845">608845</a>) bound the BBS protein complex. Depletion of ARL6 in human RPE cells did not affect assembly of the complex, but it blocked its localization to cilia. Targeting of ARL6 and the protein complex to cilia required GTP binding by ARL6, but not ARL6 GTPase activity. When in the GTP-bound form, the N-terminal amphipathic helix of ARL6 bound brain lipid liposomes and recruited the BBS protein complex. Upon recruitment, the complex appeared to polymerize into an electron-dense planar coat, and it functioned in lateral transport of test cargo proteins to ciliary membranes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603001" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By mass spectrometric analysis of transgenic mouse testis, <a href="#17" class="mim-tip-reference" title="Seo, S., Zhang, Q., Bugge, K., Breslow, D. K., Searby, C. C., Nachury, M. V., Sheffield, V. C. <strong>A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened.</strong> PLoS Genet. 7: e1002358, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22072986/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22072986</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22072986[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/10.1371/journal.pgen.1002358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22072986">Seo et al. (2011)</a> found that Lxtfl1 (<a href="/entry/606568">606568</a>) copurified with human BBS4 and with the core mouse BBS complex subunits Bbs1, Bbs2, Bbs5, Bbs7, Bbs8, and Bbs9. Immunohistochemical analysis of human RPE cells showed colocalization of LXTFL1 and BBS9 in cytoplasmic punctae. Use of small interfering RNA revealed distinct functions for each BBS subunit in BBS complex assembly and trafficking. LZTFL1 depletion and overexpression studies showed a negative role for LZTFL1 in BBS complex trafficking, but no effect of LZTFL1 on BBS complex assembly. Mutation analysis revealed that the C-terminal half of Lztfl1 interacted with the C-terminal domain of Bbs9 and that the N-terminal half of Lztfl1 negatively regulated BBS complex trafficking. Depletion of several BBS subunits and LZTFL1 also altered Hedgehog (SHH; <a href="/entry/600725">600725</a>) signaling, as measured by GLI1 (<a href="/entry/165220">165220</a>) expression and ciliary trafficking of SMO (SMOH; <a href="/entry/601500">601500</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22072986" 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="Anosov, M., Birk, R. <strong>Bardet-Biedl syndrome obesity: BBS regulates cellular ER stress in early adipogenesis.</strong> Molec. Genet. Metab. 126: 495-503, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30902542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30902542</a>] [<a href="https://doi.org/10.1016/j.ymgme.2019.03.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30902542">Anosov and Birk (2019)</a> studied the expression of BBS4 in preadipocyte mouse cell lines. Using immunocytochemisty and cellular protein fractionation, they showed that BBS4 localizes to the endoplasmic reticulum. siRNA knockdown of BBS4 at day 3 of mouse preadipocyte cell differentiation resulted in a significant decrease in cleaved ATF6 (<a href="/entry/605537">605537</a>) and phosphorylated IRE1A (<a href="/entry/604033">604033</a>) at baseline and in response to induced ER stress. Induction of ER stress in BBS4 knockdown mouse adipocytes resulted in ER retention of XBP1 (<a href="/entry/194355">194355</a>) during adipocyte differentiation, indicating a role for BBS4 in the ER stress response and ER trafficking. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30902542" 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>Using computational analysis, <a href="#7" class="mim-tip-reference" title="Jin, H., White, S. R., Shida, T., Schulz, S., Aguiar, M., Gygi, S. P., Bazan, J. F., Nachury, M. V. <strong>The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.</strong> Cell 141: 1208-1219, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603001">Jin et al. (2010)</a> found that the BBS protein complex shares structural features with the canonical coat complexes COPI (<a href="/entry/601924">601924</a>), COPII (see <a href="/entry/610511">610511</a>), and clathrin AP1 (see <a href="/entry/603531">603531</a>). BBS4 and BBS8 consist almost entirely of tetratricopeptide repeats (TPRs) (13 and 12.5 TPRs, respectively), which are predicted to fold into extended rod-shaped alpha solenoids. BBS1, BBS2, BBS7, and BBS9 each have an N-terminal beta-propeller fold followed by an amphipathic helical linker and a gamma-adaptin (AP1G1; <a href="/entry/603533">603533</a>) ear motif. In BBS2, BBS7, and BBS9, the ear motif is followed by an alpha/beta platform domain and an alpha helix. In BBS1, a 4-helix bundle is inserted between the second and third blades of the beta propeller. BBS5 contains 2 pleckstrin (PLEK; <a href="/entry/173570">173570</a>) homology domains and a 3-helix bundle, while BBIP10 consists of 2 alpha helices. <a href="#7" class="mim-tip-reference" title="Jin, H., White, S. R., Shida, T., Schulz, S., Aguiar, M., Gygi, S. P., Bazan, J. F., Nachury, M. V. <strong>The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.</strong> Cell 141: 1208-1219, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20603001/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20603001</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20603001[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.cell.2010.05.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20603001">Jin et al. (2010)</a> concluded that the abundance of beta propellers, alpha solenoids, and appendage domains inside the BBS protein complex suggests that it shares an evolutionary relationship with canonical coat complexes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20603001" 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 the proband of the BBS4-linked Bedouin kindred in which the BBS4 locus was initially mapped (<a href="#3" class="mim-tip-reference" title="Carmi, R., Rokhlina, T., Kwitek-Black, A. E., Elbedour, K., Nishimura, D., Stone, E. M., Sheffield, V. C. <strong>Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15.</strong> Hum. Molec. Genet. 4: 9-13, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711739</a>] [<a href="https://doi.org/10.1093/hmg/4.1.9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7711739">Carmi et al., 1995</a>), <a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> sequenced the BBS4 gene coding region and consensus splice sites and detected a homozygous G-to-C transversion in exon 12, predicting an arginine-to-proline substitution at codon 295 (R295P; <a href="#0001">600374.0001</a>). This R295P variant segregated completely with the disease in the family and was not found in 48 unrelated Bedouin Arab controls. In affected members of an Italian BBS4 family, they found partial deletion of the gene (<a href="#0002">600374.0002</a>). The same deletion was found in an Israeli Arab family. Two different homozygous mutations were found in 2 European families. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7711739+11381270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Katsanis, N., Eichers, E. R., Ansley, S. J., Lewis, R. A., Kayserili, H., Hoskins, B. E., Scambler, P. J., Beales, P. L., Lupski, J. R. <strong>BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.</strong> Am. J. Hum. Genet. 71: 22-29, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12016587[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016587">Katsanis et al. (2002)</a> evaluated the spectrum of mutations in the BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families with BBS. Consistent with predictions from previous genetic analyses, the data suggested that mutations in BBS4 could contribute to BBS in less than 3% of affected families. Furthermore, integrated mutational data from the BBS2, BBS4, and BBS6 (<a href="/entry/604896">604896</a>) genes raised the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12016587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#10" class="mim-tip-reference" title="Kulaga, H. M., Leitch, C. C., Eichers, E. R., Badano, J. L., Lesemann, A., Hoskins, B. E., Lupski, J. R., Beales, P. L., Reed, R. R., Katsanis, N. <strong>Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse.</strong> Nature Genet. 36: 994-998, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15322545/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15322545</a>] [<a href="https://doi.org/10.1038/ng1418" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15322545">Kulaga et al. (2004)</a> examined mice with deletions of the Bbs1 or Bbs4 genes. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15322545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Mykytyn, K., Mullins, R. F., Andrews, M., Chiang, A. P., Swiderski, R. E., Yang, B., Braun, T., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.