4691 lines
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Entry
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- *601498 - PEROXISOME BIOGENESIS FACTOR 6; PEX6
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- OMIM
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<p>
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<span class="h4">*601498</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#nomenclature">Nomenclature</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/601498">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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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000124587;t=ENST00000304611" 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=5190" 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=601498" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000124587;t=ENST00000304611" 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_000287,NM_001316313,NR_133009,XM_011514661,XM_047418872,XM_047418873" 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_000287" 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=601498" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=03293&isoform_id=03293_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/PEX6" 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/1354753,1747316,7453117,12644408,18147118,18147120,18147122,29477006,62087392,119624530,119624531,119624532,119624533,119624534,189054381,194018488,767940163,937834196,2217361722,2217361724,2462608823,2462608825,2462608827" 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/Q13608" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5190" 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=ENSG00000124587;t=ENST00000304611" 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=PEX6" 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=PEX6" 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+5190" 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/PEX6" 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:5190" 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/5190" 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=ENST00000304611.13&hgg_start=42963865&hgg_end=42979181&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:8859" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601498[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601498[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/PEX6/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/ENSG00000124587" 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=PEX6" 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=PEX6" 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=PEX6" 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="http://www.dbpex.org/" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=PEX6&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/PA33201" 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:8859" 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/FBgn0033564.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:2385054" 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/PEX6#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:2385054" 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/5190/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=5190" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00004195;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-081104-252" 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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:601498" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
|
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5190" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=PEX6&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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601498
|
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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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|
PEROXISOME BIOGENESIS FACTOR 6; PEX6
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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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
PEROXIN 6<br />
|
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PEROXISOMAL ASSEMBLY FACTOR 2; PAF2<br />
|
|
PEROXISOMAL-TYPE ATPase 1; PXAAA1
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=PEX6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">PEX6</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/6/509?start=-3&limit=10&highlight=509">6p21.1</a>
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|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr6:42963865-42979181&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'})">6:42,963,865-42,979,181</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
</span>
|
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</p>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=616617,614862,614863" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/6/509?start=-3&limit=10&highlight=509">
|
|
