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Entry
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- *607273 - FOLLICULIN; FLCN
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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">*607273</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<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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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607273">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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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-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=ENSG00000154803;t=ENST00000285071" 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=201163" 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=607273" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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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=ENSG00000154803;t=ENST00000285071" 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_001353229,NM_001353230,NM_001353231,NM_144606,NM_144997,XM_011523714,XM_011523718,XM_011523721,XM_017024305,XM_017024308,XM_017024309,XM_047435531,XM_047435532,XM_047435533,XM_047435534,XM_047435535,XM_047435536,XM_047435537,XM_047435538,XM_047435539,XM_047435540,XM_047435541,XM_047435542" 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_144997" 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=607273" 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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<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=06278&isoform_id=06278_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/FLCN" 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/15990553,21389403,21732385,22255880,22907034,34533643,34535030,34785024,74751276,119576119,119576120,125993427,767991784,767991792,767991798,957951886,957951889,1034598602,1034598609,1034598612,1213953124,1213953154,1213953359,2217310466,2217310468,2217310470,2217310472,2217310475,2217310477,2217310479,2217310481,2217310484,2217310487,2217310489,2217310492,2462553667,2462553669,2462553671,2462553673,2462553675,2462553677,2462553679,2462553681,2462553683,2462553685,2462553687,2462553689,2462553691,2462553693,2462553695,2462553697,2462553699,2462553701" 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/Q8NFG4" 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 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=201163" 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=ENSG00000154803;t=ENST00000285071" 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=FLCN" 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=FLCN" 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+201163" 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/FLCN" 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:201163" 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/201163" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr17&hgg_gene=ENST00000427497.3&hgg_start=17212212&hgg_end=17237330&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:27310" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:27310" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/flcn" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607273[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=607273[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/FLCN/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000154803" 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=FLCN" 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=FLCN" 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=FLCN" 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://skingenedatabase.com/" title="The Folliculin Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">The Folliculin Mutation Da…</a></div><div style="margin-left: 0.5em;"><a href="http://www.lovd.nl/FLCN" title="Folliculin (FLCN) variation database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Folliculin (FLCN) variatio…</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=FLCN&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/PA134901005" 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:27310" 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/FBgn0261111.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:2442184" 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/FLCN#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:2442184" 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/201163/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001335/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=201163" 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=WBGene00017699;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-060421-3470" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:201163" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=FLCN&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 1263460007, 328561000119107<br />
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<strong>ICD10CM:</strong> J93.11<br />
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<strong>ICD9CM:</strong> 512.81<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607273
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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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FOLLICULIN; FLCN
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
FLCL<br />
|
|
BHD GENE; BHD
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FLCN" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FLCN</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/17/264?start=-3&limit=10&highlight=264">17p11.2</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr17:17212212-17237330&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">17:17,212,212-17,237,330</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=135150,114500,173600,144700" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
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<p>By positional cloning in a 700-kb critical region for Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>) on chromosome 17p11.2, <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> identified a novel gene encoding a deduced 579-amino acid protein designated folliculin. The protein contains a conserved SLS potential phosphorylation site, a glutamic acid-rich coiled-coil domain, an N-glycosylation site, and 3 myristoylation sites. High sequence conservation was found between human folliculin and homologs in mice, Drosophila, and C. elegans. Northern blot analysis detected expression of a 3.8-kb transcript in most normal adult tissues, including skin, lung, and kidney, and in fetal lung, kidney, liver, and brain tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The FLCN gene contains 14 exons (<a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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 positional cloning, <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> identified the FLCN gene on chromosome 17p11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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 coimmunoprecipitation of FNIP1 (<a href="/entry/610594">610594</a>) and FLCN expressed in HEK293 cells and in vitro binding assays, <a href="#1" class="mim-tip-reference" title="Baba, M., Hong, S.-B., Sharma, N., Warren, M. B., Nickerson, M. L., Iwamatsu, A., Esposito, D., Gillette, W. K., Hopkins, R. F., III, Hartley, J. L., Furihata, M., Oishi, S., Zhen, W., Burke, T. R., Jr., Linehan, W. M., Schmidt, L. S., Zbar, B. <strong>Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.</strong> Proc. Nat. Acad. Sci. 103: 15552-15557, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17028174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17028174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17028174[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.0603781103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17028174">Baba et al. (2006)</a> showed that the C terminus of FLCN and amino acids 300 to 1166 of FNIP1 were required for optimal FLCN-FNIP1 binding. FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern. FNIP1 was phosphorylated by AMPK (see <a href="/entry/602739">602739</a>), and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR (<a href="/entry/601231">601231</a>) and AMPK signaling. <a href="#1" class="mim-tip-reference" title="Baba, M., Hong, S.-B., Sharma, N., Warren, M. B., Nickerson, M. L., Iwamatsu, A., Esposito, D., Gillette, W. K., Hopkins, R. F., III, Hartley, J. L., Furihata, M., Oishi, S., Zhen, W., Burke, T. R., Jr., Linehan, W. M., Schmidt, L. S., Zbar, B. <strong>Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.</strong> Proc. Nat. Acad. Sci. 103: 15552-15557, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17028174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17028174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17028174[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.0603781103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17028174">Baba et al. (2006)</a> concluded that FLCN and FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17028174" 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 small interfering RNAs with several human cell lines, <a href="#5" class="mim-tip-reference" title="Hartman, T. R., Nicolas, E., Klein-Szanto, A., Al-Saleem, T., Cash, T. P., Simon, M. C., Henske, E. P. <strong>The role of the Birt-Hogg-Dube protein in mTOR activation and renal tumorigenesis.</strong> Oncogene 28: 1594-1604, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234517</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19234517[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2009.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234517">Hartman et al. (2009)</a> found that downregulation of TSC2 (<a href="/entry/191092">191092</a>) enhanced phosphorylation of ribosomal protein S6 (RPS6; <a href="/entry/180460">180460</a>), whereas downregulation of BHD reduced phosphorylation of RPS6, suggesting that TSC2 and BHD down- and upregulate activity of the TORC1 complex (see <a href="/entry/601231">601231</a>), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19234517" 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="Hudon, V., Sabourin, S., Dydensborg, A. B., Kottis, V., Ghazi, A., Paquet, M., Crosby, K., Pomerleau, V., Uetani, N., Pause, A. <strong>Renal tumour suppressor function of the Birt-Hogg-Dube syndrome gene product folliculin.</strong> J. Med. Genet. 47: 182-189, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843504</a>] [<a href="https://doi.org/10.1136/jmg.2009.072009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843504">Hudon et al. (2010)</a> confirmed the tumor suppressor activity of FLCN by nude mouse xenograft assays of 2 human renal cell carcinoma (RCC) lines with either diminished or reexpressed FLCN. Loss of FLCN expression led to context-dependent effects on RPS6. The authors observed diminished and increased activation of Rps6 resulting from diminished and increased expression levels of FLCN in human RCC cells when grown subcutaneously as solid tumors. In mouse Flcn +/- kidney sections, Rps6 was elevated in multilocular and large cysts from polycystic kidneys but was absent in small single cysts and very low in surrounding normal tissue. <a href="#8" class="mim-tip-reference" title="Hudon, V., Sabourin, S., Dydensborg, A. B., Kottis, V., Ghazi, A., Paquet, M., Crosby, K., Pomerleau, V., Uetani, N., Pause, A. <strong>Renal tumour suppressor function of the Birt-Hogg-Dube syndrome gene product folliculin.</strong> J. Med. Genet. 47: 182-189, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843504</a>] [<a href="https://doi.org/10.1136/jmg.2009.072009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843504">Hudon et al. (2010)</a> concluded that FLCN is a general tumor suppressor in the kidney, and that loss of FLCN expression results in improperly elevated or diminished activation of RPS6, depending on cellular context. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843504" 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 immunoprecipitation analysis of transfected HEK293 cells, followed by protein pull-down assays, <a href="#23" class="mim-tip-reference" title="Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z. <strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong> Hum. Molec. Genet. 25: 83-96, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>] [<a href="https://doi.org/10.1093/hmg/ddv450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26516189">Xia et al. (2016)</a> showed that FLCN interacted directly with TDP43 (TARDBP; <a href="/entry/605078">605078</a>). Overexpression of FLCN led to localization of TDP43 in cytoplasm, where it colocalized with markers of lysosomes, autophagosomes, and the ubiquitin-proteasome system. Under arsenite stress, TDP43 colocalized with stress granules. In contrast, RNA interference-mediated depletion of FLCN in arsenite-treated cells caused dissociation of TDP43 from stress granules and nuclear accumulation of TDP43. <a href="#23" class="mim-tip-reference" title="Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z. <strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong> Hum. Molec. Genet. 25: 83-96, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>] [<a href="https://doi.org/10.1093/hmg/ddv450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26516189">Xia et al. (2016)</a> concluded that FLCN is critical for TDP43 translocation from nucleus to cytoplasm, which is required for stress granule assembly. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26516189" 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="#2" class="mim-tip-reference" title="Benhammou, J. N., Vocke, C. D., Santani, A., Schmidt, L. S., Baba, M., Seyama, K., Wu, X., Korolevich, S., Nathanson, K. L., Stolle, C. A., Linehan, W. M. <strong>Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome.</strong> Genes Chromosomes Cancer 50: 466-477, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412933[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/gcc.20872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412933">Benhammou et al. (2011)</a> identified heterozygosity for deletion rearrangements in the FLCN gene in 9 patients from 6 families with BHD1. The mutations were identified by a combination of real-time qPCR, multiplex ligation-dependent probe amplification assay (MLPA), array-based genomic hybridization, and Sanger sequencing. Patient 1 (family A) had a deletion involving exons 2-5, patients 2 and 3 (family B) had a mutation involving exons 7-14, and patients 4-9 from 4 families (families C-F) had mutations involving exon 1. A luciferase reporter assay testing the shared region among patients 4-9 demonstrated decreased activity compared to wildtype FLCN. The deletions in FLCN in families A, C, and E were flanked by Alu repeats, which <a href="#2" class="mim-tip-reference" title="Benhammou, J. N., Vocke, C. D., Santani, A., Schmidt, L. S., Baba, M., Seyama, K., Wu, X., Korolevich, S., Nathanson, K. L., Stolle, C. A., Linehan, W. M. <strong>Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome.</strong> Genes Chromosomes Cancer 50: 466-477, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412933[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/gcc.20872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412933">Benhammou et al. (2011)</a> hypothesized explained the deletion mechanism. Clinical features in this patient cohort were similar to those in patients with point mutations in the FLCN gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21412933" 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><strong><em>Birt-Hogg-Dube Syndrome 1</em></strong></p><p>
