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Entry
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- *605654 - F-BOX AND LEUCINE-RICH REPEAT PROTEIN 4; FBXL4
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- OMIM
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<p>
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<span class="h4">*605654</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605654">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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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=ENSG00000112234;t=ENST00000369244" 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=26235" 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=605654" 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000112234;t=ENST00000369244" 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_001278716,NM_012160,NR_103836,NR_103837,XM_005266930,XM_017010726,XM_017010727,XM_047418625,XM_047418626,XM_047418627,XM_047418628" 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_001278716" 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=605654" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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<div 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=05738&isoform_id=05738_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/FBXL4" 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/6103637,6164723,6456735,16306588,21263631,32822905,60552833,119568873,119568874,119568875,189053650,524585204,530383594,1034649818,1034649821,2217360980,2217360984,2217360986,2217360988,2462607836,2462607838,2462607840,2462607842,2462607844,2462607846,2462607848" 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/Q9UKA2" 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=26235" 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=ENSG00000112234;t=ENST00000369244" 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=FBXL4" 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=FBXL4" 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+26235" 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/FBXL4" 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:26235" 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/26235" 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=chr6&hgg_gene=ENST00000369244.7&hgg_start=98868535&hgg_end=98947946&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:13601" 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/fbxl4" 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=605654[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 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=605654[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/FBXL4/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/ENSG00000112234" 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=FBXL4" 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=FBXL4" 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=FBXL4" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FBXL4&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/PA28024" 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:13601" 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/FBgn0030555.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:2140367" 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/FBXL4#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:2140367" 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/26235/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=26235" 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://zfin.org/ZDB-GENE-041114-187" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=FBXL4&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> 765403009<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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605654
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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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F-BOX AND LEUCINE-RICH REPEAT PROTEIN 4; FBXL4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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FBL4
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FBXL4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FBXL4</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/6/722?start=-3&limit=10&highlight=722">6q16.1-q16.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:98868535-98947946&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'})">6:98,868,535-98,947,946</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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<a href="/geneMap/6/722?start=-3&limit=10&highlight=722">
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6q16.1-q16.2
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615471"> 615471 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/605654" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/605654" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
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<strong>TEXT</strong>
|
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</span>
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</span>
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</h4>
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<div>
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p>The F box, named after cyclin F (CCNF; <a href="/entry/600227">600227</a>), in which it was originally observed, is an approximately 40-amino acid motif that binds SKP1 (<a href="/entry/601434">601434</a>). F-box proteins, such as FBXL4, are components of modular E3 ubiquitin protein ligases called SCFs (SKP1, cullin (see <a href="/entry/603134">603134</a>), F-box proteins), which function in phosphorylation-dependent ubiquitination.</p>
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<p>Using a yeast 2-hybrid screen with SKP1 as bait, followed by searching sequence databases, <a href="#6" class="mim-tip-reference" title="Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., Harper, J. W. <strong>A family of mammalian F-box proteins.</strong> Curr. Biol. 9: 1180-1182, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531037</a>] [<a href="https://doi.org/10.1016/S0960-9822(00)80021-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531037">Winston et al. (1999)</a> and <a href="#2" class="mim-tip-reference" title="Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano, M. <strong>Identification of a family of human F-box proteins.</strong> Curr. Biol. 9: 1177-1179, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531035</a>] [<a href="https://doi.org/10.1016/S0960-9822(00)80020-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531035">Cenciarelli et al. (1999)</a> identified 33 mammalian and 26 human F-box proteins, respectively. These contained C termini with leucine-rich repeats (FBXLs, e.g., SKP2 (<a href="/entry/601436">601436</a>)), WD40 domains (FBXWs, e.g., BTRCP (<a href="/entry/603482">603482</a>)), or no recognizable motifs (FBXOs, e.g., CCNF). Using RT-PCR analysis, <a href="#6" class="mim-tip-reference" title="Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., Harper, J. W. <strong>A family of mammalian F-box proteins.</strong> Curr. Biol. 9: 1180-1182, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531037</a>] [<a href="https://doi.org/10.1016/S0960-9822(00)80021-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10531037">Winston et al. (1999)</a> detected FBXL4 expression in heart, kidney, liver, lung, pancreas, and placenta, but not in skeletal muscle. Immunofluorescence microscopy demonstrated both nuclear and cytoplasmic expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10531035+10531037" 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 searching sequence databases, <a href="#4" class="mim-tip-reference" title="Ilyin, G. P., Rialland, M., Pigeon, C., Guguen-Guillouzo, C. <strong>cDNA cloning and expression analysis of new members of the mammalian F-box protein family.