6p21.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Heimler syndrome 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/616617"> 616617 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<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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<p>Peroxisomal targeting signals (PTSs) are discrete amino acid sequences capable of directing proteins to the peroxisome. Most peroxisomal matrix proteins contain PTS1, a C-terminal tripeptide of the sequence ser-lys-leu (SKL) or a conservative variant. In contrast, the N-terminal PTS2 consists of approximately 10 amino acids (arg/lys-leu-X5-gln/his-leu) and has been observed in only 3 peroxisomal proteins. The only documented human PTS2-containing proteins are peroxisomal thiolase (<a href="/entry/604054">604054</a>) and phytanic acid oxidase (<a href="/entry/266500">266500</a>). <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> stated that the only known human PTS2-containing protein is thiolase. The most extensively studied of the factors involved in peroxisomal protein import is the PTS1 receptor, encoded by the peroxin-5 gene (PEX5; <a href="/entry/600414">600414</a>) and defective in Zellweger syndrome. Human PEX5 was originally identified by homology probing the human EST database with the S. cerevisiae PAS8 protein sequence. The continued application of this approach by <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> led to the cloning and characterization of a novel human gene (called PXAAA1 by them) based on its similarity to PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris. The 980-amino acid protein product belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein. <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> found that substitution of an arginine for the conserved lysine residue in the ATPase domain of the PXAAA1 protein abolished its biologic activity, suggesting that it is an ATPase. Furthermore, they showed that the protein is required for stability of the predominantly cytoplasmic PTS1 receptor. <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> concluded that the PXAAA1 protein plays a direct role in peroxisomal protein import and is required for PTS1 receptor activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8670792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Distel, B., Erdmann, R., Gould, S. J., Blobel, G., Crane, D. I., Cregg, J. M., Dodt, G., Fujiki, Y., Goodman, J. M., Just, W. W., Kiel, J. A. K. W., Kunau, W.-H., Lazarow, P. B., Mannaerts, G. P., Moser, H. W., Osumi, T., Rachubinski, R. A., Roscher, A., Subramani, S., Tabak, H. F., Tsukamoto, T., Valle, D., van der Klei, I., van Veldhoven, P. P., Veenhuis, M. <strong>A unified nomenclature for peroxisome biogenesis factors.</strong> J. Cell Biol. 135: 1-3, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8858157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8858157</a>] [<a href="https://doi.org/10.1083/jcb.135.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8858157">Distel et al. (1996)</a> listed the peroxisomal assembly factor isolated in the rat by <a href="#12" class="mim-tip-reference" title="Tsukamoto, T., Miura, S., Nakai, T., Yokota, S., Shimozawa, N., Suzuki, Y., Orii, T., Fujiki, Y., Sakai, F., Bogaki, A., Yasumo, H., Osumi, T. <strong>Peroxisome assembly factor-2, a putative ATPase cloned by functional complementation on a peroxisome-deficient mammalian cell mutant.</strong> Nature Genet. 11: 395-401, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493019</a>] [<a href="https://doi.org/10.1038/ng1295-395" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7493019">Tsukamoto et al. (1995)</a> as identical to PXAAA1 (or PEX6). <a href="#12" class="mim-tip-reference" title="Tsukamoto, T., Miura, S., Nakai, T., Yokota, S., Shimozawa, N., Suzuki, Y., Orii, T., Fujiki, Y., Sakai, F., Bogaki, A., Yasumo, H., Osumi, T. <strong>Peroxisome assembly factor-2, a putative ATPase cloned by functional complementation on a peroxisome-deficient mammalian cell mutant.</strong> Nature Genet. 11: 395-401, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7493019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7493019</a>] [<a href="https://doi.org/10.1038/ng1295-395" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7493019">Tsukamoto et al. (1995)</a> isolated rat peroxisome assembly factor-2 (PAF2) cDNA by functional complementation of the peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP92, using a transient transfection assay. This cDNA encodes a 978-amino acid protein with 2 putative ATP-binding sites. The investigators stated that PAF2 is a member of a putative ATPase family which includes 2 yeast gene products essential for peroxisome assembly. The stable transformant of ZP92 with the cDNA was morphologically and biochemically restored for peroxisome biogenesis. Fibroblasts derived from patients deficient in peroxisome biogenesis (complementation group C) were also complemented with rat PAF2 cDNA, indicating that PAF2 is a strong candidate for the site of the mutation in one peroxisomal complementation group. The proteins of the ATPase family (AAA proteins) participate in a broad range of cellular processes, as indicated by the designation AAA which comes from 'ATPases associated with diverse cellular activities.' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7493019+8858157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T., Hashiguchi, N., Osumi, T., Masuno, M., Imaizumi, K., Kuroki, Y., Fujiki, Y., Orii, T., Kondo, N. <strong>Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.</strong> Am. J. Hum. Genet. 