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Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>) is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. In 9 BHD1 families and an additional 53 probands from small BHD1 families, <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> identified insertion or deletion mutations within a hypermutable C8 tract in exon 11 of the BHD gene in 27 (44%) of 62 patients. Eighteen had a 1-bp duplication (1285dupC; <a href="#0001">607273.0001</a>), and 9 had a 1-bp deletion (1285delC; <a href="#0002">607273.0002</a>) in the C8 tract. A slippage-mediated mechanism during DNA replication was thought to be responsible for these frameshift mutations leading to protein truncation. <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> also identified an insertion-deletion mutation (<a href="#0003">607273.0003</a>), a 28-bp duplication (<a href="#0004">607273.0004</a>), and a tyr463-to-ter (Y463X; <a href="#0005">607273.0005</a>) mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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>The studies of <a href="#10" class="mim-tip-reference" title="Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S. <strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong> J. Med. Genet. 39: 906-912, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471204</a>] [<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471204">Khoo et al. (2002)</a> further confirmed that the poly(C) tract in exon 11 of the BHD gene is a mutation hotspot. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Shin, J.-H., Shin, Y.-K., Ku, J.-L., Jeong, S.-Y., Hong, S.-H., Park, S.-Y., Kim, W.-H., Park, J.-G. <strong>Mutations of the Birt-Hogg-Dube (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability.</strong> J. Med. Genet. 40: 364-367, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746401</a>] [<a href="https://doi.org/10.1136/jmg.40.5.364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746401">Shin et al. (2003)</a> screened the poly(C)8 tract of the BHD gene and identified mutations in 5 (16%) of 32 microsatellite instability (MSI) sporadic colorectal carcinomas and in 1 (7.7%) of 13 MSI colorectal carcinoma cell lines. They were unable, however, to find any frameshift mutation in 80 microsatellite stable (MSS) sporadic carcinomas or 9 MSS colorectal carcinoma cell lines. In addition, they identified 2 heterozygous missense mutations in different cell lines with MSI. <a href="#20" class="mim-tip-reference" title="Shin, J.-H., Shin, Y.-K., Ku, J.-L., Jeong, S.-Y., Hong, S.-H., Park, S.-Y., Kim, W.-H., Park, J.-G. <strong>Mutations of the Birt-Hogg-Dube (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability.</strong> J. Med. Genet. 40: 364-367, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746401</a>] [<a href="https://doi.org/10.1136/jmg.40.5.364" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12746401">Shin et al. (2003)</a> found that the 16% frequency of mutations in the BHD gene was the same as that in the IGF2R gene (<a href="/entry/147280">147280</a>) and this was less than that of the TGFBR2 (<a href="/entry/190182">190182</a>), MSH3 (<a href="/entry/600887">600887</a>), BAX (<a href="/entry/600040">600040</a>), and MSH6 (<a href="/entry/600678">600678</a>) genes. All tumors with the BHD gene mutation harbored concurrent mutations of the poly(C)8 tract of the MSH6 gene, but the frameshift mutations of the BHD and IGF2R genes were mutually exclusive. These findings strongly suggested that the BHD gene is associated with colon cancer and that putative MSI target genes are involved in the development of MSI colorectal carcinomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746401" 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="#10" class="mim-tip-reference" title="Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S. <strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong> J. Med. Genet. 39: 906-912, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471204</a>] [<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471204">Khoo et al. (2002)</a> reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. <a href="#9" class="mim-tip-reference" title="Kahnoski, K., Khoo, S. K., Nassif, N. T., Chen, J., Lobo, G. P., Segelov, E., Teh, B. T. <strong>Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours.</strong> J. Med. Genet. 40: 511-515, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843323</a>] [<a href="https://doi.org/10.1136/jmg.40.7.511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843323">Kahnoski et al. (2003)</a> evaluated the role of the BHD gene in 47 unselected colorectal tumors (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analyzing 46 of the tumors for loss of heterozygosity (LOH) in the chromosome region surrounding the BHD locus. Alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues. They reported the detection of 2 novel somatic missense mutations of the BHD gene and LOH in 81% of primary sporadic colorectal tumors with no change in promoter methylation profile. All mutations were detected in microsatellite stable (MSS) tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12843323+12471204" 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="Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M. <strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong> Am. J. Hum. Genet. 76: 1023-1033, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15852235[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/10.1086/430842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15852235">Schmidt et al. (2005)</a> performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (<a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al., 2002</a>), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD; 27 (53%) of the mutations involved either a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (<a href="#0001">607273.0001</a> and <a href="#0002">607273.0002</a>, respectively), which appears to represent a mutation hotspot. <a href="#19" class="mim-tip-reference" title="Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M. <strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong> Am. J. Hum. Genet. 76: 1023-1033, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15852235[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/10.1086/430842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15852235">Schmidt et al. (2005)</a> noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+15852235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected individuals from 51 (88%) of 58 families with BHD, <a href="#21" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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/10.1136/jmg.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., <a href="#0014">607273.0014</a>). The 1285insC and 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except 1 were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18234728" 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="Nahorski, M. S., Lim, D. H. K., Martin, L., Gille, J. J. P., McKay, K., Rehal, P. K., Ploeger, H. M., van Steensel, M., Tomlinson, I. P., Latif, F., Menko, F. H., Maher, E. R. <strong>Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.</strong> J. Med. Genet. 47: 385-390, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522427</a>] [<a href="https://doi.org/10.1136/jmg.2009.073304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522427">Nahorski et al. (2010)</a> did not find any germline mutations in the FLCN gene among 50 patients with familial nonsyndromic colorectal cancer. In the same study involving 51 families with BHD, the authors found that those with the 1285dupC mutation (<a href="#0001">607273.0001</a>) had a higher risk of colorectal neoplasia compared to those with the 610delGCinsTA mutation (<a href="#0016">607273.0016</a>) (p = 0.016). Furthermore, somatic frameshift mutations in the exon 11 C(8) mononucleotide tract of FLCN were detected in 7 (23%) of 30 sporadic colorectal cancers with microsatellite instability, and the frequency of these somatic mutations was more common in tumors that also showed loss of MLH1 (<a href="/entry/120436">120436</a>) or MSH2 (<a href="/entry/609309">609309</a>) protein expression. The findings suggested that FLCN inactivation may contribute to colorectal tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20522427" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs (patients 10 and 11, family G) with BHD, <a href="#2" class="mim-tip-reference" title="Benhammou, J. N., Vocke, C. D., Santani, A., Schmidt, L. S., Baba, M., Seyama, K., Wu, X., Korolevich, S., Nathanson, K. L., Stolle, C. A., Linehan, W. M. <strong>Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome.</strong> Genes Chromosomes Cancer 50: 466-477, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412933[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/gcc.20872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412933">Benhammou et al. (2011)</a> identified a duplication involving exons 10-11 in the FLCN gene (<a href="#0018">607273.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21412933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Primary Spontaneous Pneumothorax</em></strong></p><p>
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Primary spontaneous pneumothorax (PSP; <a href="/entry/173600">173600</a>), a condition in which air enters the pleural space and causes secondary lung collapse, is most often a sporadic trait but also occurs in families. In almost all patients it is associated with emphysema-like changes (bullae) in the lungs. By a genomewide scan in a large Finnish family with a dominantly inherited tendency to PSP, <a href="#17" class="mim-tip-reference" title="Painter, J. N., Tapanainen, H., Somer, M., Tukiainen, P., Aittomaki, K. <strong>A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.</strong> Am. J. Hum. Genet. 76: 522-527, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15657874[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/10.1086/428455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657874">Painter et al. (2005)</a> mapped the PSP locus to chromosome 17p11 where the FLCN gene maps. Screening of the FLCN gene revealed a 4-bp deletion in the first coding exon, which created a frameshift and protein truncation (<a href="#0009">607273.0009</a>). All carriers of the deletion had bullous lung lesions. Unlike previously identified mutations in the FLCN gene, the exon 4 deletion seemed to be associated only with PSP, which showed 100% penetrance. The results suggested that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema. Because of the strong association between primary spontaneous pneumothorax and the Birt-Hogg-Dube syndrome, <a href="#17" class="mim-tip-reference" title="Painter, J. N., Tapanainen, H., Somer, M., Tukiainen, P., Aittomaki, K. <strong>A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.</strong> Am. J. Hum. Genet. 76: 522-527, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15657874[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/10.1086/428455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657874">Painter et al. (2005)</a> suggested that patients with familial PSP should be investigated for increased risk of renal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15657874" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 of 8 unrelated Japanese patients with multiple lung cysts and spontaneous pneumothorax, but without skin or renal lesions, <a href="#4" class="mim-tip-reference" title="Gunji, Y., Akiyoshi, T., Sato, T., Kurihara, M., Tominaga, S., Takahashi, K., Seyama, K. <strong>Mutations of the Birt-Hogg-Dube gene in patients with multiple lung cysts and recurrent pneumothorax. (Letter)</strong> J. Med. Genet. 44: 588-593, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17496196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17496196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17496196[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/10.1136/jmg.2007.049874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17496196">Gunji et al. (2007)</a> identified mutations in the BHD gene (see, e.g., <a href="#0001">607273.0001</a>; <a href="#0010">607273.0010</a>; <a href="#0011">607273.0011</a>). All 5 patients had a family history of the disorder. <a href="#4" class="mim-tip-reference" title="Gunji, Y., Akiyoshi, T., Sato, T., Kurihara, M., Tominaga, S., Takahashi, K., Seyama, K. <strong>Mutations of the Birt-Hogg-Dube gene in patients with multiple lung cysts and recurrent pneumothorax. (Letter)</strong> J. Med. Genet. 44: 588-593, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17496196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17496196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17496196[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/10.1136/jmg.2007.049874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17496196">Gunji et al. (2007)</a> suggested that isolated pulmonary cysts and pneumothorax may be a milder form of the BHD syndrome and that patients should be monitored for renal or skin lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17496196" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 10 of 102 Chinese probands with spontaneous pneumothorax, <a href="#18" class="mim-tip-reference" title="Ren, H.-Z., Zhu, C.-C., Yang, C., Chen, S.-L., Xie, J., Hou, Y.-Y., Xu, Z.-F., Wang, D.-J., Mu, D.-K., Ma, D.-H., Wang, Y., Ye, M.-H., Ye, Z.-R., Chen, B.-F., Wang, C.-G., Lin, J., Qiao, D., Yi, L. <strong>Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax.</strong> Clin. Genet. 74: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18505456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18505456</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01030.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18505456">Ren et al. (2008)</a> identified 4 different mutations in the FLCN gene (see, e.g., <a href="#0001">607273.0001</a>; <a href="/entry/607272#0012">607272.0012</a>-<a href="/entry/607272#0013">607272.0013</a>). Although only 5 of the probands reported a family history of the disorder, genetic analysis showed that 8 of the probands had family members with either pneumothorax or pulmonary cysts as determined by imaging studies. Two mutation carriers from 2 different families did not have pulmonary cysts. The findings indicated reduced penetrance of both the pneumothorax phenotype and the cyst phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18505456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K. <strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong> J. Med. Genet. 47: 281-287, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413710[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/10.1136/jmg.2009.070565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413710">Kunogi et al. (2010)</a> identified 15 different heterozygous germline FLCN mutations, including 2 large genomic deletions (see, e.g., <a href="#0017">607273.0017</a>), in 25 (69.4%) of the 36 Japanese patients with multiple lung cysts of undetermined cause, all but 1 of whom had suffered at least 1 pneumothorax. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors. <a href="#12" class="mim-tip-reference" title="Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K. <strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong> J. Med. Genet. 47: 281-287, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413710[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/10.1136/jmg.2009.070565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413710">Kunogi et al. (2010)</a> noted that mutations were most frequently identified in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutation had a very low incidence of skin and renal involvement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20413710" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutations</em></strong></p><p>
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<a href="#9" class="mim-tip-reference" title="Kahnoski, K., Khoo, S. K., Nassif, N. T., Chen, J., Lobo, G. P., Segelov, E., Teh, B. T. <strong>Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours.</strong> J. Med. Genet. 40: 511-515, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843323</a>] [<a href="https://doi.org/10.1136/jmg.40.7.511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843323">Kahnoski et al. (2003)</a> reported the detection of 2 novel somatic missense mutations in the BHD gene (<a href="#0007">607273.0007</a> and <a href="#0008">607273.0008</a>) and LOH in 81% of primary sporadic colorectal tumors with no change in promoter methylation profile. The mutations were detected in microsatellite stable (MSS) tumors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843323" 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="Nahorski, M. S., Lim, D. H. K., Martin, L., Gille, J. J. P., McKay, K., Rehal, P. K., Ploeger, H. M., van Steensel, M., Tomlinson, I. P., Latif, F., Menko, F. H., Maher, E. R. <strong>Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.</strong> J. Med. Genet. 47: 385-390, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522427</a>] [<a href="https://doi.org/10.1136/jmg.2009.073304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522427">Nahorski et al. (2010)</a> detected somatic frameshift mutations in the exon 11 C(8) mononucleotide tract of FLCN in 7 (23%) of 30 sporadic colorectal cancers with microsatellite instability, and the frequency of these somatic mutations was more common in tumors that also showed loss of MLH1 (<a href="/entry/120436">120436</a>) or MSH2 (<a href="/entry/609309">609309</a>) protein expression. The findings suggested that FLCN inactivation may contribute to colorectal tumorigenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20522427" 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="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> pointed to mapping studies suggesting that germline mutations in dog and rat BHD homologs lead to inherited renal cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" 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>Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German shepherd dogs. <a href="#13" class="mim-tip-reference" title="Lingaas, F., Comstock, K. E., Kirkness, E. F., Sorensen, A., Aarskaug, T., Hitte, C., Nickerson, M. L., Moe, L., Schmidt, L. S., Thomas, R., Breen, M., Galibert, F., Zbar, B., Ostrander, E. A. <strong>A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.</strong> Hum. Molec. Genet. 12: 3043-3053, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532326</a>] [<a href="https://doi.org/10.1093/hmg/ddg336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14532326">Lingaas et al. (2003)</a> narrowed the RCND interval to a small region on canine chromosome 5 that overlapped the human BHD gene. The authors described a his255-to-arg mutation in exon 7 of the canine Bhd gene that segregated with the disease phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532326" 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="Okimoto, K., Sakurai, J., Kobayashi, T., Mitani, H., Hirayama, Y., Nickerson, M. L., Warren, M. B., Zbar, B., Schmidt, L. S., Hino, O. <strong>A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.</strong> Proc. Nat. Acad. Sci. 101: 2023-2027, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14769940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14769940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14769940[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.0308071100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14769940">Okimoto et al. (2004)</a> studied a model of renal carcinoma found in a colony of Sprague-Dawley rats in Japan. This hereditary renal carcinoma model was designated the 'Nihon' rat. In heterozygotes, renal carcinomas developed from early preneoplastic lesions, seen as early as 3 weeks of age, into adenomas by 8 weeks of age with complete penetrance of this renal carcinoma gene by the age of 6 months. The renal carcinomas that developed in heterozygotes were predominantly of the clear cell type, as is the case in the Eker rat, which likewise carries a single gene mutation, in the TSC2 gene (<a href="/entry/191092">191092</a>), as the cause of renal carcinoma. The Nihon mutation is tightly linked to genes located on the distal part of rat chromosome 10 close to the TSC2 gene (<a href="#7" class="mim-tip-reference" title="Hino, O., Okimoto, K., Kouchi, M., Sakurai, J. <strong>A novel renal carcinoma predisposing gene of the Nihon rat maps on chromosome 10.</strong> Jpn. J. Cancer Res. 92: 1147-1149, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11714437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11714437</a>] [<a href="https://doi.org/10.1111/j.1349-7006.2001.tb02133.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11714437">Hino et al., 2001</a>). In the Nihon rat, <a href="#16" class="mim-tip-reference" title="Okimoto, K., Sakurai, J., Kobayashi, T., Mitani, H., Hirayama, Y., Nickerson, M. L., Warren, M. B., Zbar, B., Schmidt, L. S., Hino, O. <strong>A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.