</strong> Genomics 67: 40-47, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945468</a>] [<a href="https://doi.org/10.1006/geno.2000.6211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945468">Ilyin et al. (2000)</a> identified a cDNA encoding FBXL4, which they referred to as FBL5. The deduced 621-amino acid protein contains at least 9 leucine-rich repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945468" 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="Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W. <strong>Systematic analysis and nomenclature of mammalian F-box proteins.</strong> Genes Dev. 18: 2573-2580, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520277[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/10.1101/gad.1255304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520277">Jin et al. (2004)</a> reported that the FBXL4 protein contains an F box in its N-terminal half, followed by 11 leucine-rich repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520277" 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 computational analysis followed by immunolocalization studies, <a href="#1" class="mim-tip-reference" title="Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others. <strong>Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.</strong> Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993193">Bonnen et al. (2013)</a> demonstrated that the FBXL4 protein localizes to the mitochondria via an N-terminal mitochondrial localization signal. <a href="#3" class="mim-tip-reference" title="Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. <strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong> Am. J. Hum. Genet. 93: 482-495, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993194">Gai et al. (2013)</a> also found FBXL4 localization to the mitochondria in several cell lines using immunofluorescence studies; nuclear localization was not observed. The protein appeared to be present in the intermembrane space. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=23993193+23993194" 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 its inclusion within a mapped clone, <a href="#4" class="mim-tip-reference" title="Ilyin, G. P., Rialland, M., Pigeon, C., Guguen-Guillouzo, C. <strong>cDNA cloning and expression analysis of new members of the mammalian F-box protein family.</strong> Genomics 67: 40-47, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945468</a>] [<a href="https://doi.org/10.1006/geno.2000.6211" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10945468">Ilyin et al. (2000)</a> mapped the FBXL4 gene to 6q16.1-q16.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945468" 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="Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W. <strong>Systematic analysis and nomenclature of mammalian F-box proteins.</strong> Genes Dev. 18: 2573-2580, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520277[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/10.1101/gad.1255304" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15520277">Jin et al. (2004)</a> stated that the mouse Fbxl4 gene maps to chromosome 4A3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15520277" 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="#3" class="mim-tip-reference" title="Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. <strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong> Am. J. Hum. Genet. 93: 482-495, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993194">Gai et al. (2013)</a> demonstrated that FBXL4 is targeted to mitochondria and localizes within the intermembrane space. Immunoblot analysis showed that it is present in an approximately 400-kD quaternary protein complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected individuals from 3 consanguineous Arabian families with encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13; <a href="/entry/615471">615471</a>), <a href="#1" class="mim-tip-reference" title="Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others. <strong>Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.</strong> Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993193">Bonnen et al. (2013)</a> identified 3 different homozygous mutations in the FBXL4 gene (see, e.g., <a href="#0001">605654.0001</a> and <a href="#0002">605654.0002</a>). The mutations, which were found by whole-exome sequencing in the probands, segregated with the disorder in the families. Two of the mutations were truncating mutations. The patients presented at birth or in early infancy with global developmental delay, hypotonia, and persistent lactic acidosis. More variable features included facial dysmorphism, congenital cataracts, and brain atrophy. All patients except 1 died in early childhood. Patient skeletal muscle biopsies and fibroblasts showed defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion. Expression of wildtype FBXL4 in patient cells rescued the mitochondrial biochemical defects and mtDNA depletion. The findings suggested that FBXL4 plays an important role in the maintenance of mtDNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993193" 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 9 patients from 7 families with MTDPS13, <a href="#3" class="mim-tip-reference" title="Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. <strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong> Am. J. Hum. Genet. 93: 482-495, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993194">Gai et al. (2013)</a> identified biallelic mutations in the FBXL4 gene (see, e.g., <a href="#0003">605654.0003</a>-<a href="#0005">605654.0005</a>). Most patients presented shortly after birth with lactic acidosis, often with hyperammonemia and signs of renal tubular acidosis. All patients showed severe psychomotor delay with hypotonia and failure to thrive. Three children died in infancy from metabolic decompensation during intercurrent infections. Brain MRI showed global brain atrophy, thin corpus callosum, and altered signals in the supratentorial white matter with variable involvement of the basal ganglia, thalami, and infratentorial structures. Patient muscle homogenates or isolated mitochondria showed variably decreased activities of the mitochondrial respiratory chain complexes as well as decreased mtDNA content. Cultured skin fibroblasts had reduced maximal oxygen consumption rate and increased fragmentation of the mitochondrial network. At least 1 patient cell line studied showed a significant reduction of the mitochondrial membrane potential. These defects could be rescued by expression of wildtype FBXL4 in patient cells. The findings indicated that FBXL4 is necessary for the homeostasis of mitochondrial bioenergetics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993194" 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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FBXL4, GLN519TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398123059 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123059;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=rs398123059" 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=rs398123059" 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=RCV000056327 OR RCV001090674" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056327, RCV001090674" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056327...</a>