59: 1210-1220, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940266</a>]" pmid="8940266">Fukuda et al. (1996)</a> found that the 2,940-bp open reading frame of the human PAF2 cDNA encodes a 980-amino acid protein that shows 87.1% identity with rat PAF2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940266" 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="#16" class="mim-tip-reference" title="Zhang, Z., Suzuki, Y., Shimozawa, N., Fukuda, S., Imamura, A., Tsukamoto, T., Osumi, T., Fujiki, Y., Orii, T., Wanders, R. J. A., Barth, P. G., Moser, H. W., Paton, B. C., Besley, G. T., Kondo, N. <strong>Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders.</strong> Hum. Mutat. 13: 487-496, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408779</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<487::AID-HUMU9>3.0.CO;2-T" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408779">Zhang et al. (1999)</a> determined that the PEX6 gene consists of 17 exons and 16 introns, spanning about 14 kb. The largest exon, exon 1, has at least 952 nucleotides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408779" 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>To determine the chromosomal localization of PXAAA1, <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> probed a panel of mouse/human hybrid cell lines with the full-length PXAAA1 cDNA. Hybridizing fragments specific for human genomic DNA were detected only in the cell lines containing human chromosome 6. The human cDNA was also used to determine the map position of the mouse ortholog by RFLP analysis of an interspecific backcross DNA panel. The mouse gene mapped to chromosome 17 between markers that show homology of synteny to human 6p22-p11. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8670792" 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 fluorescence in situ hybridization, <a href="#4" class="mim-tip-reference" title="Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T., Hashiguchi, N., Osumi, T., Masuno, M., Imaizumi, K., Kuroki, Y., Fujiki, Y., Orii, T., Kondo, N. <strong>Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.</strong> Am. J. Hum. Genet. 59: 1210-1220, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940266</a>]" pmid="8940266">Fukuda et al. (1996)</a> mapped the human PEX6 gene to 6p21.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an Arabidopsis pex6 mutant with defects in peroxisomal matrix protein import, oil body utilization, peroxisomal metabolism and seedling growth, <a href="#5" class="mim-tip-reference" title="Gonzalez, K. L., Ratzel, S. E., Burks, K. H., Danan, C. H., Wages, J. M., Zolman, B. k., Bartel, B. <strong>A pex1 missense mutation improves peroxisome function in a subset of Arabidopsis pex6 mutants without restoring PEX5 recycling.</strong> Proc. Nat. Acad. Sci. 115: E3163-E3172, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29555730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29555730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29555730[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1721279115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29555730">Gonzalez et al. (2018)</a> found that a pex1 missense mutation (pex1-1), uncovered in a screen for second-site suppressors, can restore the growth defect. Although a major function of PEX6 is involvement in PEX5 retrotranslocation from the peroxisomal membrane (via a PEX1-PEX6 heterohexameric ATPase), <a href="#5" class="mim-tip-reference" title="Gonzalez, K. L., Ratzel, S. E., Burks, K. H., Danan, C. H., Wages, J. M., Zolman, B. k., Bartel, B. <strong>A pex1 missense mutation improves peroxisome function in a subset of Arabidopsis pex6 mutants without restoring PEX5 recycling.</strong> Proc. Nat. Acad. Sci. 115: E3163-E3172, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29555730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29555730</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29555730[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1721279115" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29555730">Gonzalez et al. (2018)</a> found that the pex1-1 mutant restored seedling growth without restoring PEX5 levels. This supports the hypothesis that PEX6 has additional functions in the peroxisome beyond PEX5 recycling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29555730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Peroxisome Biogenesis Disorder 4A (Zellweger)</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> observed that expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 of the peroxisomal biogenesis disorders (PBD4A,; <a href="/entry/614862">614862</a>). Consistent with this observation, a complementation group 4 patient was found to carry mutations in PXAAA1 (<a href="#0001">601498.0001</a> and <a href="#0002">601498.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8670792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T., Hashiguchi, N., Osumi, T., Masuno, M., Imaizumi, K., Kuroki, Y., Fujiki, Y., Orii, T., Kondo, N. <strong>Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.</strong> Am. J. Hum. Genet. 