</strong> Proc. Nat. Acad. Sci. 101: 8664-8669, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15173597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15173597</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15173597[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0402354101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15173597">Mykytyn et al. (2004)</a> found that mice lacking the Bbs4 protein had major components of the human Bardet-Biedl syndrome-4 phenotype, including obesity and retinal degeneration. BBS4 retinopathy involves apoptotic death of photoreceptors, the primary ciliated cells of the retina. Bbs4-null mice developed both motile and primary cilia, demonstrating that Bbs4 is not required for global cilia formation. Male Bbs4-null mice did not form spermatozoa flagella. These mutation data demonstrated a connection between the function of a Bbs protein and cilia. To further evaluate an association between cilia and BBS, <a href="#14" class="mim-tip-reference" title="Mykytyn, K., Mullins, R. F., Andrews, M., Chiang, A. P., Swiderski, R. E., Yang, B., Braun, T., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.</strong> Proc. Nat. Acad. Sci. 101: 8664-8669, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15173597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15173597</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15173597[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0402354101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15173597">Mykytyn et al. (2004)</a> performed homology comparisons of BBS proteins in model organisms and found that BBS proteins are specifically conserved in ciliated organisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15173597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Eichers, E. R., Abd-El-Barr, M. M., Paylor, R., Lewis, R. A., Bi, W., Lin, X., Meehan, T. P., Stockton, D. W., Wu, S. M., Lindsay, E., Justice, M. J., Beales, P. L., Katsanis, N., Lupski, J. R. <strong>Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expression.</strong> Hum. Genet. 120: 211-226, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16794820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16794820</a>] [<a href="https://doi.org/10.1007/s00439-006-0197-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16794820">Eichers et al. (2006)</a> generated a mouse model of BBS4 by targeted inactivation of the murine Bbs4 gene. Although the mice were initially runted compared to wildtype, they later became obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal liver profiles, signs of liver dysfunction, and increased insulin and leptin levels similar to the metabolic syndrome (see <a href="/entry/605552">605552</a>). Affected mice also developed age-dependent retinal dystrophy and displayed anxiety-related behavior. Birth defects, such an neural tube defects, occurred rarely. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16794820" 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="#19" class="mim-tip-reference" title="Swiderski, R. E., Nishimura, D. Y., Mullins, R. F., Olvera, M. A., Ross, J. L., Huang, J., Stone, E. M., Sheffield, V. C. <strong>Gene expression analysis of photoreceptor cell loss in Bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage.</strong> Invest. Ophthal. Vis. Sci. 48: 3329-3340, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17591906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17591906</a>] [<a href="https://doi.org/10.1167/iovs.06-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17591906">Swiderski et al. (2007)</a> identified and characterized gene expression changes associated with photoreceptor cell loss in a Bbs4-knockout mouse model of retinal degeneration. Three hundred fifty-four probes were differentially expressed in Bbs4 -/- eyes compared with controls using a 2-fold cutoff. Numerous vision-related transcripts decreased because of photoreceptor cell loss. Increased expression of the stress response genes Edn2 (<a href="/entry/131241">131241</a>), Lcn2 (<a href="/entry/600181">600181</a>), Serpina3n, and Socs3 (<a href="/entry/604176">604176</a>) was noted as early as postnatal week 4 in the eyes of 4 BBS mouse model strains. A burst of apoptotic activity in the photoreceptor outer nuclear layer at postnatal week 2 and highly disorganized outer segments by postnatal weeks 4 to 6 were observed in all 4 strains. The specific loss of photoreceptors in Bbs4 -/- mice allowed <a href="#19" class="mim-tip-reference" title="Swiderski, R. E., Nishimura, D. Y., Mullins, R. F., Olvera, M. A., Ross, J. L., Huang, J., Stone, E. M., Sheffield, V. C. <strong>Gene expression analysis of photoreceptor cell loss in Bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage.</strong> Invest. Ophthal. Vis. Sci. 48: 3329-3340, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17591906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17591906</a>] [<a href="https://doi.org/10.1167/iovs.06-1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17591906">Swiderski et al. (2007)</a> to identify a set of genes that were preferentially expressed in photoreceptors compared with other cell types. The animal model eyes implied that BBS proteins play a critical early role in establishing the correct structure and function of photoreceptors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17591906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By immunostaining for axonemal proteins, <a href="#20" class="mim-tip-reference" title="Tan, P. L., Barr, T., Inglis, P. N., Mitsuma, N., Huang, S. M., Garcia-Gonzalez, M. A., Bradley, B. A., Coforio, S., Albrecht, P. J., Watnick, T., Germino, G. G., Beales, P. L., Caterina, M. J., Leroux, M. R., Rice, F. L., Katsanis, N. <strong>Loss of Bardet-Biedl syndrome proteins causes defects in peripheral sensory innervation and function.</strong> Proc. Nat. Acad. Sci. 104: 17524-17529, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17959775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17959775</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17959775[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0706618104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17959775">Tan et al. (2007)</a> demonstrated that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and Bbs4-null mice demonstrated behavioral deficits in thermosensation and mechanosensation associated with alterations in the trafficking of the thermosensory channel Trpv1 (<a href="/entry/602076">602076</a>) and the mechanosensory channel Stoml3 (<a href="/entry/608327">608327</a>) within sensory neurons. The findings were replicated in C. elegans lacking Bbs7 or Bbs8 (TTC8; <a href="/entry/608132">608132</a>). Detailed examination of 9 patients with BBS showed a noticeable decrease in peripheral sensation in most of them. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17959775" 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 mice lacking Bbs2, Bbs4, or Bbs6 and mice with the met390-to-arg (M390R; <a href="/entry/209901#0001">209901.0001</a>) mutation in Bbs1 (<a href="/entry/209901">209901</a>), <a href="#18" class="mim-tip-reference" title="Shah, A. S., Farmen, S. L., Moninger, T. O., Businga, T. R., Andrews, M. P., Bugge, K., Searby, C. C., Nishimura, D., Brogden, K. A., Kline, J. N., Sheffield, V. C., Welsh, M. J. <strong>Loss of Bardet-Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia.</strong> Proc. Nat. Acad. Sci. 105: 3380-3385, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18299575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18299575</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18299575[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0712327105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18299575">Shah et al. (2008)</a> showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18299575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C., Mykytyn, K. <strong>Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia.</strong> Proc. Nat. Acad. Sci. 105: 4242-4246, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18334641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18334641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18334641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711027105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18334641">Berbari et al. (2008)</a> reported that BBS proteins are required for the localization of G protein-coupled receptors to primary cilia on central mouse neurons. Neurons deficient in Bbs2 or Bbs4 lacked ciliary localization of Sstr3 (<a href="/entry/182453">182453</a>) and Mchr1 (GPR24; <a href="/entry/601751">601751</a>). Because MCHR1 is involved in the regulation of feeding behavior, <a href="#2" class="mim-tip-reference" title="Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C., Mykytyn, K. <strong>Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia.</strong> Proc. Nat. Acad. Sci. 105: 4242-4246, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18334641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18334641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18334641[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0711027105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18334641">Berbari et al. (2008)</a> concluded that the BBS phenotype is due to altered signaling caused by mislocalization of ciliary signaling proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18334641" 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="#16" class="mim-tip-reference" title="Rahmouni, K., Fath, M. A., Seo, S., Thedens, D. R., Berry, C. J., Weiss, R., Nishimura, D. Y., Sheffield, V. C. <strong>Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome.</strong> J. Clin. Invest. 118: 1458-1467, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18317593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18317593</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18317593[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/10.1172/JCI32357" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18317593">Rahmouni et al. (2008)</a> studied Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice and found that obesity was associated with hyperleptinemia (<a href="/entry/164160">164160</a>) and resistance to the anorectic and weight-reducing effects of leptin. Although all 3 of the BBS mouse models were similarly resistant to the metabolic actions of leptin, only Bbs4 -/- and Bbs6 -/- mice remained responsive to the effects of leptin on renal sympathetic nerve activity and arterial pressure and developed hypertension. The authors also found that BBS mice had decreased hypothalamic expression of proopiomelanocortin (POMC; <a href="/entry/176830">176830</a>), and suggested that BBS genes play an important role in maintaining leptin sensitivity in POMC neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18317593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=600374[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434632 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434632;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/rs121434632?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=rs121434632" 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=rs121434632" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In the large inbred Bedouin kindred with Bardet-Biedl syndrome (BBS4; <a href="/entry/615982">615982</a>) in which BBS4 was identified (<a href="#3" class="mim-tip-reference" title="Carmi, R., Rokhlina, T., Kwitek-Black, A. E., Elbedour, K., Nishimura, D., Stone, E. M., Sheffield, V. C. <strong>Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15.</strong> Hum. Molec. Genet. 4: 9-13, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711739</a>] [<a href="https://doi.org/10.1093/hmg/4.1.9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7711739">Carmi et al., 1995</a>), mapping to 15q, <a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> identified, in affected members, an arg295-to-pro missense mutation in exon 12 of a novel gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7711739+11381270" 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 an Italian family and an Israeli Arab family with Bardet-Biedl syndrome (BBS4; <a href="/entry/615982">615982</a>), <a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a> found deletion of exons 3 and 4 (48 codons) from a novel gene designated BBS4. The deletion breakpoints occurred within Alu repeat elements in introns 2 and 4. Haplotype analysis suggested that the mutation occurred independently in the 2 families. The deletion involved 6 kb. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11381270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Iannaccone, A., Mykytyn, K., Persico, A. M., Searby, C. C., Baldi, A., Jablonski, M. M., Sheffield, V. C. <strong>Clinical evidence of decreased olfaction in Bardet-Biedl syndrome caused by a deletion in the BBS4 gene.</strong> Am. J. Med. Genet. 132A: 343-346, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654695/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654695</a>] [<a href="https://doi.org/10.1002/ajmg.a.30512" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654695">Iannaccone et al. (2005)</a> described decreased olfaction in 2 individuals from the Italian family reported previously by <a href="#13" class="mim-tip-reference" title="Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C. <strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong> Nature Genet. 28: 188-191, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11381270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11381270</a>] [<a href="https://doi.org/10.1038/88925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11381270">Mykytyn et al. (2001)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15654695+11381270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 BARDET-BIEDL SYNDROME 4</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> rs113994192 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994192;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/rs113994192?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=rs113994192" 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=rs113994192" 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=RCV000009718 OR RCV000020932" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009718, RCV000020932" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009718...</a>
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<p>In individuals with Bardet-Biedl syndrome (BBS4; <a href="/entry/615982">615982</a>) in a consanguineous Saudi Arabian family, <a href="#8" class="mim-tip-reference" title="Katsanis, N., Eichers, E. R., Ansley, S. J., Lewis, R. A., Kayserili, H., Hoskins, B. E., Scambler, P. J., Beales, P. L., Lupski, J. R. <strong>BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.</strong> Am. J. Hum. Genet. 71: 22-29, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12016587[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016587">Katsanis et al. (2002)</a> identified homozygosity for an A-to-G transition at the acceptor splicer site of exon 4 (IVS3-2A-G) in the BBS4 gene. Alteration was thought to be pathogenic since it was not found in 108 ethnically matched control chromosomes and was predicted to result in a null allele due to missplicing and subsequent nonsense-mediated RNA decay (<a href="#12" class="mim-tip-reference" title="Losson, R., Lacroute, F. <strong>Interference of nonsense mutations with eukaryotic messenger RNA stability.</strong> Proc. Nat. Acad. Sci. 76: 5134-5137, 1979.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/388431/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">388431</a>] [<a href="https://doi.org/10.1073/pnas.76.10.5134" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="388431">Losson and Lacroute, 1979</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12016587+388431" 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> rs28938468 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28938468;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/rs28938468?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=rs28938468" 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=rs28938468" 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=RCV000009719 OR RCV003228893" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000009719, RCV003228893" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000009719...</a>
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<p>In a consanguineous sibship of Kurdish origin, <a href="#8" class="mim-tip-reference" title="Katsanis, N., Eichers, E. R., Ansley, S. J., Lewis, R. A., Kayserili, H., Hoskins, B. E., Scambler, P. J., Beales, P. L., Lupski, J. R. <strong>BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.</strong> Am. J. Hum. Genet. 71: 22-29, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12016587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12016587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12016587[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/341031" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12016587">Katsanis et al. (2002)</a> observed that BBS4 (<a href="/entry/615982">615982</a>) was related to homozygosity for a 1091C-A transversion in the BBS4 gene, predicted to result in an ala364-to-glu (A364E) alteration, a potentially deleterious change in the local polarity of the polypeptide. The mutation was not detected in 384 control chromosomes, including 84 Kurdish chromosomes. The affected individual was the only homozygous person in the kindred; 2 unaffected sibs were carriers. Genetic data had excluded this family from all other BBS loci by haplotype analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12016587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#Dallapiccola1971" class="mim-tip-reference" title="Dallapiccola, B. <strong>Familial translocation t(2p-; 17p+).</strong> Ann. Genet. 14: 153-155, 1971.">Dallapiccola (1971)</a>
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Anosov, M., Birk, R.