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<p>In 5 affected members of a highly consanguineous Arabian family with fatal mitochondrial DNA depletion syndrome-13 (MTDPS13; <a href="/entry/615471">615471</a>), <a href="#1" class="mim-tip-reference" title="Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others. <strong>Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.</strong> Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993193">Bonnen et al. (2013)</a> identified a homozygous c.1555C-T transition in the FBXL4 gene, resulting in a gln519-to-ter (Q519X) substitution in the C-terminal LRR domain. The mutation was found by whole-exome sequencing of the proband and showed complete segregation with the disorder in the family. The variant was not present in the NHLBI Exome Sequencing Project or 1000 Genomes Project databases, or in 408 ethnically matched control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993193" 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>.0002 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</strong>
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FBXL4, ARG435TER
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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> rs201889294 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs201889294;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/rs201889294?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=rs201889294" 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=rs201889294" 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=RCV000056328 OR RCV000604628 OR RCV000622490 OR RCV001837446" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056328, RCV000604628, RCV000622490, RCV001837446" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056328...</a>
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<span class="mim-text-font">
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<p>In a child, born of consanguineous Arabian parents, with fatal MTDPS13 (<a href="/entry/615471">615471</a>), <a href="#1" class="mim-tip-reference" title="Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others. <strong>Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.</strong> Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993193[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993193">Bonnen et al. (2013)</a> identified a homozygous c.1303C-T transition in the FBXL4 gene, resulting in an arg435-to-ter (R435X) substitution. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. The variant was not present in the 1000 Genomes Project database or in 408 ethnically matched controls; it was found in 1 of 13,005 chromosomes in the NHLBI Exome Sequencing Project. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993193" 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="0003" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</strong>
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</h4>
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FBXL4, GLY568ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398123060 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123060;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=rs398123060" 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=rs398123060" 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=RCV000056329" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056329" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056329</a>
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<span class="mim-text-font">
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<p>In a 4-year-old boy, born of consanguineous Saudi Arabian parents, with MTDPS13 (<a href="/entry/615471">615471</a>), <a href="#3" class="mim-tip-reference" title="Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. <strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong> Am. J. Hum. Genet. 93: 482-495, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993194">Gai et al. (2013)</a> identified a homozygous c.1703G-C transversion in the FBXL4 gene, resulting in a gly568-to-ala (G568A) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. The mutation was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993194" 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="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</strong>
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FBXL4, ARG482TRP
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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> rs398123061 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123061;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/rs398123061?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=rs398123061" 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=rs398123061" 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=RCV000056330 OR RCV000162170 OR RCV000224233 OR RCV003155062 OR RCV003242974" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056330, RCV000162170, RCV000224233, RCV003155062, RCV003242974" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056330...</a>
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<span class="mim-text-font">
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<p>In 3 sibs, born of consanguineous Saudi Arabian parents, with MTDPS13 (<a href="/entry/615471">615471</a>), <a href="#3" class="mim-tip-reference" title="Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. <strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong> Am. J. Hum. Genet. 93: 482-495, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993194">Gai et al. (2013)</a> identified a homozygous c.1444C-T transition in the FBXL4 gene, resulting in an arg482-to-trp (R481W) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. It was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993194" 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="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</strong>
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FBXL4, ASP565GLY
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398123062 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398123062;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=rs398123062" 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=rs398123062" 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=RCV000056331 OR RCV005089466" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000056331, RCV005089466" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000056331...</a>
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<p>In an Albanian male infant with MTDPS13 (<a href="/entry/615471">615471</a>), <a href="#3" class="mim-tip-reference" title="Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others. <strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong> Am. J. Hum. Genet. 93: 482-495, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23993194">Gai et al. (2013)</a> identified a homozygous c.1694A-G transition in the FBXL4 gene, resulting in an asp565-to-gly (D565G) substitution at a highly conserved residue in the LRR domain. The mutation was found by whole-exome sequencing and was not present in 4,500 in-house European control chromosomes or in the Exome Variant Server database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23993194" 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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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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<li>
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<a id="1" class="mim-anchor"></a>
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<a id="Bonnen2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others.