</strong> Proc. Nat. Acad. Sci. 101: 2023-2027, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14769940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14769940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14769940[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.0308071100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14769940">Okimoto et al. (2004)</a> identified a germline mutation in the BHD gene caused by insertion of a single nucleotide, resulting in a frameshift with a stop codon 26 amino acids downstream. They found that the homozygous mutant condition was lethal at an early stage of fetal life in the rat. They detected loss of heterozygosity (LOH) at the BHD locus in 10 of 11 primary renal carcinomas and found a nonsense point mutation in 1 LOH-negative case, fitting the Knudson 2-hit model. <a href="#16" class="mim-tip-reference" title="Okimoto, K., Sakurai, J., Kobayashi, T., Mitani, H., Hirayama, Y., Nickerson, M. L., Warren, M. B., Zbar, B., Schmidt, L. S., Hino, O. <strong>A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.</strong> Proc. Nat. Acad. Sci. 101: 2023-2027, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14769940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14769940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14769940[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.0308071100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14769940">Okimoto et al. (2004)</a> concluded that the Nihon rat provides insights into a tumor suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome. In the rat, the TSC2 gene on chromosome 10 is separated from the BHD gene by the IL3 gene (<a href="/entry/147740">147740</a>). In the human, the TSC2 gene is located on 16p13.3 and the BHD gene on 17p11.2. Demonstration of a germline mutation in the BHD gene in the Nihon rat indicates that there is no homology of synteny in this case. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11714437+14769940" 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="Hartman, T. R., Nicolas, E., Klein-Szanto, A., Al-Saleem, T., Cash, T. P., Simon, M. C., Henske, E. P. <strong>The role of the Birt-Hogg-Dube protein in mTOR activation and renal tumorigenesis.</strong> Oncogene 28: 1594-1604, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19234517/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19234517</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19234517[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/onc.2009.14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19234517">Hartman et al. (2009)</a> found that targeted deletion of Bhd in mice was embryonic lethal. Bhd +/- mice had no obvious physical or behavioral abnormalities, but they developed renal cysts and solid tumors made up of oncocyte-like cells. These cysts and tumors were visible microscopically between 3 and 6 months of age, and they increased in size and severity with age. Between 9 and 17 months of age, Bhd +/- mice also showed various hyperproliferative diseases of lung, skin, heart, liver, and spleen. Renal cyst formation in Bhd +/- mice was enhanced by exposure to the mitogen N-ethyl-N-nitrosourea. The oncocytic cells lining renal cysts were uniformly negative for phosphorylated Rps6, while adjacent normal tubules were moderately positive. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19234517" 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="Hasumi, Y., Baba, M., Ajima, R., Hasumi, H., Valera, V. A., Klein, M. E., Haines, D. C., Merino, M. J., Hong, S.-B., Yamaguchi, T. P., Schmidt, L. S., Linehan, W. M. <strong>Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2.</strong> Proc. Nat. Acad. Sci. 106: 18722-18727, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19850877/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19850877</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19850877[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.0908853106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19850877">Hasumi et al. (2009)</a> reported that heterozygous loss of Bhd in mice caused kidney tumor development with activation of Torc1 (CRTC1; <a href="/entry/607536">607536</a>) and Torc2 (CRTC2; <a href="/entry/608972">608972</a>). Human BHD kidney tumors showed similar activation of TORC1 and TORC2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19850877" 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="Hudon, V., Sabourin, S., Dydensborg, A. B., Kottis, V., Ghazi, A., Paquet, M., Crosby, K., Pomerleau, V., Uetani, N., Pause, A. <strong>Renal tumour suppressor function of the Birt-Hogg-Dube syndrome gene product folliculin.</strong> J. Med. Genet. 47: 182-189, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843504</a>] [<a href="https://doi.org/10.1136/jmg.2009.072009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843504">Hudon et al. (2010)</a> generated a mouse model of Birt-Hogg-Dube syndrome. Flcn -/- mice died before embryonic day 8.5, whereas heterozygous mice manifested early preneoplastic kidney lesions, devoid of Flcn expression, that progressed toward malignancy, including cytopapillary adenomas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Gosis, B. S., Wada, S., Thorsheim, C., Li, K., Jung, S., Rhoades, J. H., Yang, Y., Brandimarto, J., Li, L., Uehara, K., Jang, C., Lanza, M., Sanford, N. B., Bornstein, M. R., Jeong, S., Titchenell, P. M., Biddinger, S. B., Arany, Z. <strong>Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.</strong> Science 376: eabf8271, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35420934/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35420934</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35420934[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/10.1126/science.abf8271" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35420934">Gosis et al. (2022)</a> showed that mice with a liver-specific knockout of Flcn were partially protected against nonalcoholic fatty liver disease (NAFLD) when fed a diet high in trans fat, fructose, and cholesterol. The loss of Flcn in the liver prevented the mice from developing nonalcoholic steatohepatitis (NASH) and reversed disease when it had developed. The mechanism of action was proposed to be that, when FLCN is absent, mTORC1 (<a href="/entry/601231">601231</a>), which normally phosphorylates TFE3 (<a href="/entry/314310">314310</a>), is selectively inhibited. The unphosphorylated TFE3 then activates lipid catabolism and suppresses genes necessary for lipogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35420934" 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>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, the 1733dupC mutation has been renumbered as 1285dupC. <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> found that 27 (44%) of 62 cases of Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>) were due to a duplication (1285dupC) or a deletion (1285delC; <a href="#0002">607273.0002</a>) of 1 cytosine in a hypermutable C8 tract in exon 11 of the FLCN gene. In 18 (29%) of 62 unrelated BHD patients, they found the 1285dupC mutation, also known as the C9 mutation, resulted in a frameshift and protein truncation. In 9 (15%) of 62 BHD patients, they found the 1285delC mutation, also known as the C7 mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+19562744" 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="#10" class="mim-tip-reference" title="Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S. <strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong> J. Med. Genet. 39: 906-912, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471204</a>] [<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471204">Khoo et al. (2002)</a> found the 1285insC and 1285delC mutations in exon 11 of the FLCN gene in 3 of 4 families with BHD1 as well as in 2 of 4 sporadic cases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471204" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Gunji, Y., Akiyoshi, T., Sato, T., Kurihara, M., Tominaga, S., Takahashi, K., Seyama, K. <strong>Mutations of the Birt-Hogg-Dube gene in patients with multiple lung cysts and recurrent pneumothorax. (Letter)</strong> J. Med. Genet. 44: 588-593, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17496196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17496196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17496196[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/10.1136/jmg.2007.049874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17496196">Gunji et al. (2007)</a> identified the 1285insC mutation in a Japanese patient with isolated pulmonary cysts and primary spontaneous pneumothorax (<a href="/entry/173600">173600</a>), but no renal or skin manifestations of the BHD syndrome. She had her first pneumothorax at age 16 years and had a cousin with spontaneous pneumothorax. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17496196" 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="#18" class="mim-tip-reference" title="Ren, H.-Z., Zhu, C.-C., Yang, C., Chen, S.-L., Xie, J., Hou, Y.-Y., Xu, Z.-F., Wang, D.-J., Mu, D.-K., Ma, D.-H., Wang, Y., Ye, M.-H., Ye, Z.-R., Chen, B.-F., Wang, C.-G., Lin, J., Qiao, D., Yi, L. <strong>Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax.</strong> Clin. Genet. 74: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18505456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18505456</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01030.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18505456">Ren et al. (2008)</a> identified the 1285insC mutation in affected members of a Chinese family with primary spontaneous pneumothorax and pulmonary cysts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18505456" 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="Nahorski, M. S., Lim, D. H. K., Martin, L., Gille, J. J. P., McKay, K., Rehal, P. K., Ploeger, H. M., van Steensel, M., Tomlinson, I. P., Latif, F., Menko, F. H., Maher, E. R. <strong>Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.</strong> J. Med. Genet. 47: 385-390, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522427</a>] [<a href="https://doi.org/10.1136/jmg.2009.073304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522427">Nahorski et al. (2010)</a>, who referred to this mutation as 1285dupC based on numbering of +1 at the A of the initiation codon, found this mutation in 37 individuals from 9 families with BHD syndrome. Five individuals developed a colorectal neoplasm, including 3 with a malignant colorectal neoplasm, suggesting a genotype/phenotype correlation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20522427" 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> rs80338682 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338682;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/rs80338682?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=rs80338682" 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=rs80338682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <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> rs80338683 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80338683;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/rs80338683?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=rs80338683" 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=rs80338683" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, the 1733delC mutation has been renumbered as 1285delC. See <a href="#0001">607273.0001</a> and <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a>. The 1285delC mutation, which occurs in exon 11 of the FLCN gene, produces a frameshift and protein truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+19562744" 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">rs879255661 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255661;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879255661" 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=rs879255661" 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=RCV000239710 OR RCV000657236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239710, RCV000657236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239710...</a>
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<p>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, the 1087delAGinsC mutation has been renumbered as 632delAGinsC. In affected members of a family with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>), <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> found an insertion-deletion mutation in exon 7 of the FLCN gene, resulting in a frameshift with protein truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+19562744" 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=RCV000082645 OR RCV000239656 OR RCV000492117 OR RCV000781384" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000082645, RCV000239656, RCV000492117, RCV000781384" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000082645...</a>
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<p>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, the 1378_1405dup mutation has been renumbered as 923_950dup. In a family with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>), <a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> found that affected members had a 28-bp duplication in exon 9 of the FLCN gene. The mutation produced a frameshift and protein truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+19562744" 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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FLCN, TYR463TER
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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> rs137852929 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852929;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/rs137852929?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=rs137852929" 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=rs137852929" 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=RCV000003534 OR RCV000166580 OR RCV000255586 OR RCV000781382 OR RCV003914800 OR RCV004786235" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003534, RCV000166580, RCV000255586, RCV000781382, RCV003914800, RCV004786235" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003534...</a>
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<p><a href="#15" class="mim-tip-reference" title="Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S. <strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong> Cancer Cell 2: 157-164, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>] [<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12204536">Nickerson et al. (2002)</a> found that affected members of a family with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>) had a tyr463-to-ter (Y463X) mutation resulting from a C-to-G transversion at nucleotide 1844 in exon 12. Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 1389C-G. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12204536+19562744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 RENAL CARCINOMA, CHROMOPHOBE, SOMATIC</strong>
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FLCN, 2-BP DEL, 1284TC AND 1-BP INS, 1284A
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003535" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003535" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003535</a>
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<p>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 1284delTCinsA. In a chromophobe renal carcinoma occurring in a patient with Birt-Hogg-Dube syndrome (BHD; <a href="/entry/135150">135150</a>), <a href="#10" class="mim-tip-reference" title="Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S. <strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong> J. Med. Genet. 39: 906-912, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471204</a>] [<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471204">Khoo et al. (2002)</a> identified a novel somatic mutation, 1732delTCinsA. This demonstrated that the Knudson second hit in some BHD-related tumors is a somatic mutation rather than loss of heterozygosity. The pedigree indicated affected members in 3 successive generations and by inference in a fourth earlier generation. The germline mutation occurred in the poly(C) tract in exon 11 of the FLCN gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12471204+19562744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 COLORECTAL CANCER, SOMATIC</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<div style="float: left;">
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FLCN, SER79TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs137852930 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs137852930;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs137852930" 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=rs137852930" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003536 OR RCV002512711" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003536, RCV002512711" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003536...</a>
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<span class="mim-text-font">
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<p>In a colorectal carcinoma (<a href="/entry/114500">114500</a>), <a href="#9" class="mim-tip-reference" title="Kahnoski, K., Khoo, S. K., Nassif, N. T., Chen, J., Lobo, G. P., Segelov, E., Teh, B. T. <strong>Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours.</strong> J. Med. Genet. 40: 511-515, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843323</a>] [<a href="https://doi.org/10.1136/jmg.40.7.511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843323">Kahnoski et al. (2003)</a> identified a somatic ser79-to-trp (S79W) missense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 COLORECTAL CANCER, SOMATIC</strong>
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<span class="mim-text-font">
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FLCN, ALA445THR
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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> rs41419545 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs41419545;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/rs41419545?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=rs41419545" 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=rs41419545" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003537 OR RCV000034789 OR RCV000121112 OR RCV000163302 OR RCV000232087 OR RCV000336471" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003537, RCV000034789, RCV000121112, RCV000163302, RCV000232087, RCV000336471" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003537...</a>