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<strong>Bardet-Biedl syndrome obesity: BBS regulates cellular ER stress in early adipogenesis.</strong>
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Molec. Genet. Metab. 126: 495-503, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30902542/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30902542</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30902542" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C., Mykytyn, K.
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<strong>Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia.</strong>
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Proc. Nat. Acad. Sci. 105: 4242-4246, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18334641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18334641</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18334641[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=18334641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0711027105" target="_blank">Full Text</a>]
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Carmi, R., Rokhlina, T., Kwitek-Black, A. E., Elbedour, K., Nishimura, D., Stone, E. M., Sheffield, V. C.
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<strong>Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15.</strong>
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Hum. Molec. Genet. 4: 9-13, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7711739/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7711739</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7711739" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Dallapiccola, B.
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<strong>Familial translocation t(2p-; 17p+).</strong>
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Ann. Genet. 14: 153-155, 1971.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/5314804/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">5314804</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=5314804" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Eichers, E. R., Abd-El-Barr, M. M., Paylor, R., Lewis, R. A., Bi, W., Lin, X., Meehan, T. P., Stockton, D. W., Wu, S. M., Lindsay, E., Justice, M. J., Beales, P. L., Katsanis, N., Lupski, J. R.
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<strong>Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expression.</strong>
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Hum. Genet. 120: 211-226, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16794820/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16794820</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16794820" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.30512" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2010.05.015" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/341031" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1352" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng1418" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.devcel.2008.11.001" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.76.10.5134" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/88925" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.0402354101" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2007.03.053" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 05/18/2020
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Patricia A. Hartz - updated : 11/12/2012<br>Patricia A. Hartz - updated : 10/13/2010<br>Cassandra L. Kniffin - updated : 8/12/2008<br>Marla J. F. O'Neill - updated : 7/22/2008<br>Patricia A. Hartz - updated : 7/2/2008<br>Patricia A. Hartz - updated : 5/21/2008<br>Jane Kelly - updated : 4/15/2008<br>Cassandra L. Kniffin - updated : 11/2/2006<br>Marla J. F. O'Neill - updated : 3/3/2005<br>Victor A. McKusick - updated : 7/13/2004<br>Victor A. McKusick - updated : 4/26/2004<br>Victor A. McKusick - updated : 7/17/2002<br>Victor A. McKusick - updated : 5/24/2001<br>Victor A. McKusick - updated : 4/14/1997
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Creation Date:
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Victor A. McKusick : 2/6/1995
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carol : 05/18/2020
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carol : 02/05/2016<br>carol : 1/30/2016<br>alopez : 10/16/2014<br>mgross : 11/12/2012<br>mgross : 10/15/2010<br>terry : 10/13/2010<br>wwang : 8/22/2008<br>ckniffin : 8/12/2008<br>wwang : 7/23/2008<br>terry : 7/22/2008<br>wwang : 7/9/2008<br>terry : 7/2/2008<br>mgross : 5/21/2008<br>carol : 4/15/2008<br>wwang : 11/7/2006<br>ckniffin : 11/2/2006<br>alopez : 6/12/2006<br>terry : 4/4/2005<br>carol : 3/3/2005<br>carol : 8/19/2004<br>tkritzer : 7/16/2004<br>terry : 7/13/2004<br>alopez : 5/3/2004<br>alopez : 4/27/2004<br>terry : 4/26/2004<br>cwells : 11/7/2003<br>alopez : 7/18/2002<br>terry : 7/17/2002<br>alopez : 10/5/2001<br>alopez : 10/5/2001<br>alopez : 6/4/2001<br>alopez : 5/31/2001<br>alopez : 5/29/2001<br>terry : 5/24/2001<br>alopez : 4/2/2001<br>alopez : 7/8/1997<br>mark : 4/14/1997<br>mark : 4/14/1997<br>terry : 4/10/1997<br>terry : 4/18/1996<br>mimadm : 9/23/1995<br>carol : 2/6/1995
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<span class="mim-font">
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<strong>*</strong> 600374
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<h3>
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BBS4 GENE; BBS4
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<strong><em>HGNC Approved Gene Symbol: BBS4</em></strong>
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Cytogenetic location: 15q24.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:72,686,207-72,738,473 </span>
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</em>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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15q24.1
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Bardet-Biedl syndrome 4
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<span class="mim-font">
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615982
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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>BBS4 is 1 of 7 BBS proteins that form the stable core of a protein complex required for ciliogenesis (Nachury et al., 2007). </p>
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<strong>Cloning and Expression</strong>
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<p>Mykytyn et al. (2001) analyzed an EST cluster within the critical mapping region for Bardet-Biedl syndrome-4 (BBS4; see 209900) on chromosome 15q22 and identified a contig with an open reading frame of 519 codons. </p><p>Using microarray analysis, Shah et al. (2008) showed that human airway epithelia expressed all 12 BBS genes. Immunohistochemical analysis localized BBS2 and BBS4 to cellular structures associated with motile cilia. </p>
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<strong>Gene Structure</strong>
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<p>Mykytyn et al. (2001) found that the BBS4 gene contains 16 exons and spans approximately 52 kb. </p>
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<strong>Mapping</strong>
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<span class="mim-text-font">
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<p>By sequence analysis, Mykytyn et al. (2001) mapped the BBS4 gene to chromosome 15q22. </p>
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<strong>Gene Function</strong>