59: 1210-1220, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940266</a>]" pmid="8940266">Fukuda et al. (1996)</a> found that human PAF2 restores peroxisome assembly after gene transfer to fibroblasts of group C patients. In 2 patients with what they termed group C Zellweger syndrome (group 4 in the Kennedy-Krieger Institute Classification), the authors demonstrated homozygosity for 2 different mutations in the PAF2 gene. Direct sequencing of the PAF2 gene revealed a homozygous 1-bp insertion at nucleotide 510 in 1 patient (<a href="#0003">601498.0003</a>) and a splice site mutation in intron 3 resulting in skipping of exon 3 in a second patient (<a href="#0004">601498.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Zhang, Z., Suzuki, Y., Shimozawa, N., Fukuda, S., Imamura, A., Tsukamoto, T., Osumi, T., Fujiki, Y., Orii, T., Wanders, R. J. A., Barth, P. G., Moser, H. W., Paton, B. C., Besley, G. T., Kondo, N. <strong>Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders.</strong> Hum. Mutat. 13: 487-496, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408779</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<487::AID-HUMU9>3.0.CO;2-T" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408779">Zhang et al. (1999)</a> clarified the genomic DNA structure of PEX6 and identified mutations in patients from various ethnic groups. Eleven novel mutations (18 alleles) were identified by direct sequencing of the PEX6 cDNA from 10 patients. There was no common mutation, but an exon skip was identified in 2 unrelated Japanese patients. Most of the mutations led to premature termination or large deletions of the PEX6 protein and resulted in the most severe peroxisome biogenesis disorder phenotype of Zellweger syndrome. A patient with an atypical Zellweger syndrome had a missense mutation that was shown to disrupt the cell's ability to form peroxisomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Peroxisome Biogenesis Disorder 4B</em></strong></p><p>
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<a href="#7" class="mim-tip-reference" title="Matsumoto, N., Tamura, S., Moser, A., Moser, H. W., Braverman, N., Suzuki, Y., Shimozawa, N., Kondo, N., Fujiki, Y. <strong>The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6.</strong> J. Hum. Genet. 46: 273-277, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11355018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11355018</a>] [<a href="https://doi.org/10.1007/s100380170078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11355018">Matsumoto et al. (2001)</a> provided several lines of evidence indicating that PEX6, the pathogenic gene for PBD of complementation group 4, is impaired also in complementation group 6 PBD. They found that expression of PEX6 restored peroxisome assembly in fibroblasts from a PBD patient (PBD4B; <a href="/entry/614863">614863</a>) who was a compound heterozygote for PEX6 gene alleles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11355018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M331, they identified a homozygous missense mutation in the PEX6 gene (<a href="#0009">601498.0009</a>) in 5 sibs with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R. <strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong> Am. J. Hum. Genet. 101: 965-976, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29220678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29220678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29220678[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.2017.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29220678">Falkenberg et al. (2017)</a> reported heterozygous mutation in the PEX6 gene resulting in a peroxisome biogenesis disorder ('Zellweger spectrum disorder,' ZSD) due to allelic expression imbalance (AEI) promoting the overrepresentation of a pathogenic allele. In 7 unrelated patients with a ZSD and 1 affected half brother, the authors identified heterozygosity for a missense mutation in the PEX6 gene (R860W; <a href="#0015">601498.0015</a>), which was inherited from an unaffected parent in 3 of the families. All affected individuals exhibited AEI, with mutant allele levels 3 to 5 times greater than those of the wildtype allele, whereas the heterozygous parents did not show AEI. Analysis of common variants in PEX6 revealed a polymorphic 4-bp deletion in the 3-prime UTR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144286892;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144286892</a>; <a href="#0014">601498.0014</a>) that correlated with AEI of PEX6 when present in heterozygosity but not in homozygosity, being heterozygous and located in cis with the R860W mutation in all 8 affected individuals, but homozygous in the 3 unaffected carrier parents. Functional analysis indicated that the PEX6 R860W mutation has a negative effect on PEX1 (<a href="/entry/602136">602136</a>)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29220678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Heimler Syndrome 2</em></strong></p><p>