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<div>
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<span class="mim-text-font">
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<p>In a colorectal carcinoma (<a href="/entry/114500">114500</a>), <a href="#9" class="mim-tip-reference" title="Kahnoski, K., Khoo, S. K., Nassif, N. T., Chen, J., Lobo, G. P., Segelov, E., Teh, B. T. <strong>Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours.</strong> J. Med. Genet. 40: 511-515, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12843323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12843323</a>] [<a href="https://doi.org/10.1136/jmg.40.7.511" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12843323">Kahnoski et al. (2003)</a> identified a somatic ala445-to-thr (A445T) missense mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12843323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
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FLCN, 4-BP DEL, 235TCGG
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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> rs750146811 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs750146811;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/rs750146811?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=rs750146811" 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=rs750146811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003538 OR RCV000222354 OR RCV000239626 OR RCV000255605" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003538, RCV000222354, RCV000239626, RCV000255605" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003538...</a>
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<p>In affected members of a Finnish family with primary spontaneous pneumothorax (<a href="/entry/173600">173600</a>) inherited in an autosomal dominant pattern, <a href="#17" class="mim-tip-reference" title="Painter, J. N., Tapanainen, H., Somer, M., Tukiainen, P., Aittomaki, K. <strong>A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.</strong> Am. J. Hum. Genet. 76: 522-527, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15657874[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/10.1086/428455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15657874">Painter et al. (2005)</a> identified a 4-bp deletion in exon 4 (the first coding exon) of the FLCN gene (733delTCGG, or 690delTCGG), causing a frameshift and a stop codon 50 amino acids downstream. All family members with bullous lung lesions were heterozygous for the mutation with the exception of 1 male who had experienced one PSP episode; the authors considered PSP in this individual to be sporadic. Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 235delTCGG. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19562744+15657874" 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">rs886037608 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037608;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037608" 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=rs886037608" 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=RCV000003539 OR RCV003326113" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003539, RCV003326113" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003539...</a>
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<p>In affected members of a Japanese family with pulmonary cysts and primary spontaneous pneumothorax (<a href="/entry/173600">173600</a>), <a href="#4" class="mim-tip-reference" title="Gunji, Y., Akiyoshi, T., Sato, T., Kurihara, M., Tominaga, S., Takahashi, K., Seyama, K. <strong>Mutations of the Birt-Hogg-Dube gene in patients with multiple lung cysts and recurrent pneumothorax. (Letter)</strong> J. Med. Genet. 44: 588-593, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17496196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17496196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17496196[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/10.1136/jmg.2007.049874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17496196">Gunji et al. (2007)</a> identified a heterozygous 4-bp deletion (1988delGATG) in exon 13 of the FLCN gene, resulting in a frameshift and premature protein termination. Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 1533delGATG. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19562744+17496196" 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>.0011 PNEUMOTHORAX, PRIMARY SPONTANEOUS</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">rs886037609 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037609;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037609" 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=rs886037609" 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=RCV000003540 OR RCV003326114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003540, RCV003326114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003540...</a>
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<p>In a Japanese woman with pulmonary cysts and spontaneous pneumothorax (<a href="/entry/173600">173600</a>), <a href="#4" class="mim-tip-reference" title="Gunji, Y., Akiyoshi, T., Sato, T., Kurihara, M., Tominaga, S., Takahashi, K., Seyama, K. <strong>Mutations of the Birt-Hogg-Dube gene in patients with multiple lung cysts and recurrent pneumothorax. (Letter)</strong> J. Med. Genet. 44: 588-593, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17496196/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17496196</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17496196[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/10.1136/jmg.2007.049874" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17496196">Gunji et al. (2007)</a> identified a heterozygous 1-bp deletion (857DELC) in exon 6 of the FLCN gene, resulting in a frameshift and premature protein termination. She had her first pneumothorax at age 25 years. Her brother and father were affected; her father also had a history of renal cancer. Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 404delC. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19562744+17496196" 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>.0012 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
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FLCN, 3-BP DEL, 469TTC
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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> rs786203218 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs786203218;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/rs786203218?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=rs786203218" 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=rs786203218" 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=RCV000003541 OR RCV000166434 OR RCV000239623 OR RCV000256108 OR RCV002498825 OR RCV004567302 OR RCV004745245" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003541, RCV000166434, RCV000239623, RCV000256108, RCV002498825, RCV004567302, RCV004745245" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003541...</a>
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<p>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 469delTTC. In affected members of 4 unrelated Chinese families with spontaneous pneumothorax and/or pulmonary cysts (<a href="/entry/173600">173600</a>), <a href="#18" class="mim-tip-reference" title="Ren, H.-Z., Zhu, C.-C., Yang, C., Chen, S.-L., Xie, J., Hou, Y.-Y., Xu, Z.-F., Wang, D.-J., Mu, D.-K., Ma, D.-H., Wang, Y., Ye, M.-H., Ye, Z.-R., Chen, B.-F., Wang, C.-G., Lin, J., Qiao, D., Yi, L. <strong>Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax.</strong> Clin. Genet. 74: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18505456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18505456</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01030.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18505456">Ren et al. (2008)</a> identified a 3-bp in-frame deletion (924delTTC) in exon 6 of the FLCN gene, resulting in loss of the phe157 residue. One of the families had 6 mutation carriers. Two patients from different families were unaffected. Haplotype analysis excluded a common ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18505456+19562744" 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>.0013 PNEUMOTHORAX, PRIMARY SPONTANEOUS</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">rs886037610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037610;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037610" 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=rs886037610" 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=RCV000003542" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003542" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003542</a>
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<p>Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 1156_1175del. In affected members of 4 unrelated Chinese families with spontaneous pneumothorax and/or pulmonary cysts (<a href="/entry/173600">173600</a>), <a href="#18" class="mim-tip-reference" title="Ren, H.-Z., Zhu, C.-C., Yang, C., Chen, S.-L., Xie, J., Hou, Y.-Y., Xu, Z.-F., Wang, D.-J., Mu, D.-K., Ma, D.-H., Wang, Y., Ye, M.-H., Ye, Z.-R., Chen, B.-F., Wang, C.-G., Lin, J., Qiao, D., Yi, L. <strong>Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax.</strong> Clin. Genet. 74: 178-183, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18505456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18505456</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2008.01030.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18505456">Ren et al. (2008)</a> identified a 20-bp deletion at nucleotide 1611 in exon 10 of the FLCN gene, resulting a frameshift and premature termination. Haplotype analysis excluded a common ancestry. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18505456+19562744" 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>.0014 BIRT-HOGG-DUBE SYNDROME 1</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> rs398124533 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398124533;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/rs398124533?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=rs398124533" 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=rs398124533" 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=RCV000082633 OR RCV000239670 OR RCV000492149 OR RCV003421978 OR RCV005003458" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000082633, RCV000239670, RCV000492149, RCV003421978, RCV005003458" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000082633...</a>
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<p>In affected individuals from 4 unrelated families with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>), <a href="#21" class="mim-tip-reference" title="Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M. <strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong> J. Med. Genet. 45: 321-331, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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/10.1136/jmg.2007.054304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18234728">Toro et al. (2008)</a> identified a heterozygous A-to-G transition in intron 4 of the FLCN gene, predicted to result in premature protein termination. Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, this mutation has been renumbered as 250-2A-G. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19562744+18234728" 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">rs878854340 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878854340;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs878854340" 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=rs878854340" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs878854341 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs878854341;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs878854341" 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=rs878854341" 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=RCV000003544 OR RCV003500521 OR RCV003607274" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003544, RCV003500521, RCV003607274" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003544...</a>
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<p>In 18 members of a large Dutch family with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>), <a href="#11" class="mim-tip-reference" title="Kluijt, I., de Jong, D., Teertstra, H. J., Axwijk, P. H., Gille, J. J. P., Bell, K., van Rens, A., van der Velden, A. W. G., Middelton, L., Horenblas, S. <strong>Early onset of renal cancer in a family with Birt-Hogg-Dube syndrome.</strong> Clin. Genet. 75: 537-543, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320655</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2009.01159.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19320655">Kluijt et al. (2009)</a> identified a heterozygous complex mutation in the FLCN gene consisting of an 11-bp deletion in intron 11 (c.1756-7del11), resulting in the deletion of the splice acceptor site of exon 12, and a 1-bp deletion/2-bp insertion in exon 12 (c.1778delCinsGA). Two family members developed early-onset renal cancer at age 27 and 32 years, respectively. Based on the numbering system used by <a href="#22" class="mim-tip-reference" title="Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R. <strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong> Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/humu.21075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19562744">Wei et al. (2009)</a>, these mutations have been renumbered as c.1301-2del11 and c.1323delCinsGA, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19320655+19562744" 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">rs398124538 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398124538;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398124538" 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=rs398124538" 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=RCV000082640 OR RCV000133394" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000082640, RCV000133394" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000082640...</a>
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<p>In 32 individuals from 6 families with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>), <a href="#14" class="mim-tip-reference" title="Nahorski, M. S., Lim, D. H. K., Martin, L., Gille, J. J. P., McKay, K., Rehal, P. K., Ploeger, H. M., van Steensel, M., Tomlinson, I. P., Latif, F., Menko, F. H., Maher, E. R. <strong>Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.</strong> J. Med. Genet. 47: 385-390, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522427</a>] [<a href="https://doi.org/10.1136/jmg.2009.073304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20522427">Nahorski et al. (2010)</a> identified a heterozygous 2-bp deletion and 2-bp insertion (610delGCinsTA) in exon 6 of the FLCN gene. None of the patients with this mutation developed a colorectal polyp or colorectal cancer. The authors noted that the mutation had been previously designated 1065_1066delGCinsTA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20522427" 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=RCV000003546" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003546" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003546</a>
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<p>In a Japanese patient with multiple lung cysts and recurrent pneumothorax (<a href="/entry/173600">173600</a>), <a href="#12" class="mim-tip-reference" title="Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K. <strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong> J. Med. Genet. 47: 281-287, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413710[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/10.1136/jmg.2009.070565" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20413710">Kunogi et al. (2010)</a> identified a large heterozygous deletion encompassing exons 9 to 14 of the FLCN gene using quantitative PCR and confirmed by Southern blot analysis. The patient had 7 pneumothorax episodes but no skin lesions or renal disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20413710" 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=RCV003229505" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003229505" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003229505</a>
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<p>In 2 patients from a family (family G) with Birt-Hogg-Dube syndrome (BHD1; <a href="/entry/135150">135150</a>), <a href="#2" class="mim-tip-reference" title="Benhammou, J. N., Vocke, C. D., Santani, A., Schmidt, L. S., Baba, M., Seyama, K., Wu, X., Korolevich, S., Nathanson, K. L., Stolle, C. A., Linehan, W. M. <strong>Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome.</strong> Genes Chromosomes Cancer 50: 466-477, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21412933/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21412933</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21412933[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/gcc.20872" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21412933">Benhammou et al. (2011)</a> identified heterozygosity for a 1,342-bp duplication (c.1063-154_1300+410dup) in exons 10-11 of the FLCN gene, resulting in a frameshift and premature termination (Glu434GlyfsTer35). The mutation was identified by a combination of real-time qPCR, multiplex ligation-dependent probe amplification assay (MLPA), and Sanger sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21412933" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1073/pnas.0603781103" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/gcc.20872" target="_blank">Full Text</a>]
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Gosis, B. S., Wada, S., Thorsheim, C., Li, K., Jung, S., Rhoades, J. H., Yang, Y., Brandimarto, J., Li, L., Uehara, K., Jang, C., Lanza, M., Sanford, N. B., Bornstein, M. R., Jeong, S., Titchenell, P. M., Biddinger, S. B., Arany, Z.