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<p>Mykytyn et al. (2001) pointed out that the predicted protein sequence of BBS4 shows strongest homology to O-linked N-acetylglucosamine transferase (OGT; 300255) from several species, including archaebacteria and plants. The plant OGT is a signal transduction protein involved in a variety of developmental processes in Arabidopsis. In humans, OGT has been implicated in insulin resistance and may play a role in diabetes. </p><p>Kim et al. (2004) showed that BBS4 localizes to the centriolar satellites of centrosomes and basal bodies of primary cilia, where it functions as an adaptor of the p150(glued) subunit of the dynein transport machinery (DCTN1; 601143) to recruit pericentriolar material-1 protein (PCM1; 600299) and its associated cargo to the satellites. Silencing of BBS4 induces PCM1 mislocalization and concomitant deanchoring of centrosomal microtubules, arrest in cell division, and apoptotic cell death. Expression of 2 truncated forms of BBS4 that are similar to those found in some individuals with Bardet-Biedl syndrome had a similar effect on PCM1 and microtubules. These findings indicated that defective targeting or anchoring of pericentriolar proteins and microtubule disorganization contribute to the BBS phenotype and provide new insights into possible causes of familial obesity, diabetes, and retinal degeneration. Kim et al. (2004) commented that Bardet-Biedl syndrome appeared to the first pleiotropic phenotype attributable to pericentriolar dysfunction. </p><p>Nachury et al. (2007) found that BBS1 (209901), BBS2 (606151), BBS4, BBS5 (603650), BBS7 (607590), BBS8 (TTC8; 608132), and BBS9 (607968) copurified in stoichiometric amounts from human retinal pigment epithelium (RPE) cells and from mouse testis. PCM1 and alpha-tubulin (see 602529)/beta-tubulin (191130) copurified in substoichiometric amounts. The apparent molecular mass of the complex, which Nachury et al. (2007) called the BBSome, was 438 kD, and it had a sedimentation coefficient of 14S. The complex localized with PCM1 to nonmembranous centriolar satellites in the cytoplasm and, in the absence of PCM1, to the ciliary membrane. Cotransfection and immunoprecipitation experiments suggested that BBS9 was the complex-organizing subunit and that BBS5 mediated binding to phospholipids, predominantly phosphatidylinositol 3-phosphate. BBS1 mediated interaction with RABIN8 (RAB3IP; 608686), the guanine nucleotide exchange factor for the small G protein RAB8 (RAB8A; 165040). Nachury et al. (2007) found that RAB8 promoted ciliary membrane growth through fusion of exocytic vesicles to the base of the ciliary membrane. They concluded that BBS proteins likely function in membrane trafficking to the primary cilium. </p><p>Loktev et al. (2008) found that BBIP10 (613605) copurified and cosedimented with the BBS protein complex from RPE cells. Knockdown of BBIP10 in RPE cells via small interfering RNA compromised assembly of the BBS protein complex and caused failure of ciliogenesis. Knockdown of BBS1, BBS5, or PCM1 resulted in a similar failure of ciliogenesis in RPE cells. Depletion of BBIP10 or BBS8 increased the frequency of centrosome splitting in interphase cells. BBIP10 also had roles in cytoplasmic microtubule stabilization and acetylation that appeared to be independent of its role in assembly of the BBS protein complex. </p><p>Using a protein pull-down assay with homogenized bovine retina, Jin et al. (2010) showed that ARL6 (608845) bound the BBS protein complex. Depletion of ARL6 in human RPE cells did not affect assembly of the complex, but it blocked its localization to cilia. Targeting of ARL6 and the protein complex to cilia required GTP binding by ARL6, but not ARL6 GTPase activity. When in the GTP-bound form, the N-terminal amphipathic helix of ARL6 bound brain lipid liposomes and recruited the BBS protein complex. Upon recruitment, the complex appeared to polymerize into an electron-dense planar coat, and it functioned in lateral transport of test cargo proteins to ciliary membranes. </p><p>By mass spectrometric analysis of transgenic mouse testis, Seo et al. (2011) found that Lxtfl1 (606568) copurified with human BBS4 and with the core mouse BBS complex subunits Bbs1, Bbs2, Bbs5, Bbs7, Bbs8, and Bbs9. Immunohistochemical analysis of human RPE cells showed colocalization of LXTFL1 and BBS9 in cytoplasmic punctae. Use of small interfering RNA revealed distinct functions for each BBS subunit in BBS complex assembly and trafficking. LZTFL1 depletion and overexpression studies showed a negative role for LZTFL1 in BBS complex trafficking, but no effect of LZTFL1 on BBS complex assembly. Mutation analysis revealed that the C-terminal half of Lztfl1 interacted with the C-terminal domain of Bbs9 and that the N-terminal half of Lztfl1 negatively regulated BBS complex trafficking. Depletion of several BBS subunits and LZTFL1 also altered Hedgehog (SHH; 600725) signaling, as measured by GLI1 (165220) expression and ciliary trafficking of SMO (SMOH; 601500). </p><p>Anosov and Birk (2019) studied the expression of BBS4 in preadipocyte mouse cell lines. Using immunocytochemisty and cellular protein fractionation, they showed that BBS4 localizes to the endoplasmic reticulum. siRNA knockdown of BBS4 at day 3 of mouse preadipocyte cell differentiation resulted in a significant decrease in cleaved ATF6 (605537) and phosphorylated IRE1A (604033) at baseline and in response to induced ER stress. Induction of ER stress in BBS4 knockdown mouse adipocytes resulted in ER retention of XBP1 (194355) during adipocyte differentiation, indicating a role for BBS4 in the ER stress response and ER trafficking. </p>
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<strong>Biochemical Features</strong>
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</h4>
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<p>Using computational analysis, Jin et al. (2010) found that the BBS protein complex shares structural features with the canonical coat complexes COPI (601924), COPII (see 610511), and clathrin AP1 (see 603531). BBS4 and BBS8 consist almost entirely of tetratricopeptide repeats (TPRs) (13 and 12.5 TPRs, respectively), which are predicted to fold into extended rod-shaped alpha solenoids. BBS1, BBS2, BBS7, and BBS9 each have an N-terminal beta-propeller fold followed by an amphipathic helical linker and a gamma-adaptin (AP1G1; 603533) ear motif. In BBS2, BBS7, and BBS9, the ear motif is followed by an alpha/beta platform domain and an alpha helix. In BBS1, a 4-helix bundle is inserted between the second and third blades of the beta propeller. BBS5 contains 2 pleckstrin (PLEK; 173570) homology domains and a 3-helix bundle, while BBIP10 consists of 2 alpha helices. Jin et al. (2010) concluded that the abundance of beta propellers, alpha solenoids, and appendage domains inside the BBS protein complex suggests that it shares an evolutionary relationship with canonical coat complexes. </p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>In the proband of the BBS4-linked Bedouin kindred in which the BBS4 locus was initially mapped (Carmi et al., 1995), Mykytyn et al. (2001) sequenced the BBS4 gene coding region and consensus splice sites and detected a homozygous G-to-C transversion in exon 12, predicting an arginine-to-proline substitution at codon 295 (R295P; 600374.0001). This R295P variant segregated completely with the disease in the family and was not found in 48 unrelated Bedouin Arab controls. In affected members of an Italian BBS4 family, they found partial deletion of the gene (600374.0002). The same deletion was found in an Israeli Arab family. Two different homozygous mutations were found in 2 European families. </p><p>Katsanis et al. (2002) evaluated the spectrum of mutations in the BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families with BBS. Consistent with predictions from previous genetic analyses, the data suggested that mutations in BBS4 could contribute to BBS in less than 3% of affected families. Furthermore, integrated mutational data from the BBS2, BBS4, and BBS6 (604896) genes raised the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins. </p>