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In affected individuals from 2 unrelated families with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; <a href="/entry/616617">616617</a>), <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> identified compound heterozygosity for mutations in the PEX6 gene (<a href="#0010">601498.0010</a>-<a href="#0013">601498.0013</a>). The authors noted that in contrast to patients with PBDs at the severe end of the clinical spectrum, these patients showed no identifiable dysmorphic or additional neurologic features. Complementation assays in PEX6-null cells with variants from patients with Heimler syndrome-2 demonstrated that all affected individuals had at least 1 PEX variant with residual activity in peroxisomal biogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26387595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sibs with HMLR2, born of consanguineous Egyptian parents, <a href="#15" class="mim-tip-reference" title="Zaki, M. S., Heller, R., Thoenes, M., Nurnberg, G., Stern-Schneider, G., Nurnberg, P., Karnati, S., Swan, D., Fateen, E., Nagel-Wolfrum, K., Mostafa, M. I., Thiele, H., Wolfrum, U., Baumgart-Vogt, E., Bolz, H. J. <strong>PEX6 is expressed in photoreceptor cilia and mutated in deafblindness with enamel dysplasia and microcephaly.</strong> Hum. Mutat. 37: 170-174, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26593283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26593283</a>] [<a href="https://doi.org/10.1002/humu.22934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26593283">Zaki et al. (2016)</a> identified a homozygous missense mutation (G413V; <a href="#0016">601498.0016</a>) in the PEX6 gene. The mutation, which was identified by genomewide linkage analysis and whole-exome sequencing, segregated with the disorder in the family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26593283" 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="#1" class="mim-tip-reference" title="Distel, B., Erdmann, R., Gould, S. J., Blobel, G., Crane, D. I., Cregg, J. M., Dodt, G., Fujiki, Y., Goodman, J. M., Just, W. W., Kiel, J. A. K. W., Kunau, W.-H., Lazarow, P. B., Mannaerts, G. P., Moser, H. W., Osumi, T., Rachubinski, R. A., Roscher, A., Subramani, S., Tabak, H. F., Tsukamoto, T., Valle, D., van der Klei, I., van Veldhoven, P. P., Veenhuis, M. <strong>A unified nomenclature for peroxisome biogenesis factors.</strong> J. Cell Biol. 135: 1-3, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8858157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8858157</a>] [<a href="https://doi.org/10.1083/jcb.135.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8858157">Distel et al. (1996)</a> provided a unified nomenclature for peroxisome biogenesis. By the use of genetic approaches in a wide variety of experimental organisms, 13 proteins required for peroxisome biogenesis had been identified in the previous 10 years. Three of these had been shown to be defective in lethal peroxisome biogenesis disorders (PBDs). However, the diversity of experimental systems had led to a profusion of names for peroxisome assembly genes and proteins and a great array of numbering systems. <a href="#1" class="mim-tip-reference" title="Distel, B., Erdmann, R., Gould, S. J., Blobel, G., Crane, D. I., Cregg, J. M., Dodt, G., Fujiki, Y., Goodman, J. M., Just, W. W., Kiel, J. A. K. W., Kunau, W.-H., Lazarow, P. B., Mannaerts, G. P., Moser, H. W., Osumi, T., Rachubinski, R. A., Roscher, A., Subramani, S., Tabak, H. F., Tsukamoto, T., Valle, D., van der Klei, I., van Veldhoven, P. P., Veenhuis, M. <strong>A unified nomenclature for peroxisome biogenesis factors.</strong> J. Cell Biol. 135: 1-3, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8858157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8858157</a>] [<a href="https://doi.org/10.1083/jcb.135.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8858157">Distel et al. (1996)</a> suggested that proteins involved in peroxisome biogenesis should be designated 'peroxins,' with PEX representing the gene acronym. Even though defects in peroxisomal metabolic enzymes or transcription factors may affect peroxisome proliferation and/or morphology, such proteins should not, they recommended, be included in this group. The proteins and genes were to be numbered by date of published characterization, both for known factors and those identified in the future. When necessary, species of origin could be specified by 1-letter abbreviations for genus and species (e.g., hsPEX2). To minimize ambiguities in naming additional proteins identified in the future, <a href="#1" class="mim-tip-reference" title="Distel, B., Erdmann, R., Gould, S. J., Blobel, G., Crane, D. I., Cregg, J. M., Dodt, G., Fujiki, Y., Goodman, J. M., Just, W. W., Kiel, J. A. K. W., Kunau, W.-H., Lazarow, P. B., Mannaerts, G. P., Moser, H. W., Osumi, T., Rachubinski, R. A., Roscher, A., Subramani, S., Tabak, H. F., Tsukamoto, T., Valle, D., van der Klei, I., van Veldhoven, P. P., Veenhuis, M. <strong>A unified nomenclature for peroxisome biogenesis factors.</strong> J. Cell Biol. 135: 1-3, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8858157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8858157</a>] [<a href="https://doi.org/10.1083/jcb.135.1.1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8858157">Distel et al. (1996)</a> urged authors before publication to contact the ad hoc nomenclature committee. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8858157" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=601498[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267608229 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608229;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/rs267608229?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=rs267608229" 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=rs267608229" 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=RCV000665084 OR RCV001280661 OR RCV002224971 OR RCV003472068 OR RCV005034234" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000665084, RCV001280661, RCV002224971, RCV003472068, RCV005034234" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000665084...</a>