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<strong>Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.</strong>
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Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993193/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993193</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993193[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=23993193" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.07.017" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="2" class="mim-anchor"></a>
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<a id="Cenciarelli1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano, M.
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<strong>Identification of a family of human F-box proteins.</strong>
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Curr. Biol. 9: 1177-1179, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531035/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531035</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10531035" 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/S0960-9822(00)80020-2" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="3" class="mim-anchor"></a>
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<a id="Gai2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others.
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<strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong>
|
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Am. J. Hum. Genet. 93: 482-495, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23993194/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23993194</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23993194[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=23993194" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.07.016" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="4" class="mim-anchor"></a>
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<a id="Ilyin2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ilyin, G. P., Rialland, M., Pigeon, C., Guguen-Guillouzo, C.
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<strong>cDNA cloning and expression analysis of new members of the mammalian F-box protein family.</strong>
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Genomics 67: 40-47, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10945468/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10945468</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10945468" 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/10.1006/geno.2000.6211" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="5" class="mim-anchor"></a>
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<a id="Jin2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W.
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<strong>Systematic analysis and nomenclature of mammalian F-box proteins.</strong>
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Genes Dev. 18: 2573-2580, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15520277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15520277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15520277[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=15520277" 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/10.1101/gad.1255304" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Winston1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., Harper, J. W.
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<strong>A family of mammalian F-box proteins.</strong>
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|
Curr. Biol. 9: 1180-1182, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10531037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10531037</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10531037" 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/S0960-9822(00)80021-4" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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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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Cassandra L. Kniffin - updated : 10/10/2013
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 12/14/2004
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</div>
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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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Paul J. Converse : 2/15/2001
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</span>
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</div>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/17/2013
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</span>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 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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carol : 10/14/2013<br>ckniffin : 10/10/2013<br>mgross : 12/14/2004<br>mgross : 2/15/2001
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</span>
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</div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605654
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<div>
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<h3>
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<span class="mim-font">
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F-BOX AND LEUCINE-RICH REPEAT PROTEIN 4; FBXL4
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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FBL4
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</span>
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</h4>
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<div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: FBXL4</em></strong>
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</span>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 765403009;
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</span>
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<div>
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<br />
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</div>
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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: 6q16.1-q16.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:98,868,535-98,947,946 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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6q16.1-q16.2
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</span>
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</td>
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<td>
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<span class="mim-font">
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Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)
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</span>
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</td>
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<td>
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<span class="mim-font">
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615471