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[<a href="https://doi.org/10.1126/science.abf8271" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.2007.049874" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/onc.2009.14" target="_blank">Full Text</a>]
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<strong>Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2.</strong>
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[<a href="https://doi.org/10.1073/pnas.0908853106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1349-7006.2001.tb02133.x" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843504</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843504" 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/10.1136/jmg.2009.072009" target="_blank">Full Text</a>]
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<strong>Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours.</strong>
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[<a href="https://doi.org/10.1136/jmg.40.7.511" target="_blank">Full Text</a>]
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<a id="Khoo2002" class="mim-anchor"></a>
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Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S.
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<strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong>
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[<a href="https://doi.org/10.1136/jmg.39.12.906" target="_blank">Full Text</a>]
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<a id="Kluijt2009" class="mim-anchor"></a>
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Kluijt, I., de Jong, D., Teertstra, H. J., Axwijk, P. H., Gille, J. J. P., Bell, K., van Rens, A., van der Velden, A. W. G., Middelton, L., Horenblas, S.
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<strong>Early onset of renal cancer in a family with Birt-Hogg-Dube syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19320655/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19320655</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19320655" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2009.01159.x" target="_blank">Full Text</a>]
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<a id="Kunogi2010" class="mim-anchor"></a>
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Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K.
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<strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20413710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20413710</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20413710[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=20413710" 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/10.1136/jmg.2009.070565" target="_blank">Full Text</a>]
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<a id="Lingaas2003" class="mim-anchor"></a>
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Lingaas, F., Comstock, K. E., Kirkness, E. F., Sorensen, A., Aarskaug, T., Hitte, C., Nickerson, M. L., Moe, L., Schmidt, L. S., Thomas, R., Breen, M., Galibert, F., Zbar, B., Ostrander, E. A.
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<strong>A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14532326/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14532326</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14532326" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg336" target="_blank">Full Text</a>]
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<a id="Nahorski2010" class="mim-anchor"></a>
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Nahorski, M. S., Lim, D. H. K., Martin, L., Gille, J. J. P., McKay, K., Rehal, P. K., Ploeger, H. M., van Steensel, M., Tomlinson, I. P., Latif, F., Menko, F. H., Maher, E. R.
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<strong>Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20522427/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20522427</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20522427" 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/10.1136/jmg.2009.073304" target="_blank">Full Text</a>]
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<strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12204536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12204536</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12204536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s1535-6108(02)00104-6" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Okimoto2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Okimoto, K., Sakurai, J., Kobayashi, T., Mitani, H., Hirayama, Y., Nickerson, M. L., Warren, M. B., Zbar, B., Schmidt, L. S., Hino, O.
|
|
<strong>A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 2023-2027, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14769940/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14769940</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14769940[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=14769940" 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.0308071100" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Painter2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Painter, J. N., Tapanainen, H., Somer, M., Tukiainen, P., Aittomaki, K.
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|
<strong>A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.</strong>
|
|
Am. J. Hum. Genet. 76: 522-527, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15657874/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15657874</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15657874[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=15657874" 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/10.1086/428455" target="_blank">Full Text</a>]
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Ren2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ren, H.-Z., Zhu, C.-C., Yang, C., Chen, S.-L., Xie, J., Hou, Y.-Y., Xu, Z.-F., Wang, D.-J., Mu, D.-K., Ma, D.-H., Wang, Y., Ye, M.-H., Ye, Z.-R., Chen, B.-F., Wang, C.-G., Lin, J., Qiao, D., Yi, L.
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<strong>Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax.</strong>
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Clin. Genet. 74: 178-183, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18505456/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18505456</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18505456" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2008.01030.x" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Schmidt2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M.
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<strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong>
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Am. J. Hum. Genet. 76: 1023-1033, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15852235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15852235</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15852235[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=15852235" 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/10.1086/430842" target="_blank">Full Text</a>]
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Shin2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shin, J.-H., Shin, Y.-K., Ku, J.-L., Jeong, S.-Y., Hong, S.-H., Park, S.-Y., Kim, W.-H., Park, J.-G.
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<strong>Mutations of the Birt-Hogg-Dube (BHD) gene in sporadic colorectal carcinomas and colorectal carcinoma cell lines with microsatellite instability.</strong>
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J. Med. Genet. 40: 364-367, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12746401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12746401</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12746401" 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/10.1136/jmg.40.5.364" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Toro2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M.
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<strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong>
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J. Med. Genet. 45: 321-331, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18234728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18234728</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18234728[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=18234728" 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/10.1136/jmg.2007.054304" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Wei2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R.
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<strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong>
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Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19562744/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19562744</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19562744[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=19562744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.21075" target="_blank">Full Text</a>]
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<a id="23" class="mim-anchor"></a>
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<a id="Xia2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z.
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<strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong>
|
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Hum. Molec. Genet. 25: 83-96, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26516189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26516189</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26516189" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddv450" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 05/23/2023
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Alan F. Scott - updated : 08/30/2022<br>Patricia A. Hartz - updated : 06/07/2016<br>Patricia A. Hartz - updated : 9/17/2012<br>Marla J. F. O'Neill - updated : 9/24/2010<br>Patricia A. Hartz - updated : 8/30/2010<br>Marla J. F. O'Neill - updated : 7/8/2010<br>Cassandra L. Kniffin - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 6/1/2010<br>Cassandra L. Kniffin - updated : 10/2/2008<br>Cassandra L. Kniffin - updated : 8/19/2008<br>Cassandra L. Kniffin - updated : 10/31/2007<br>Dorothy S. Reilly - updated : 11/27/2006<br>George E. Tiller - updated : 1/11/2006<br>Marla J. F. O'Neill - updated : 5/26/2005<br>Victor A. McKusick - updated : 2/9/2005<br>Victor A. McKusick - updated : 4/21/2004<br>Victor A. McKusick - updated : 1/9/2004<br>Victor A. McKusick - updated : 11/6/2003<br>Victor A. McKusick - updated : 6/30/2003
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 10/3/2002
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 03/22/2024
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<div class="row collapse" id="mimCollapseEditHistory">
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carol : 11/02/2023<br>carol : 08/04/2023<br>carol : 05/24/2023<br>carol : 05/23/2023<br>carol : 09/01/2022<br>carol : 08/31/2022<br>carol : 08/30/2022<br>carol : 10/19/2016<br>mgross : 06/07/2016<br>carol : 9/24/2013<br>alopez : 4/25/2013<br>carol : 3/21/2013<br>mgross : 9/19/2012<br>terry : 9/17/2012<br>wwang : 9/27/2010<br>terry : 9/24/2010<br>mgross : 9/24/2010<br>mgross : 9/24/2010<br>terry : 8/30/2010<br>wwang : 7/26/2010<br>wwang : 7/8/2010<br>wwang : 7/8/2010<br>ckniffin : 7/7/2010<br>wwang : 6/2/2010<br>ckniffin : 6/1/2010<br>wwang : 7/21/2009<br>wwang : 10/8/2008<br>ckniffin : 10/2/2008<br>wwang : 8/25/2008<br>ckniffin : 8/19/2008<br>wwang : 11/13/2007<br>ckniffin : 10/31/2007<br>wwang : 11/27/2006<br>wwang : 1/23/2006<br>terry : 1/11/2006<br>tkritzer : 6/1/2005<br>terry : 5/26/2005<br>carol : 2/11/2005<br>terry : 2/9/2005<br>tkritzer : 5/5/2004<br>tkritzer : 5/4/2004<br>terry : 4/21/2004<br>alopez : 1/14/2004<br>terry : 1/9/2004<br>tkritzer : 11/10/2003<br>terry : 11/6/2003<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>carol : 10/8/2002<br>carol : 10/8/2002<br>tkritzer : 10/3/2002
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<strong>*</strong> 607273
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<div>
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<h3>
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<span class="mim-font">
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FOLLICULIN; FLCN
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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FLCL<br />
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BHD GENE; BHD
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FLCN</em></strong>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 1263460007, 328561000119107;
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<strong>ICD10CM:</strong> J93.11;
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<strong>ICD9CM:</strong> 512.81;
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</span>
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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: 17p11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 17:17,212,212-17,237,330 </span>
|
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</em>
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</strong>
|
|
<span class="small">(from NCBI)</span>
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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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|
<h4>
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|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
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|
</span>
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|
</h4>
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|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="4">
|
|
<span class="mim-font">
|
|
17p11.2
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Birt-Hogg-Dube syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
135150
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
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|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
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|
|
|
|
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|
|
|
|
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|
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</tr>
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|
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|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Colorectal cancer, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
114500
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Pneumothorax, primary spontaneous
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
173600
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Renal carcinoma, chromophobe, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
144700
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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<div>
|
|
<br />
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</div>
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<div>
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|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>By positional cloning in a 700-kb critical region for Birt-Hogg-Dube syndrome (BHD1; 135150) on chromosome 17p11.2, Nickerson et al. (2002) identified a novel gene encoding a deduced 579-amino acid protein designated folliculin. The protein contains a conserved SLS potential phosphorylation site, a glutamic acid-rich coiled-coil domain, an N-glycosylation site, and 3 myristoylation sites. High sequence conservation was found between human folliculin and homologs in mice, Drosophila, and C. elegans. Northern blot analysis detected expression of a 3.8-kb transcript in most normal adult tissues, including skin, lung, and kidney, and in fetal lung, kidney, liver, and brain tissue. </p>