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<p>After demonstrating that a newly isolated gene they called PXAAA1 corrected the defect in complementation group 4 PBD, <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> used a gene-specific primer to synthesize PXAAA1 cDNA from normal and group 4 (CG4; PBD4A, <a href="/entry/614862">614862</a>) fibroblasts. Fragments of the open reading frame were then amplified by PCR and subjected to SSCP analysis. PXAAA1 SSCP migration variants were detected in 9 of 13 CG4 patients examined, even though only 40% of the ORF had been examined. Direct sequencing of RT-PCR-generated cDNA fragments revealed that one patient was a compound heterozygote for 2 different deletions: an 8-bp deletion (nucleotides 1962-1969), and a 20-bp deletion (nucleotides 2398-2417) together with insertion of a single T (<a href="#0002">601498.0002</a>). Direct sequencing of amplified genomic DNA revealed that 1 allele contained a G-to-A transition at the -1 position of a splice acceptor site. This resulted in the use of a cryptic splice acceptor site 8 bp downstream of the normal site, generating the 8-bp deletion observed in the cDNA. The father was heterozygous for this splice site mutation. The mother was found to be heterozygous for the 20-bp deletion/1-bp insertion found in the other allele of the patient. Both mutations in this patient (whose cell line had the designation PBD106) shifted the reading frame of the PXAAA1 mRNA. The product of the first allele lacked the C-terminal 326 amino acids of the protein product and instead contained the 3 amino acids trp-leu-asp (WLD) in their place. The product of the second allele lacked the C-terminal 181 amino acids and instead contained 15 novel amino acids. Previous studies cited by <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a> demonstrated that mutations which affect the reading frame of an mRNA commonly result in mRNA instability and decreased steady-state levels of mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8670792" 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 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs62653602 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs62653602;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/rs62653602?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=rs62653602" 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=rs62653602" 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=RCV000734495 OR RCV001243165 OR RCV002279940 OR RCV003472271 OR RCV005036073" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000734495, RCV001243165, RCV002279940, RCV003472271, RCV005036073" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000734495...</a>
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<p>For discussion of the 20-bp deletion (nucleotides 2398-2417) and insertion of a single T in the PEX6 gene that was found in compound heterozygous state in PBD4A (<a href="/entry/614862">614862</a>) fibroblasts by <a href="#13" class="mim-tip-reference" title="Yahraus, T., Braverman, N., Dodt, G., Kalish, J. E., Morrell, J. C., Moser, H. W., Valle, D., Gould, S. J. <strong>The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor.</strong> EMBO J. 15: 2914-2923, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8670792/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8670792</a>]" pmid="8670792">Yahraus et al. (1996)</a>, see <a href="#0001">601498.0001</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8670792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1491384052 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1491384052;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=rs1491384052" 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=rs1491384052" 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=RCV000665973 OR RCV000780593 OR RCV002279939" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000665973, RCV000780593, RCV002279939" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000665973...</a>
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<p>In a cell line from a patient with typical clinical features of Zellweger syndrome (PBD4A; <a href="/entry/614862">614862</a>) and ghost peroxisomes (GM04340 in the Coriell Cell Repositories), <a href="#4" class="mim-tip-reference" title="Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T., Hashiguchi, N., Osumi, T., Masuno, M., Imaizumi, K., Kuroki, Y., Fujiki, Y., Orii, T., Kondo, N. <strong>Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.</strong> Am. J. Hum. Genet. 59: 1210-1220, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940266</a>]" pmid="8940266">Fukuda et al. (1996)</a> identified homozygosity for a 1-bp insertion at nucleotide 511 which introduced a premature termination codon in the PXAAA1 gene. The patient was the product of a father-daughter mating. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