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</table>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The F box, named after cyclin F (CCNF; 600227), in which it was originally observed, is an approximately 40-amino acid motif that binds SKP1 (601434). F-box proteins, such as FBXL4, are components of modular E3 ubiquitin protein ligases called SCFs (SKP1, cullin (see 603134), F-box proteins), which function in phosphorylation-dependent ubiquitination.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using a yeast 2-hybrid screen with SKP1 as bait, followed by searching sequence databases, Winston et al. (1999) and Cenciarelli et al. (1999) identified 33 mammalian and 26 human F-box proteins, respectively. These contained C termini with leucine-rich repeats (FBXLs, e.g., SKP2 (601436)), WD40 domains (FBXWs, e.g., BTRCP (603482)), or no recognizable motifs (FBXOs, e.g., CCNF). Using RT-PCR analysis, Winston et al. (1999) detected FBXL4 expression in heart, kidney, liver, lung, pancreas, and placenta, but not in skeletal muscle. Immunofluorescence microscopy demonstrated both nuclear and cytoplasmic expression. </p><p>By searching sequence databases, Ilyin et al. (2000) identified a cDNA encoding FBXL4, which they referred to as FBL5. The deduced 621-amino acid protein contains at least 9 leucine-rich repeats. </p><p>Jin et al. (2004) reported that the FBXL4 protein contains an F box in its N-terminal half, followed by 11 leucine-rich repeats. </p><p>By computational analysis followed by immunolocalization studies, Bonnen et al. (2013) demonstrated that the FBXL4 protein localizes to the mitochondria via an N-terminal mitochondrial localization signal. Gai et al. (2013) also found FBXL4 localization to the mitochondria in several cell lines using immunofluorescence studies; nuclear localization was not observed. The protein appeared to be present in the intermembrane space. </p>
|
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Based on its inclusion within a mapped clone, Ilyin et al. (2000) mapped the FBXL4 gene to 6q16.1-q16.3. </p><p>Jin et al. (2004) stated that the mouse Fbxl4 gene maps to chromosome 4A3. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gai et al. (2013) demonstrated that FBXL4 is targeted to mitochondria and localizes within the intermembrane space. Immunoblot analysis showed that it is present in an approximately 400-kD quaternary protein complex. </p>
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</span>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p>In affected individuals from 3 consanguineous Arabian families with encephalomyopathic mitochondrial DNA depletion syndrome-13 (MTDPS13; 615471), Bonnen et al. (2013) identified 3 different homozygous mutations in the FBXL4 gene (see, e.g., 605654.0001 and 605654.0002). The mutations, which were found by whole-exome sequencing in the probands, segregated with the disorder in the families. Two of the mutations were truncating mutations. The patients presented at birth or in early infancy with global developmental delay, hypotonia, and persistent lactic acidosis. More variable features included facial dysmorphism, congenital cataracts, and brain atrophy. All patients except 1 died in early childhood. Patient skeletal muscle biopsies and fibroblasts showed defects in mitochondrial respiratory chain enzyme activities, loss of mitochondrial membrane potential, a disturbance of the dynamic mitochondrial network, and mtDNA depletion. Expression of wildtype FBXL4 in patient cells rescued the mitochondrial biochemical defects and mtDNA depletion. The findings suggested that FBXL4 plays an important role in the maintenance of mtDNA. </p><p>In 9 patients from 7 families with MTDPS13, Gai et al. (2013) identified biallelic mutations in the FBXL4 gene (see, e.g., 605654.0003-605654.0005). Most patients presented shortly after birth with lactic acidosis, often with hyperammonemia and signs of renal tubular acidosis. All patients showed severe psychomotor delay with hypotonia and failure to thrive. Three children died in infancy from metabolic decompensation during intercurrent infections. Brain MRI showed global brain atrophy, thin corpus callosum, and altered signals in the supratentorial white matter with variable involvement of the basal ganglia, thalami, and infratentorial structures. Patient muscle homogenates or isolated mitochondria showed variably decreased activities of the mitochondrial respiratory chain complexes as well as decreased mtDNA content. Cultured skin fibroblasts had reduced maximal oxygen consumption rate and increased fragmentation of the mitochondrial network. At least 1 patient cell line studied showed a significant reduction of the mitochondrial membrane potential. These defects could be rescued by expression of wildtype FBXL4 in patient cells. The findings indicated that FBXL4 is necessary for the homeostasis of mitochondrial bioenergetics. </p>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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FBXL4, GLN519TER
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<br />
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SNP: rs398123059,
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ClinVar: RCV000056327, RCV001090674
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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 5 affected members of a highly consanguineous Arabian family with fatal mitochondrial DNA depletion syndrome-13 (MTDPS13; 615471), Bonnen et al. (2013) identified a homozygous c.1555C-T transition in the FBXL4 gene, resulting in a gln519-to-ter (Q519X) substitution in the C-terminal LRR domain. The mutation was found by whole-exome sequencing of the proband and showed complete segregation with the disorder in the family. The variant was not present in the NHLBI Exome Sequencing Project or 1000 Genomes Project databases, or in 408 ethnically matched control chromosomes. </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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<h4>
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<span class="mim-font">
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<strong>.0002 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</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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FBXL4, ARG435TER
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<br />
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SNP: rs201889294,
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gnomAD: rs201889294,
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ClinVar: RCV000056328, RCV000604628, RCV000622490, RCV001837446
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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 child, born of consanguineous Arabian parents, with fatal MTDPS13 (615471), Bonnen et al. (2013) identified a homozygous c.1303C-T transition in the FBXL4 gene, resulting in an arg435-to-ter (R435X) substitution. The mutation was found by whole-exome sequencing and segregated with the disorder in the family. The variant was not present in the 1000 Genomes Project database or in 408 ethnically matched controls; it was found in 1 of 13,005 chromosomes in the NHLBI Exome Sequencing Project. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</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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FBXL4, GLY568ALA
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<br />
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SNP: rs398123060,