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</span>
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<div>
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<br />
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|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<span class="mim-text-font">
|
|
<p>The FLCN gene contains 14 exons (Nickerson et al., 2002). </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>By positional cloning, Nickerson et al. (2002) identified the FLCN gene on chromosome 17p11.2. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Using coimmunoprecipitation of FNIP1 (610594) and FLCN expressed in HEK293 cells and in vitro binding assays, Baba et al. (2006) showed that the C terminus of FLCN and amino acids 300 to 1166 of FNIP1 were required for optimal FLCN-FNIP1 binding. FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern. FNIP1 was phosphorylated by AMPK (see 602739), and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR (601231) and AMPK signaling. Baba et al. (2006) concluded that FLCN and FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. </p><p>Using small interfering RNAs with several human cell lines, Hartman et al. (2009) found that downregulation of TSC2 (191092) enhanced phosphorylation of ribosomal protein S6 (RPS6; 180460), whereas downregulation of BHD reduced phosphorylation of RPS6, suggesting that TSC2 and BHD down- and upregulate activity of the TORC1 complex (see 601231), respectively. </p><p>Hudon et al. (2010) confirmed the tumor suppressor activity of FLCN by nude mouse xenograft assays of 2 human renal cell carcinoma (RCC) lines with either diminished or reexpressed FLCN. Loss of FLCN expression led to context-dependent effects on RPS6. The authors observed diminished and increased activation of Rps6 resulting from diminished and increased expression levels of FLCN in human RCC cells when grown subcutaneously as solid tumors. In mouse Flcn +/- kidney sections, Rps6 was elevated in multilocular and large cysts from polycystic kidneys but was absent in small single cysts and very low in surrounding normal tissue. Hudon et al. (2010) concluded that FLCN is a general tumor suppressor in the kidney, and that loss of FLCN expression results in improperly elevated or diminished activation of RPS6, depending on cellular context. </p><p>By immunoprecipitation analysis of transfected HEK293 cells, followed by protein pull-down assays, Xia et al. (2016) showed that FLCN interacted directly with TDP43 (TARDBP; 605078). Overexpression of FLCN led to localization of TDP43 in cytoplasm, where it colocalized with markers of lysosomes, autophagosomes, and the ubiquitin-proteasome system. Under arsenite stress, TDP43 colocalized with stress granules. In contrast, RNA interference-mediated depletion of FLCN in arsenite-treated cells caused dissociation of TDP43 from stress granules and nuclear accumulation of TDP43. Xia et al. (2016) concluded that FLCN is critical for TDP43 translocation from nucleus to cytoplasm, which is required for stress granule assembly. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Benhammou et al. (2011) identified heterozygosity for deletion rearrangements in the FLCN gene in 9 patients from 6 families with BHD1. The mutations were identified by a combination of real-time qPCR, multiplex ligation-dependent probe amplification assay (MLPA), array-based genomic hybridization, and Sanger sequencing. Patient 1 (family A) had a deletion involving exons 2-5, patients 2 and 3 (family B) had a mutation involving exons 7-14, and patients 4-9 from 4 families (families C-F) had mutations involving exon 1. A luciferase reporter assay testing the shared region among patients 4-9 demonstrated decreased activity compared to wildtype FLCN. The deletions in FLCN in families A, C, and E were flanked by Alu repeats, which Benhammou et al. (2011) hypothesized explained the deletion mechanism. Clinical features in this patient cohort were similar to those in patients with point mutations in the FLCN gene. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Birt-Hogg-Dube Syndrome 1</em></strong></p><p>
|
|
Birt-Hogg-Dube syndrome (BHD1; 135150) is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. In 9 BHD1 families and an additional 53 probands from small BHD1 families, Nickerson et al. (2002) identified insertion or deletion mutations within a hypermutable C8 tract in exon 11 of the BHD gene in 27 (44%) of 62 patients. Eighteen had a 1-bp duplication (1285dupC; 607273.0001), and 9 had a 1-bp deletion (1285delC; 607273.0002) in the C8 tract. A slippage-mediated mechanism during DNA replication was thought to be responsible for these frameshift mutations leading to protein truncation. Nickerson et al. (2002) also identified an insertion-deletion mutation (607273.0003), a 28-bp duplication (607273.0004), and a tyr463-to-ter (Y463X; 607273.0005) mutation. </p><p>The studies of Khoo et al. (2002) further confirmed that the poly(C) tract in exon 11 of the BHD gene is a mutation hotspot. </p><p>Shin et al. (2003) screened the poly(C)8 tract of the BHD gene and identified mutations in 5 (16%) of 32 microsatellite instability (MSI) sporadic colorectal carcinomas and in 1 (7.7%) of 13 MSI colorectal carcinoma cell lines. They were unable, however, to find any frameshift mutation in 80 microsatellite stable (MSS) sporadic carcinomas or 9 MSS colorectal carcinoma cell lines. In addition, they identified 2 heterozygous missense mutations in different cell lines with MSI. Shin et al. (2003) found that the 16% frequency of mutations in the BHD gene was the same as that in the IGF2R gene (147280) and this was less than that of the TGFBR2 (190182), MSH3 (600887), BAX (600040), and MSH6 (600678) genes. All tumors with the BHD gene mutation harbored concurrent mutations of the poly(C)8 tract of the MSH6 gene, but the frameshift mutations of the BHD and IGF2R genes were mutually exclusive. These findings strongly suggested that the BHD gene is associated with colon cancer and that putative MSI target genes are involved in the development of MSI colorectal carcinomas. </p><p>Khoo et al. (2002) reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. Kahnoski et al. (2003) evaluated the role of the BHD gene in 47 unselected colorectal tumors (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analyzing 46 of the tumors for loss of heterozygosity (LOH) in the chromosome region surrounding the BHD locus. Alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues. They reported the detection of 2 novel somatic missense mutations of the BHD gene and LOH in 81% of primary sporadic colorectal tumors with no change in promoter methylation profile. All mutations were detected in microsatellite stable (MSS) tumors. </p><p>Schmidt et al. (2005) performed direct sequencing of the BHD gene in 30 families with BHD and reported that combined with their previous data (Nickerson et al., 2002), they had identified germline BHD mutations in 51 (84%) of 61 families with BHD; 27 (53%) of the mutations involved either a cytosine insertion or deletion in the mononucleotide tract of 8 cytosines in exon 11 (607273.0001 and 607273.0002, respectively), which appears to represent a mutation hotspot. Schmidt et al. (2005) noted that most reported mutations were predicted to terminate folliculin prematurely and to result in loss of function and suggested that BHD may act as a tumor suppressor gene. </p><p>In affected individuals from 51 (88%) of 58 families with BHD, Toro et al. (2008) identified 23 different mutations in the FLCN gene, including 13 novel mutations (see, e.g., 607273.0014). The 1285insC and 1285delC mutations were most common, occurring in 14 and 5 families, respectively. All mutations except 1 were predicted to result in a truncated protein. There were no apparent genotype/phenotype correlations. </p><p>Nahorski et al. (2010) did not find any germline mutations in the FLCN gene among 50 patients with familial nonsyndromic colorectal cancer. In the same study involving 51 families with BHD, the authors found that those with the 1285dupC mutation (607273.0001) had a higher risk of colorectal neoplasia compared to those with the 610delGCinsTA mutation (607273.0016) (p = 0.016). Furthermore, somatic frameshift mutations in the exon 11 C(8) mononucleotide tract of FLCN were detected in 7 (23%) of 30 sporadic colorectal cancers with microsatellite instability, and the frequency of these somatic mutations was more common in tumors that also showed loss of MLH1 (120436) or MSH2 (609309) protein expression. The findings suggested that FLCN inactivation may contribute to colorectal tumorigenesis. </p><p>In 2 sibs (patients 10 and 11, family G) with BHD, Benhammou et al. (2011) identified a duplication involving exons 10-11 in the FLCN gene (607273.0018). </p><p><strong><em>Primary Spontaneous Pneumothorax</em></strong></p><p>
|
|
Primary spontaneous pneumothorax (PSP; 173600), a condition in which air enters the pleural space and causes secondary lung collapse, is most often a sporadic trait but also occurs in families. In almost all patients it is associated with emphysema-like changes (bullae) in the lungs. By a genomewide scan in a large Finnish family with a dominantly inherited tendency to PSP, Painter et al. (2005) mapped the PSP locus to chromosome 17p11 where the FLCN gene maps. Screening of the FLCN gene revealed a 4-bp deletion in the first coding exon, which created a frameshift and protein truncation (607273.0009). All carriers of the deletion had bullous lung lesions. Unlike previously identified mutations in the FLCN gene, the exon 4 deletion seemed to be associated only with PSP, which showed 100% penetrance. The results suggested that changes in FLCN may have an important role in the development of PSP and, more importantly, of emphysema. Because of the strong association between primary spontaneous pneumothorax and the Birt-Hogg-Dube syndrome, Painter et al. (2005) suggested that patients with familial PSP should be investigated for increased risk of renal cancer. </p><p>In 5 of 8 unrelated Japanese patients with multiple lung cysts and spontaneous pneumothorax, but without skin or renal lesions, Gunji et al. (2007) identified mutations in the BHD gene (see, e.g., 607273.0001; 607273.0010; 607273.0011). All 5 patients had a family history of the disorder. Gunji et al. (2007) suggested that isolated pulmonary cysts and pneumothorax may be a milder form of the BHD syndrome and that patients should be monitored for renal or skin lesions. </p><p>In 10 of 102 Chinese probands with spontaneous pneumothorax, Ren et al. (2008) identified 4 different mutations in the FLCN gene (see, e.g., 607273.0001; 607272.0012-607272.0013). Although only 5 of the probands reported a family history of the disorder, genetic analysis showed that 8 of the probands had family members with either pneumothorax or pulmonary cysts as determined by imaging studies. Two mutation carriers from 2 different families did not have pulmonary cysts. The findings indicated reduced penetrance of both the pneumothorax phenotype and the cyst phenotype. </p><p>Kunogi et al. (2010) identified 15 different heterozygous germline FLCN mutations, including 2 large genomic deletions (see, e.g., 607273.0017), in 25 (69.4%) of the 36 Japanese patients with multiple lung cysts of undetermined cause, all but 1 of whom had suffered at least 1 pneumothorax. Only 6 of the mutation-positive patients had skin lesions, and 2 others had renal tumors. Kunogi et al. (2010) noted that mutations were most frequently identified in the 3-prime end of the FLCN gene, and that these Japanese patients with FLCN mutation had a very low incidence of skin and renal involvement. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
|
|
Kahnoski et al. (2003) reported the detection of 2 novel somatic missense mutations in the BHD gene (607273.0007 and 607273.0008) and LOH in 81% of primary sporadic colorectal tumors with no change in promoter methylation profile. The mutations were detected in microsatellite stable (MSS) tumors. </p><p>Nahorski et al. (2010) detected somatic frameshift mutations in the exon 11 C(8) mononucleotide tract of FLCN in 7 (23%) of 30 sporadic colorectal cancers with microsatellite instability, and the frequency of these somatic mutations was more common in tumors that also showed loss of MLH1 (120436) or MSH2 (609309) protein expression. The findings suggested that FLCN inactivation may contribute to colorectal tumorigenesis. </p>
|
|
</span>
|
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<div>
|
|
<br />
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|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Nickerson et al. (2002) pointed to mapping studies suggesting that germline mutations in dog and rat BHD homologs lead to inherited renal cancer. </p><p>Hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis (RCND) is a naturally occurring canine kidney cancer syndrome that was originally described in German shepherd dogs. Lingaas et al. (2003) narrowed the RCND interval to a small region on canine chromosome 5 that overlapped the human BHD gene. The authors described a his255-to-arg mutation in exon 7 of the canine Bhd gene that segregated with the disease phenotype. </p><p>Okimoto et al. (2004) studied a model of renal carcinoma found in a colony of Sprague-Dawley rats in Japan. This hereditary renal carcinoma model was designated the 'Nihon' rat. In heterozygotes, renal carcinomas developed from early preneoplastic lesions, seen as early as 3 weeks of age, into adenomas by 8 weeks of age with complete penetrance of this renal carcinoma gene by the age of 6 months. The renal carcinomas that developed in heterozygotes were predominantly of the clear cell type, as is the case in the Eker rat, which likewise carries a single gene mutation, in the TSC2 gene (191092), as the cause of renal carcinoma. The Nihon mutation is tightly linked to genes located on the distal part of rat chromosome 10 close to the TSC2 gene (Hino et al., 2001). In the Nihon rat, Okimoto et al. (2004) identified a germline mutation in the BHD gene caused by insertion of a single nucleotide, resulting in a frameshift with a stop codon 26 amino acids downstream. They found that the homozygous mutant condition was lethal at an early stage of fetal life in the rat. They detected loss of heterozygosity (LOH) at the BHD locus in 10 of 11 primary renal carcinomas and found a nonsense point mutation in 1 LOH-negative case, fitting the Knudson 2-hit model. Okimoto et al. (2004) concluded that the Nihon rat provides insights into a tumor suppressor gene that is related to renal carcinogenesis and an animal model of human BHD syndrome. In the rat, the TSC2 gene on chromosome 10 is separated from the BHD gene by the IL3 gene (147740). In the human, the TSC2 gene is located on 16p13.3 and the BHD gene on 17p11.2. Demonstration of a germline mutation in the BHD gene in the Nihon rat indicates that there is no homology of synteny in this case. </p><p>Hartman et al. (2009) found that targeted deletion of Bhd in mice was embryonic lethal. Bhd +/- mice had no obvious physical or behavioral abnormalities, but they developed renal cysts and solid tumors made up of oncocyte-like cells. These cysts and tumors were visible microscopically between 3 and 6 months of age, and they increased in size and severity with age. Between 9 and 17 months of age, Bhd +/- mice also showed various hyperproliferative diseases of lung, skin, heart, liver, and spleen. Renal cyst formation in Bhd +/- mice was enhanced by exposure to the mitogen N-ethyl-N-nitrosourea. The oncocytic cells lining renal cysts were uniformly negative for phosphorylated Rps6, while adjacent normal tubules were moderately positive. </p><p>Hasumi et al. (2009) reported that heterozygous loss of Bhd in mice caused kidney tumor development with activation of Torc1 (CRTC1; 607536) and Torc2 (CRTC2; 608972). Human BHD kidney tumors showed similar activation of TORC1 and TORC2. </p><p>Hudon et al. (2010) generated a mouse model of Birt-Hogg-Dube syndrome. Flcn -/- mice died before embryonic day 8.5, whereas heterozygous mice manifested early preneoplastic kidney lesions, devoid of Flcn expression, that progressed toward malignancy, including cytopapillary adenomas. </p><p>Gosis et al. (2022) showed that mice with a liver-specific knockout of Flcn were partially protected against nonalcoholic fatty liver disease (NAFLD) when fed a diet high in trans fat, fructose, and cholesterol. The loss of Flcn in the liver prevented the mice from developing nonalcoholic steatohepatitis (NASH) and reversed disease when it had developed. The mechanism of action was proposed to be that, when FLCN is absent, mTORC1 (601231), which normally phosphorylates TFE3 (314310), is selectively inhibited. The unphosphorylated TFE3 then activates lipid catabolism and suppresses genes necessary for lipogenesis. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