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<strong>Animal Model</strong>
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<p>Kulaga et al. (2004) examined mice with deletions of the Bbs1 or Bbs4 genes. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. </p><p>Mykytyn et al. (2004) found that mice lacking the Bbs4 protein had major components of the human Bardet-Biedl syndrome-4 phenotype, including obesity and retinal degeneration. BBS4 retinopathy involves apoptotic death of photoreceptors, the primary ciliated cells of the retina. Bbs4-null mice developed both motile and primary cilia, demonstrating that Bbs4 is not required for global cilia formation. Male Bbs4-null mice did not form spermatozoa flagella. These mutation data demonstrated a connection between the function of a Bbs protein and cilia. To further evaluate an association between cilia and BBS, Mykytyn et al. (2004) performed homology comparisons of BBS proteins in model organisms and found that BBS proteins are specifically conserved in ciliated organisms. </p><p>Eichers et al. (2006) generated a mouse model of BBS4 by targeted inactivation of the murine Bbs4 gene. Although the mice were initially runted compared to wildtype, they later became obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal liver profiles, signs of liver dysfunction, and increased insulin and leptin levels similar to the metabolic syndrome (see 605552). Affected mice also developed age-dependent retinal dystrophy and displayed anxiety-related behavior. Birth defects, such an neural tube defects, occurred rarely. </p><p>Swiderski et al. (2007) identified and characterized gene expression changes associated with photoreceptor cell loss in a Bbs4-knockout mouse model of retinal degeneration. Three hundred fifty-four probes were differentially expressed in Bbs4 -/- eyes compared with controls using a 2-fold cutoff. Numerous vision-related transcripts decreased because of photoreceptor cell loss. Increased expression of the stress response genes Edn2 (131241), Lcn2 (600181), Serpina3n, and Socs3 (604176) was noted as early as postnatal week 4 in the eyes of 4 BBS mouse model strains. A burst of apoptotic activity in the photoreceptor outer nuclear layer at postnatal week 2 and highly disorganized outer segments by postnatal weeks 4 to 6 were observed in all 4 strains. The specific loss of photoreceptors in Bbs4 -/- mice allowed Swiderski et al. (2007) to identify a set of genes that were preferentially expressed in photoreceptors compared with other cell types. The animal model eyes implied that BBS proteins play a critical early role in establishing the correct structure and function of photoreceptors. </p><p>By immunostaining for axonemal proteins, Tan et al. (2007) demonstrated that mouse dorsal root ganglion neurons contain cilia. Bbs1-null and Bbs4-null mice demonstrated behavioral deficits in thermosensation and mechanosensation associated with alterations in the trafficking of the thermosensory channel Trpv1 (602076) and the mechanosensory channel Stoml3 (608327) within sensory neurons. The findings were replicated in C. elegans lacking Bbs7 or Bbs8 (TTC8; 608132). Detailed examination of 9 patients with BBS showed a noticeable decrease in peripheral sensation in most of them. </p><p>Using mice lacking Bbs2, Bbs4, or Bbs6 and mice with the met390-to-arg (M390R; 209901.0001) mutation in Bbs1 (209901), Shah et al. (2008) showed that expression of BBS proteins was not required for ciliogenesis, but their loss caused structural defects in a fraction of cilia covering airway epithelia. The most common abnormality was bulges filled with vesicles near the tips of cilia, and this same misshapen appearance was present in airway cilia from all mutant mouse strains. Cilia of Bbs4-null and Bbs1 mutant mice beat at a lower frequency than wildtype cilia. Neither airway hyperresponsiveness nor inflammation increased in Bbs2- or Bbs4-null mice immunized with ovalbumin compared with wildtype mice. Instead, mutant animals were partially protected from airway hyperresponsiveness. </p><p>Berbari et al. (2008) reported that BBS proteins are required for the localization of G protein-coupled receptors to primary cilia on central mouse neurons. Neurons deficient in Bbs2 or Bbs4 lacked ciliary localization of Sstr3 (182453) and Mchr1 (GPR24; 601751). Because MCHR1 is involved in the regulation of feeding behavior, Berbari et al. (2008) concluded that the BBS phenotype is due to altered signaling caused by mislocalization of ciliary signaling proteins. </p><p>Rahmouni et al. (2008) studied Bbs2 -/-, Bbs4 -/-, and Bbs6 -/- mice and found that obesity was associated with hyperleptinemia (164160) and resistance to the anorectic and weight-reducing effects of leptin. Although all 3 of the BBS mouse models were similarly resistant to the metabolic actions of leptin, only Bbs4 -/- and Bbs6 -/- mice remained responsive to the effects of leptin on renal sympathetic nerve activity and arterial pressure and developed hypertension. The authors also found that BBS mice had decreased hypothalamic expression of proopiomelanocortin (POMC; 176830), and suggested that BBS genes play an important role in maintaining leptin sensitivity in POMC neurons. </p>
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</span>
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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>4 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 BARDET-BIEDL SYNDROME 4</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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BBS4, ARG295PRO
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<br />
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SNP: rs121434632,
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gnomAD: rs121434632,
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ClinVar: RCV000009716, RCV001002881
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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 the large inbred Bedouin kindred with Bardet-Biedl syndrome (BBS4; 615982) in which BBS4 was identified (Carmi et al., 1995), mapping to 15q, Mykytyn et al. (2001) identified, in affected members, an arg295-to-pro missense mutation in exon 12 of a novel gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 BARDET-BIEDL SYNDROME 4</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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BBS4, EX3-4 DEL
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<br />
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SNP: rs113994189,
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ClinVar: RCV000009717, RCV000020945
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Italian family and an Israeli Arab family with Bardet-Biedl syndrome (BBS4; 615982), Mykytyn et al. (2001) found deletion of exons 3 and 4 (48 codons) from a novel gene designated BBS4. The deletion breakpoints occurred within Alu repeat elements in introns 2 and 4. Haplotype analysis suggested that the mutation occurred independently in the 2 families. The deletion involved 6 kb. </p><p>Iannaccone et al. (2005) described decreased olfaction in 2 individuals from the Italian family reported previously by Mykytyn et al. (2001). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 BARDET-BIEDL SYNDROME 4</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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BBS4, IVS3, A-G, -2