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ClinVar: RCV000056329
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a 4-year-old boy, born of consanguineous Saudi Arabian parents, with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1703G-C transversion in the FBXL4 gene, resulting in a gly568-to-ala (G568A) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. The mutation was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</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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FBXL4, ARG482TRP
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<br />
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SNP: rs398123061,
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gnomAD: rs398123061,
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|
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ClinVar: RCV000056330, RCV000162170, RCV000224233, RCV003155062, RCV003242974
|
|
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</span>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 3 sibs, born of consanguineous Saudi Arabian parents, with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1444C-T transition in the FBXL4 gene, resulting in an arg482-to-trp (R481W) substitution at a highly conserved residue in the LRR domain. The mutation was found by homozygosity mapping followed by whole-exome sequencing. It was not present in 242 Saudi exomes, in 4,500 in-house European control chromosomes, or in the Exome Variant Server database. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MITOCHONDRIAL DNA DEPLETION SYNDROME 13 (ENCEPHALOMYOPATHIC TYPE)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
|
|
|
|
FBXL4, ASP565GLY
|
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|
|
<br />
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|
|
SNP: rs398123062,
|
|
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|
|
|
|
|
ClinVar: RCV000056331, RCV005089466
|
|
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|
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</span>
|
|
</div>
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an Albanian male infant with MTDPS13 (615471), Gai et al. (2013) identified a homozygous c.1694A-G transition in the FBXL4 gene, resulting in an asp565-to-gly (D565G) substitution at a highly conserved residue in the LRR domain. The mutation was found by whole-exome sequencing and was not present in 4,500 in-house European control chromosomes or in the Exome Variant Server database. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
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<p class="mim-text-font">
|
|
Bonnen, P. E., Yarham, J. W., Besse, A., Wu, P., Faqeih, E. A., Al-Asmari, A. M., Saleh, M. A. M., Eyaid, W., Hadeel, A., He, L., Smith, F., Yau, S., and 10 others.
|
|
<strong>Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance.</strong>
|
|
Am. J. Hum. Genet. 93: 471-481, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 773 only, 2013.
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[PubMed: 23993193]
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.07.017]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano, M.
|
|
<strong>Identification of a family of human F-box proteins.</strong>
|
|
Curr. Biol. 9: 1177-1179, 1999.
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|
|
[PubMed: 10531035]
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[Full Text: https://doi.org/10.1016/S0960-9822(00)80020-2]
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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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Gai, X., Ghezzi, D., Johnson, M. A., Biagosch, C. A., Shamseldin, H. E., Haack, T. B., Reyes, A., Tsukikawa, M., Sheldon, C. A., Srinivasan, S., Gorza, M., Kremer, L. S., and 28 others.
|
|
<strong>Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.</strong>
|
|
Am. J. Hum. Genet. 93: 482-495, 2013.
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[PubMed: 23993194]
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[Full Text: https://doi.org/10.1016/j.ajhg.2013.07.016]
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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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Ilyin, G. P., Rialland, M., Pigeon, C., Guguen-Guillouzo, C.
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<strong>cDNA cloning and expression analysis of new members of the mammalian F-box protein family.</strong>
|
|
Genomics 67: 40-47, 2000.
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[PubMed: 10945468]
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[Full Text: https://doi.org/10.1006/geno.2000.6211]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Jin, J., Cardozo, T., Lovering, R. C., Elledge, S. J., Pagano, M., Harper, J. W.
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<strong>Systematic analysis and nomenclature of mammalian F-box proteins.</strong>
|
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Genes Dev. 18: 2573-2580, 2004.
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[PubMed: 15520277]
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[Full Text: https://doi.org/10.1101/gad.1255304]
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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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Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., Harper, J. W.
|
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<strong>A family of mammalian F-box proteins.</strong>
|
|
Curr. Biol. 9: 1180-1182, 1999.
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[PubMed: 10531037]
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[Full Text: https://doi.org/10.1016/S0960-9822(00)80021-4]
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</p>
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</li>
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</ol>
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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 class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 10/10/2013<br>Patricia A. Hartz - updated : 12/14/2004
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</span>
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</div>
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</div>
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<br />
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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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Paul J. Converse : 2/15/2001
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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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carol : 10/17/2013<br>carol : 10/14/2013<br>ckniffin : 10/10/2013<br>mgross : 12/14/2004<br>mgross : 2/15/2001
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and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
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medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
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and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal
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medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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