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</div>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>18 Selected Examples):</strong>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0001 BIRT-HOGG-DUBE SYNDROME 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
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PNEUMOTHORAX, PRIMARY SPONTANEOUS, INCLUDED
|
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
FLCN, 1-BP DUP, 1285C
|
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<br />
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|
|
SNP: rs80338682,
|
|
|
|
|
|
gnomAD: rs80338682,
|
|
|
|
|
|
ClinVar: RCV000003529, RCV000003530, RCV000082626, RCV000130568, RCV002490302, RCV003934796, RCV004760319
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), the 1733dupC mutation has been renumbered as 1285dupC. Nickerson et al. (2002) found that 27 (44%) of 62 cases of Birt-Hogg-Dube syndrome (BHD1; 135150) were due to a duplication (1285dupC) or a deletion (1285delC; 607273.0002) of 1 cytosine in a hypermutable C8 tract in exon 11 of the FLCN gene. In 18 (29%) of 62 unrelated BHD patients, they found the 1285dupC mutation, also known as the C9 mutation, resulted in a frameshift and protein truncation. In 9 (15%) of 62 BHD patients, they found the 1285delC mutation, also known as the C7 mutation. </p><p>Khoo et al. (2002) found the 1285insC and 1285delC mutations in exon 11 of the FLCN gene in 3 of 4 families with BHD1 as well as in 2 of 4 sporadic cases. </p><p>Gunji et al. (2007) identified the 1285insC mutation in a Japanese patient with isolated pulmonary cysts and primary spontaneous pneumothorax (173600), but no renal or skin manifestations of the BHD syndrome. She had her first pneumothorax at age 16 years and had a cousin with spontaneous pneumothorax. </p><p>Ren et al. (2008) identified the 1285insC mutation in affected members of a Chinese family with primary spontaneous pneumothorax and pulmonary cysts. </p><p>Nahorski et al. (2010), who referred to this mutation as 1285dupC based on numbering of +1 at the A of the initiation codon, found this mutation in 37 individuals from 9 families with BHD syndrome. Five individuals developed a colorectal neoplasm, including 3 with a malignant colorectal neoplasm, suggesting a genotype/phenotype correlation. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 BIRT-HOGG-DUBE SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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<div>
|
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<span class="mim-text-font">
|
|
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|
FLCN, 1-BP DEL, 1285C
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|
<br />
|
|
|
|
SNP: rs80338682, rs80338683,
|
|
|
|
|
|
gnomAD: rs80338682, rs80338683,
|
|
|
|
|
|
ClinVar: RCV000003531, RCV000082625, RCV000492709, RCV003390636, RCV004566678, RCV005003321
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), the 1733delC mutation has been renumbered as 1285delC. See 607273.0001 and Nickerson et al. (2002). The 1285delC mutation, which occurs in exon 11 of the FLCN gene, produces a frameshift and protein truncation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 BIRT-HOGG-DUBE SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 2-BP DEL, 632AG AND 1-BP INS, 632C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs879255661,
|
|
|
|
|
|
|
|
ClinVar: RCV000239710, RCV000657236
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), the 1087delAGinsC mutation has been renumbered as 632delAGinsC. In affected members of a family with Birt-Hogg-Dube syndrome (BHD1; 135150), Nickerson et al. (2002) found an insertion-deletion mutation in exon 7 of the FLCN gene, resulting in a frameshift with protein truncation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 BIRT-HOGG-DUBE SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 28-BP DUP, NT923
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398124542,
|
|
|
|
|
|
gnomAD: rs398124542,
|
|
|
|
|
|
ClinVar: RCV000082645, RCV000239656, RCV000492117, RCV000781384
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), the 1378_1405dup mutation has been renumbered as 923_950dup. In a family with Birt-Hogg-Dube syndrome (BHD1; 135150), Nickerson et al. (2002) found that affected members had a 28-bp duplication in exon 9 of the FLCN gene. The mutation produced a frameshift and protein truncation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 BIRT-HOGG-DUBE SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, TYR463TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852929,
|
|
|
|
|
|
gnomAD: rs137852929,
|
|
|
|
|
|
ClinVar: RCV000003534, RCV000166580, RCV000255586, RCV000781382, RCV003914800, RCV004786235
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Nickerson et al. (2002) found that affected members of a family with Birt-Hogg-Dube syndrome (BHD1; 135150) had a tyr463-to-ter (Y463X) mutation resulting from a C-to-G transversion at nucleotide 1844 in exon 12. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1389C-G. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 RENAL CARCINOMA, CHROMOPHOBE, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 2-BP DEL, 1284TC AND 1-BP INS, 1284A
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000003535
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1284delTCinsA. In a chromophobe renal carcinoma occurring in a patient with Birt-Hogg-Dube syndrome (BHD; 135150), Khoo et al. (2002) identified a novel somatic mutation, 1732delTCinsA. This demonstrated that the Knudson second hit in some BHD-related tumors is a somatic mutation rather than loss of heterozygosity. The pedigree indicated affected members in 3 successive generations and by inference in a fourth earlier generation. The germline mutation occurred in the poly(C) tract in exon 11 of the FLCN gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 COLORECTAL CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, SER79TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs137852930,
|
|
|
|
|
|
|
|
ClinVar: RCV000003536, RCV002512711
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a colorectal carcinoma (114500), Kahnoski et al. (2003) identified a somatic ser79-to-trp (S79W) missense mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 COLORECTAL CANCER, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, ALA445THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs41419545,
|
|
|
|
|
|
gnomAD: rs41419545,
|
|
|
|
|
|
ClinVar: RCV000003537, RCV000034789, RCV000121112, RCV000163302, RCV000232087, RCV000336471
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a colorectal carcinoma (114500), Kahnoski et al. (2003) identified a somatic ala445-to-thr (A445T) missense mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 4-BP DEL, 235TCGG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs750146811,
|
|
|
|
|
|
gnomAD: rs750146811,
|
|
|
|
|
|
ClinVar: RCV000003538, RCV000222354, RCV000239626, RCV000255605
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Finnish family with primary spontaneous pneumothorax (173600) inherited in an autosomal dominant pattern, Painter et al. (2005) identified a 4-bp deletion in exon 4 (the first coding exon) of the FLCN gene (733delTCGG, or 690delTCGG), causing a frameshift and a stop codon 50 amino acids downstream. All family members with bullous lung lesions were heterozygous for the mutation with the exception of 1 male who had experienced one PSP episode; the authors considered PSP in this individual to be sporadic. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 235delTCGG. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 4-BP DEL, 1533GATG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037608,
|
|
|
|
|
|
|
|
ClinVar: RCV000003539, RCV003326113
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a Japanese family with pulmonary cysts and primary spontaneous pneumothorax (173600), Gunji et al. (2007) identified a heterozygous 4-bp deletion (1988delGATG) in exon 13 of the FLCN gene, resulting in a frameshift and premature protein termination. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1533delGATG. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 1-BP DEL, 404C
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037609,
|
|
|
|
|
|
|
|
ClinVar: RCV000003540, RCV003326114
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Japanese woman with pulmonary cysts and spontaneous pneumothorax (173600), Gunji et al. (2007) identified a heterozygous 1-bp deletion (857DELC) in exon 6 of the FLCN gene, resulting in a frameshift and premature protein termination. She had her first pneumothorax at age 25 years. Her brother and father were affected; her father also had a history of renal cancer. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 404delC. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 3-BP DEL, 469TTC
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs786203218,
|
|
|
|
|
|
gnomAD: rs786203218,
|
|
|
|
|
|
ClinVar: RCV000003541, RCV000166434, RCV000239623, RCV000256108, RCV002498825, RCV004567302, RCV004745245
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 469delTTC. In affected members of 4 unrelated Chinese families with spontaneous pneumothorax and/or pulmonary cysts (173600), Ren et al. (2008) identified a 3-bp in-frame deletion (924delTTC) in exon 6 of the FLCN gene, resulting in loss of the phe157 residue. One of the families had 6 mutation carriers. Two patients from different families were unaffected. Haplotype analysis excluded a common ancestry. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PNEUMOTHORAX, PRIMARY SPONTANEOUS</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, 20-BP DEL, NT1156
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs886037610,
|
|
|
|
|
|
|
|
ClinVar: RCV000003542
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 1156_1175del. In affected members of 4 unrelated Chinese families with spontaneous pneumothorax and/or pulmonary cysts (173600), Ren et al. (2008) identified a 20-bp deletion at nucleotide 1611 in exon 10 of the FLCN gene, resulting a frameshift and premature termination. Haplotype analysis excluded a common ancestry. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 BIRT-HOGG-DUBE SYNDROME 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FLCN, IVS4AS, A-G, -2
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs398124533,
|
|
|
|
|
|
gnomAD: rs398124533,
|
|
|
|
|
|
ClinVar: RCV000082633, RCV000239670, RCV000492149, RCV003421978, RCV005003458
|
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected individuals from 4 unrelated families with Birt-Hogg-Dube syndrome (BHD1; 135150), Toro et al. (2008) identified a heterozygous A-to-G transition in intron 4 of the FLCN gene, predicted to result in premature protein termination. Based on the numbering system used by Wei et al. (2009), this mutation has been renumbered as 250-2A-G. </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>.0015 BIRT-HOGG-DUBE SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLCN, 11-BP DEL, NT1301-2 AND 1-BP DEL/2-BP INS, NT1323
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<br />
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SNP: rs878854340, rs878854341,
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ClinVar: RCV000003544, RCV003500521, RCV003607274
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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 18 members of a large Dutch family with Birt-Hogg-Dube syndrome (BHD1; 135150), Kluijt et al. (2009) identified a heterozygous complex mutation in the FLCN gene consisting of an 11-bp deletion in intron 11 (c.1756-7del11), resulting in the deletion of the splice acceptor site of exon 12, and a 1-bp deletion/2-bp insertion in exon 12 (c.1778delCinsGA). Two family members developed early-onset renal cancer at age 27 and 32 years, respectively. Based on the numbering system used by Wei et al. (2009), these mutations have been renumbered as c.1301-2del11 and c.1323delCinsGA, respectively. </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>.0016 BIRT-HOGG-DUBE SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLCN, 2-BP DEL/2-BP INS, NT610
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<br />
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SNP: rs398124538,
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ClinVar: RCV000082640, RCV000133394
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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 32 individuals from 6 families with Birt-Hogg-Dube syndrome (BHD1; 135150), Nahorski et al. (2010) identified a heterozygous 2-bp deletion and 2-bp insertion (610delGCinsTA) in exon 6 of the FLCN gene. None of the patients with this mutation developed a colorectal polyp or colorectal cancer. The authors noted that the mutation had been previously designated 1065_1066delGCinsTA. </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>.0017 PNEUMOTHORAX, PRIMARY SPONTANEOUS</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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FLCN, EX9-14 DEL
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<br />
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ClinVar: RCV000003546
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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 Japanese patient with multiple lung cysts and recurrent pneumothorax (173600), Kunogi et al. (2010) identified a large heterozygous deletion encompassing exons 9 to 14 of the FLCN gene using quantitative PCR and confirmed by Southern blot analysis. The patient had 7 pneumothorax episodes but no skin lesions or renal disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0018 BIRT-HOGG-DUBE SYNDROME 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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FLCN, 1,342-BP DUP, EX10-11
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<br />
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ClinVar: RCV003229505
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In 2 patients from a family (family G) with Birt-Hogg-Dube syndrome (BHD1; 135150), Benhammou et al. (2011) identified heterozygosity for a 1,342-bp duplication (c.1063-154_1300+410dup) in exons 10-11 of the FLCN gene, resulting in a frameshift and premature termination (Glu434GlyfsTer35). The mutation was identified by a combination of real-time qPCR, multiplex ligation-dependent probe amplification assay (MLPA), and Sanger sequencing. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
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|
</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Baba, M., Hong, S.-B., Sharma, N., Warren, M. B., Nickerson, M. L., Iwamatsu, A., Esposito, D., Gillette, W. K., Hopkins, R. F., III, Hartley, J. L., Furihata, M., Oishi, S., Zhen, W., Burke, T. R., Jr., Linehan, W. M., Schmidt, L. S., Zbar, B.
|
|
<strong>Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 15552-15557, 2006.