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<br />
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SNP: rs113994192,
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gnomAD: rs113994192,
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ClinVar: RCV000009718, RCV000020932
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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 individuals with Bardet-Biedl syndrome (BBS4; 615982) in a consanguineous Saudi Arabian family, Katsanis et al. (2002) identified homozygosity for an A-to-G transition at the acceptor splicer site of exon 4 (IVS3-2A-G) in the BBS4 gene. Alteration was thought to be pathogenic since it was not found in 108 ethnically matched control chromosomes and was predicted to result in a null allele due to missplicing and subsequent nonsense-mediated RNA decay (Losson and Lacroute, 1979). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 BARDET-BIEDL SYNDROME 4</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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BBS4, ALA364GLU
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<br />
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SNP: rs28938468,
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gnomAD: rs28938468,
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ClinVar: RCV000009719, RCV003228893
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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 consanguineous sibship of Kurdish origin, Katsanis et al. (2002) observed that BBS4 (615982) was related to homozygosity for a 1091C-A transversion in the BBS4 gene, predicted to result in an ala364-to-glu (A364E) alteration, a potentially deleterious change in the local polarity of the polypeptide. The mutation was not detected in 384 control chromosomes, including 84 Kurdish chromosomes. The affected individual was the only homozygous person in the kindred; 2 unaffected sibs were carriers. Genetic data had excluded this family from all other BBS loci by haplotype analysis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>See Also:</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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|
Dallapiccola (1971)
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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">
|
|
<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Anosov, M., Birk, R.
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<strong>Bardet-Biedl syndrome obesity: BBS regulates cellular ER stress in early adipogenesis.</strong>
|
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Molec. Genet. Metab. 126: 495-503, 2019.
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[PubMed: 30902542]
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[Full Text: https://doi.org/10.1016/j.ymgme.2019.03.006]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C., Mykytyn, K.
|
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<strong>Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia.</strong>
|
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Proc. Nat. Acad. Sci. 105: 4242-4246, 2008.
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[PubMed: 18334641]
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[Full Text: https://doi.org/10.1073/pnas.0711027105]
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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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Carmi, R., Rokhlina, T., Kwitek-Black, A. E., Elbedour, K., Nishimura, D., Stone, E. M., Sheffield, V. C.
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<strong>Use of a DNA pooling strategy to identify a human obesity syndrome locus on chromosome 15.</strong>
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Hum. Molec. Genet. 4: 9-13, 1995.
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[PubMed: 7711739]
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[Full Text: https://doi.org/10.1093/hmg/4.1.9]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Dallapiccola, B.
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<strong>Familial translocation t(2p-; 17p+).</strong>
|
|
Ann. Genet. 14: 153-155, 1971.
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[PubMed: 5314804]
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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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Eichers, E. R., Abd-El-Barr, M. M., Paylor, R., Lewis, R. A., Bi, W., Lin, X., Meehan, T. P., Stockton, D. W., Wu, S. M., Lindsay, E., Justice, M. J., Beales, P. L., Katsanis, N., Lupski, J. R.
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<strong>Phenotypic characterization of Bbs4 null mice reveals age-dependent penetrance and variable expression.</strong>
|
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Hum. Genet. 120: 211-226, 2006.
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[PubMed: 16794820]
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[Full Text: https://doi.org/10.1007/s00439-006-0197-y]
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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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Iannaccone, A., Mykytyn, K., Persico, A. M., Searby, C. C., Baldi, A., Jablonski, M. M., Sheffield, V. C.
|
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<strong>Clinical evidence of decreased olfaction in Bardet-Biedl syndrome caused by a deletion in the BBS4 gene.</strong>
|
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Am. J. Med. Genet. 132A: 343-346, 2005.
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[PubMed: 15654695]
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[Full Text: https://doi.org/10.1002/ajmg.a.30512]
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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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Jin, H., White, S. R., Shida, T., Schulz, S., Aguiar, M., Gygi, S. P., Bazan, J. F., Nachury, M. V.
|
|
<strong>The conserved Bardet-Biedl syndrome proteins assemble a coat that traffics membrane proteins to cilia.</strong>
|
|
Cell 141: 1208-1219, 2010.
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[PubMed: 20603001]
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[Full Text: https://doi.org/10.1016/j.cell.2010.05.015]
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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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Katsanis, N., Eichers, E. R., Ansley, S. J., Lewis, R. A., Kayserili, H., Hoskins, B. E., Scambler, P. J., Beales, P. L., Lupski, J. R.
|
|
<strong>BBS4 is a minor contributor to Bardet-Biedl syndrome and may also participate in triallelic inheritance.</strong>
|
|
Am. J. Hum. Genet. 71: 22-29, 2002.
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[PubMed: 12016587]
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[Full Text: https://doi.org/10.1086/341031]
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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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Kim, J. C., Badano, J. L., Sibold, S., Esmail, M. A., Hill, J., Hoskins, B. E., Leitch, C. C., Venner, K., Ansley, S. J., Ross, A. J., Leroux, M. R., Katsanis, N., Beales, P. L.
|
|
<strong>The Bardet-Biedl protein BBS4 targets cargo to the pericentriolar region and is required for microtubule anchoring and cell cycle progression.</strong>
|
|
Nature Genet. 36: 462-470, 2004.