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[PubMed: 17028174]
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[Full Text: https://doi.org/10.1073/pnas.0603781103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Benhammou, J. N., Vocke, C. D., Santani, A., Schmidt, L. S., Baba, M., Seyama, K., Wu, X., Korolevich, S., Nathanson, K. L., Stolle, C. A., Linehan, W. M.
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<strong>Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dube syndrome.</strong>
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Genes Chromosomes Cancer 50: 466-477, 2011.
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[PubMed: 21412933]
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[Full Text: https://doi.org/10.1002/gcc.20872]
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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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Gosis, B. S., Wada, S., Thorsheim, C., Li, K., Jung, S., Rhoades, J. H., Yang, Y., Brandimarto, J., Li, L., Uehara, K., Jang, C., Lanza, M., Sanford, N. B., Bornstein, M. R., Jeong, S., Titchenell, P. M., Biddinger, S. B., Arany, Z.
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|
<strong>Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.</strong>
|
|
Science 376: eabf8271, 2022.
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[PubMed: 35420934]
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[Full Text: https://doi.org/10.1126/science.abf8271]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gunji, Y., Akiyoshi, T., Sato, T., Kurihara, M., Tominaga, S., Takahashi, K., Seyama, K.
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|
<strong>Mutations of the Birt-Hogg-Dube gene in patients with multiple lung cysts and recurrent pneumothorax. (Letter)</strong>
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|
J. Med. Genet. 44: 588-593, 2007.
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[PubMed: 17496196]
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[Full Text: https://doi.org/10.1136/jmg.2007.049874]
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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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Hartman, T. R., Nicolas, E., Klein-Szanto, A., Al-Saleem, T., Cash, T. P., Simon, M. C., Henske, E. P.
|
|
<strong>The role of the Birt-Hogg-Dube protein in mTOR activation and renal tumorigenesis.</strong>
|
|
Oncogene 28: 1594-1604, 2009.
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[PubMed: 19234517]
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[Full Text: https://doi.org/10.1038/onc.2009.14]
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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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Hasumi, Y., Baba, M., Ajima, R., Hasumi, H., Valera, V. A., Klein, M. E., Haines, D. C., Merino, M. J., Hong, S.-B., Yamaguchi, T. P., Schmidt, L. S., Linehan, W. M.
|
|
<strong>Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2.</strong>
|
|
Proc. Nat. Acad. Sci. 106: 18722-18727, 2009.
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[PubMed: 19850877]
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[Full Text: https://doi.org/10.1073/pnas.0908853106]
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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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Hino, O., Okimoto, K., Kouchi, M., Sakurai, J.
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<strong>A novel renal carcinoma predisposing gene of the Nihon rat maps on chromosome 10.</strong>
|
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Jpn. J. Cancer Res. 92: 1147-1149, 2001.
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[PubMed: 11714437]
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[Full Text: https://doi.org/10.1111/j.1349-7006.2001.tb02133.x]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Hudon, V., Sabourin, S., Dydensborg, A. B., Kottis, V., Ghazi, A., Paquet, M., Crosby, K., Pomerleau, V., Uetani, N., Pause, A.
|
|
<strong>Renal tumour suppressor function of the Birt-Hogg-Dube syndrome gene product folliculin.</strong>
|
|
J. Med. Genet. 47: 182-189, 2010.
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|
|
[PubMed: 19843504]
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|
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[Full Text: https://doi.org/10.1136/jmg.2009.072009]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Kahnoski, K., Khoo, S. K., Nassif, N. T., Chen, J., Lobo, G. P., Segelov, E., Teh, B. T.
|
|
<strong>Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal tumours.</strong>
|
|
J. Med. Genet. 40: 511-515, 2003.
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|
|
[PubMed: 12843323]
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[Full Text: https://doi.org/10.1136/jmg.40.7.511]
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</p>
|
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</li>
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<li>
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<p class="mim-text-font">
|
|
Khoo, S. K., Giraud, S., Kahnoski, K., Chen, J., Motorna, O., Nickolov, R., Binet, O., Lambert, D., Friedel, J., Levy, R., Ferlicot, S., Wolkenstein, P., Hammel, P., Bergerheim, U., Hedblad, M.-A., Bradley, M., Teh, B. T., Nordenskjold, M., Richard, S.
|
|
<strong>Clinical and genetic studies of Birt-Hogg-Dube syndrome.</strong>
|
|
J. Med. Genet. 39: 906-912, 2002. Note: Erratum: J. Med. Genet. 40: 150 only, 2003.
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|
|
[PubMed: 12471204]
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|
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[Full Text: https://doi.org/10.1136/jmg.39.12.906]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Kluijt, I., de Jong, D., Teertstra, H. J., Axwijk, P. H., Gille, J. J. P., Bell, K., van Rens, A., van der Velden, A. W. G., Middelton, L., Horenblas, S.
|
|
<strong>Early onset of renal cancer in a family with Birt-Hogg-Dube syndrome.</strong>
|
|
Clin. Genet. 75: 537-543, 2009.
|
|
|
|
|
|
[PubMed: 19320655]
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|
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|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2009.01159.x]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Kunogi, M., Kurihara, M., Ikegami, T. S., Kobayashi, T., Shindo, N., Kumasaka, T., Gunji, Y., Kikkawa, M., Iwakami, S., Hino, O., Takahashi, K., Seyama, K.
|
|
<strong>Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature.</strong>
|
|
J. Med. Genet. 47: 281-287, 2010.
|
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|
|
|
[PubMed: 20413710]
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|
|
[Full Text: https://doi.org/10.1136/jmg.2009.070565]
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</p>
|
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Lingaas, F., Comstock, K. E., Kirkness, E. F., Sorensen, A., Aarskaug, T., Hitte, C., Nickerson, M. L., Moe, L., Schmidt, L. S., Thomas, R., Breen, M., Galibert, F., Zbar, B., Ostrander, E. A.
|
|
<strong>A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog.</strong>
|
|
Hum. Molec. Genet. 12: 3043-3053, 2003.
|
|
|
|
|
|
[PubMed: 14532326]
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|
|
[Full Text: https://doi.org/10.1093/hmg/ddg336]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Nahorski, M. S., Lim, D. H. K., Martin, L., Gille, J. J. P., McKay, K., Rehal, P. K., Ploeger, H. M., van Steensel, M., Tomlinson, I. P., Latif, F., Menko, F. H., Maher, E. R.
|
|
<strong>Investigation of the Birt-Hogg-Dube tumour suppressor gene (FLCN) in familial and sporadic colorectal cancer.</strong>
|
|
J. Med. Genet. 47: 385-390, 2010.
|
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|
|
[PubMed: 20522427]
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|
|
[Full Text: https://doi.org/10.1136/jmg.2009.073304]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Nickerson, M. L., Warren, M. B., Toro, J. R., Matrosova, V., Glenn, G., Turner, M. L., Duray, P., Merino, M., Choyke, P., Pavlovich, C. P., Sharma, N., Walther, M., Munroe, D., Hill, R., Maher, E., Greenberg, C., Lerman, M. I., Linehan, W. M., Zbar, B., Schmidt, L. S.
|
|
<strong>Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome.</strong>
|
|
Cancer Cell 2: 157-164, 2002.
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|
|
[PubMed: 12204536]
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|
[Full Text: https://doi.org/10.1016/s1535-6108(02)00104-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Okimoto, K., Sakurai, J., Kobayashi, T., Mitani, H., Hirayama, Y., Nickerson, M. L., Warren, M. B., Zbar, B., Schmidt, L. S., Hino, O.
|
|
<strong>A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 2023-2027, 2004.
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|
|
[PubMed: 14769940]
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[Full Text: https://doi.org/10.1073/pnas.0308071100]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Painter, J. N., Tapanainen, H., Somer, M., Tukiainen, P., Aittomaki, K.
|
|
<strong>A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly inherited spontaneous pneumothorax.</strong>
|
|
Am. J. Hum. Genet. 76: 522-527, 2005.
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|
|
[PubMed: 15657874]
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[Full Text: https://doi.org/10.1086/428455]
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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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Ren, H.-Z., Zhu, C.-C., Yang, C., Chen, S.-L., Xie, J., Hou, Y.-Y., Xu, Z.-F., Wang, D.-J., Mu, D.-K., Ma, D.-H., Wang, Y., Ye, M.-H., Ye, Z.-R., Chen, B.-F., Wang, C.-G., Lin, J., Qiao, D., Yi, L.
|
|
<strong>Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax.</strong>
|
|
Clin. Genet. 74: 178-183, 2008.
|
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|
|
[PubMed: 18505456]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2008.01030.x]
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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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Schmidt, L. S., Nickerson, M. L., Warren, M. B., Glenn, G. M., Toro, J. R., Merino, M. J., Turner, M. L., Choyke, P. L., Sharma, N., Peterson, J., Morrison, P., Maher, E. R., Walther, M. M., Zbar, B., Linehan, W. M.
|
|
<strong>Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome.</strong>
|
|
Am. J. Hum. Genet. 76: 1023-1033, 2005.
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|
|
[PubMed: 15852235]
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[Full Text: https://doi.org/10.1086/430842]
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Shin, J.-H., Shin, Y.-K., Ku, J.-L., Jeong, S.-Y., Hong, S.-H., Park, S.-Y., Kim, W.-H., Park, J.-G.
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Toro, J. R., Wei, M.-H., Glenn, G. M., Weinreich, M., Toure, O., Vocke, C., Turner, M., Choyke, P., Merino, M. J., Pinto, P. A., Steinberg, S. M., Schmidt, L. S., Linehan, W. M.
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<strong>BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dube syndrome: a new series of 50 families and a review of published reports.</strong>
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[Full Text: https://doi.org/10.1136/jmg.2007.054304]
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Wei, M.-H., Blake, P. W., Shevchenko, J., Toro, J. R.
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<strong>The folliculin mutation database: An online database of mutations associated with Birt-Hogg-Dube syndrome.</strong>
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Hum. Mutat. 30: E880-E890, 2009. Note: Electronic Article.
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[PubMed: 19562744]
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Xia, Q., Wang, G., Wang, H., Hu, Q., Ying, Z.
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<strong>Folliculin, a tumor suppressor associated with Birt-Hogg-Dube (BHD) syndrome, is a novel modifier of TDP-43 cytoplasmic translocation and aggregation.</strong>
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Hum. Molec. Genet. 25: 83-96, 2016.
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[PubMed: 26516189]
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[Full Text: https://doi.org/10.1093/hmg/ddv450]
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Hilary J. Vernon - updated : 05/23/2023<br>Alan F. Scott - updated : 08/30/2022<br>Patricia A. Hartz - updated : 06/07/2016<br>Patricia A. Hartz - updated : 9/17/2012<br>Marla J. F. O'Neill - updated : 9/24/2010<br>Patricia A. Hartz - updated : 8/30/2010<br>Marla J. F. O'Neill - updated : 7/8/2010<br>Cassandra L. Kniffin - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 6/1/2010<br>Cassandra L. Kniffin - updated : 10/2/2008<br>Cassandra L. Kniffin - updated : 8/19/2008<br>Cassandra L. Kniffin - updated : 10/31/2007<br>Dorothy S. Reilly - updated : 11/27/2006<br>George E. Tiller - updated : 1/11/2006<br>Marla J. F. O'Neill - updated : 5/26/2005<br>Victor A. McKusick - updated : 2/9/2005<br>Victor A. McKusick - updated : 4/21/2004<br>Victor A. McKusick - updated : 1/9/2004<br>Victor A. McKusick - updated : 11/6/2003<br>Victor A. McKusick - updated : 6/30/2003
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Victor A. McKusick : 10/3/2002
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