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[PubMed: 15107855]
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[Full Text: https://doi.org/10.1038/ng1352]
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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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Kulaga, H. M., Leitch, C. C., Eichers, E. R., Badano, J. L., Lesemann, A., Hoskins, B. E., Lupski, J. R., Beales, P. L., Reed, R. R., Katsanis, N.
|
|
<strong>Loss of BBS proteins causes anosmia in humans and defects in olfactory cilia structure and function in the mouse.</strong>
|
|
Nature Genet. 36: 994-998, 2004.
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[PubMed: 15322545]
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[Full Text: https://doi.org/10.1038/ng1418]
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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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Loktev, A. V., Zhang, Q., Beck, J. S., Searby, C. C., Scheetz, T. E., Bazan, J. F., Slusarski, D. C., Sheffield, V. C., Jackson, P. K., Nachury, M. V.
|
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<strong>A BBSome subunit links ciliogenesis, microtubule stability, and acetylation.</strong>
|
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Dev. Cell 15: 854-865, 2008.
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[PubMed: 19081074]
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[Full Text: https://doi.org/10.1016/j.devcel.2008.11.001]
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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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Losson, R., Lacroute, F.
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<strong>Interference of nonsense mutations with eukaryotic messenger RNA stability.</strong>
|
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Proc. Nat. Acad. Sci. 76: 5134-5137, 1979.
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[PubMed: 388431]
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[Full Text: https://doi.org/10.1073/pnas.76.10.5134]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Mykytyn, K., Braun, T., Carmi, R., Haider, N. B., Searsby, C. C., Shastri, M., Beck, G., Wright, A. F., Iannaccone, A., Elbedour, K., Riise, R., Baldi, A., Raas-Rothschild, A., Gorman, S. W., Duhl, D. M., Jacobson, S. G., Casavant, T., Stone, E. M., Sheffield, V. C.
|
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<strong>Identification of the gene that, when mutated, causes the human obesity syndrome BBS4.</strong>
|
|
Nature Genet. 28: 188-191, 2001.
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[PubMed: 11381270]
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[Full Text: https://doi.org/10.1038/88925]
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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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Mykytyn, K., Mullins, R. F., Andrews, M., Chiang, A. P., Swiderski, R. E., Yang, B., Braun, T., Casavant, T., Stone, E. M., Sheffield, V. C.
|
|
<strong>Bardet-Biedl syndrome type 4 (BBS4)-null mice implicate Bbs4 in flagella formation but not global cilia assembly.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 8664-8669, 2004.
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[PubMed: 15173597]
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[Full Text: https://doi.org/10.1073/pnas.0402354101]
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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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Nachury, M. V., Loktev, A. V., Zhang, Q., Westlake, C. J., Peranen, J., Merdes, A., Slusarski, D. C., Scheller, R. H., Bazan, J. F., Sheffield, V. C., Jackson, P. K.
|
|
<strong>A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.</strong>
|
|
Cell 129: 1201-1213, 2007.
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[PubMed: 17574030]
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[Full Text: https://doi.org/10.1016/j.cell.2007.03.053]
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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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Rahmouni, K., Fath, M. A., Seo, S., Thedens, D. R., Berry, C. J., Weiss, R., Nishimura, D. Y., Sheffield, V. C.
|
|
<strong>Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome.</strong>
|
|
J. Clin. Invest. 118: 1458-1467, 2008.
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[PubMed: 18317593]
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[Full Text: https://doi.org/10.1172/JCI32357]
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Seo, S., Zhang, Q., Bugge, K., Breslow, D. K., Searby, C. C., Nachury, M. V., Sheffield, V. C.
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<strong>A novel protein LZTFL1 regulates ciliary trafficking of the BBSome and Smoothened.</strong>
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PLoS Genet. 7: e1002358, 2011. Note: Electronic Article.
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[PubMed: 22072986]
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[Full Text: https://doi.org/10.1371/journal.pgen.1002358]
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Shah, A. S., Farmen, S. L., Moninger, T. O., Businga, T. R., Andrews, M. P., Bugge, K., Searby, C. C., Nishimura, D., Brogden, K. A., Kline, J. N., Sheffield, V. C., Welsh, M. J.
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<strong>Loss of Bardet-Biedl syndrome proteins alters the morphology and function of motile cilia in airway epithelia.</strong>
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Proc. Nat. Acad. Sci. 105: 3380-3385, 2008.
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[PubMed: 18299575]
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[Full Text: https://doi.org/10.1073/pnas.0712327105]
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Swiderski, R. E., Nishimura, D. Y., Mullins, R. F., Olvera, M. A., Ross, J. L., Huang, J., Stone, E. M., Sheffield, V. C.
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<strong>Gene expression analysis of photoreceptor cell loss in Bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage.</strong>
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Invest. Ophthal. Vis. Sci. 48: 3329-3340, 2007.
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[PubMed: 17591906]
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[Full Text: https://doi.org/10.1167/iovs.06-1477]
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Tan, P. L., Barr, T., Inglis, P. N., Mitsuma, N., Huang, S. M., Garcia-Gonzalez, M. A., Bradley, B. A., Coforio, S., Albrecht, P. J., Watnick, T., Germino, G. G., Beales, P. L., Caterina, M. J., Leroux, M. R., Rice, F. L., Katsanis, N.
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<strong>Loss of Bardet-Biedl syndrome proteins causes defects in peripheral sensory innervation and function.</strong>
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Proc. Nat. Acad. Sci. 104: 17524-17529, 2007.
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[PubMed: 17959775]
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[Full Text: https://doi.org/10.1073/pnas.0706618104]
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Hilary J. Vernon - updated : 05/18/2020<br>Patricia A. Hartz - updated : 11/12/2012<br>Patricia A. Hartz - updated : 10/13/2010<br>Cassandra L. Kniffin - updated : 8/12/2008<br>Marla J. F. O'Neill - updated : 7/22/2008<br>Patricia A. Hartz - updated : 7/2/2008<br>Patricia A. Hartz - updated : 5/21/2008<br>Jane Kelly - updated : 4/15/2008<br>Cassandra L. Kniffin - updated : 11/2/2006<br>Marla J. F. O'Neill - updated : 3/3/2005<br>Victor A. McKusick - updated : 7/13/2004<br>Victor A. McKusick - updated : 4/26/2004<br>Victor A. McKusick - updated : 7/17/2002<br>Victor A. McKusick - updated : 5/24/2001<br>Victor A. McKusick - updated : 4/14/1997
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Victor A. McKusick : 2/6/1995
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