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PEX6, IVS3DS, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267608213 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267608213;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=rs267608213" 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=rs267608213" 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=RCV000008592 OR RCV001239904" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008592, RCV001239904" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008592...</a>
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<p>In a Japanese girl with Zellweger syndrome, complementation group C (PBD4A; <a href="/entry/614862">614862</a>), born of nonconsanguineous parents <a href="#4" class="mim-tip-reference" title="Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T., Hashiguchi, N., Osumi, T., Masuno, M., Imaizumi, K., Kuroki, Y., Fujiki, Y., Orii, T., Kondo, N. <strong>Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.</strong> Am. J. Hum. Genet. 59: 1210-1220, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8940266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8940266</a>]" pmid="8940266">Fukuda et al. (1996)</a> identified a heterozygous mutation in the consensus 5-prime splice site of intron 3 (IVS3+1G-to-A), which led to skipping of exon 3. The patient at birth was small and had severe asphyxia, profound hypotonia, and clonic convulsions. The patient died of respiratory failure at age 7 months. An insertion introducing frameshift in the transcript from the other allele was also detected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8940266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
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PEX6, IVS7, G-A, +1
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs112298166 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs112298166;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=rs112298166" 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=rs112298166" 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=RCV000008594 OR RCV002512914 OR RCV003473057" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008594, RCV002512914, RCV003473057" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008594...</a>
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<p>In 2 unrelated Japanese patients with severe Zellweger syndrome of complementation group C (PBD4A; <a href="/entry/614862">614862</a>), <a href="#16" class="mim-tip-reference" title="Zhang, Z., Suzuki, Y., Shimozawa, N., Fukuda, S., Imamura, A., Tsukamoto, T., Osumi, T., Fujiki, Y., Orii, T., Wanders, R. J. A., Barth, P. G., Moser, H. W., Paton, B. C., Besley, G. T., Kondo, N. <strong>Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders.</strong> Hum. Mutat. 13: 487-496, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408779</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<487::AID-HUMU9>3.0.CO;2-T" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408779">Zhang et al. (1999)</a> found homozygosity for a G-to-A transition in the first position of intron 7 of the PEX6 gene. Two abnormal splicing patterns were caused by this mutation: one a skipping of exon 7, and the other a skipping of exons 6 and 7. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs62641231 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs62641231;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/rs62641231?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=rs62641231" 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=rs62641231" 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=RCV000008596" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008596" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008596</a>
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<p>In a case of severe Zellweger syndrome (PBD4A; <a href="/entry/614862">614862</a>) surviving to the age of 8.5 months, <a href="#16" class="mim-tip-reference" title="Zhang, Z., Suzuki, Y., Shimozawa, N., Fukuda, S., Imamura, A., Tsukamoto, T., Osumi, T., Fujiki, Y., Orii, T., Wanders, R. J. A., Barth, P. G., Moser, H. W., Paton, B. C., Besley, G. T., Kondo, N. <strong>Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders.</strong> Hum. Mutat. 13: 487-496, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408779</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<487::AID-HUMU9>3.0.CO;2-T" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10408779">Zhang et al. (1999)</a> found homozygosity for a 1-bp deletion, 1301delC. This deletion resulted in a frameshift at serine codon 434 and the creation of a premature termination at codon 449. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 PEROXISOME BIOGENESIS DISORDER 4B</strong>
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PEX6, 264-BP DEL, NT619
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1554128347 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1554128347;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=rs1554128347" 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=rs1554128347" 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=RCV000008598" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008598" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008598</a>
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<p>In a patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) belonging to complementation group 6 of the peroxisome biogenesis disorders (PBD4B; <a href="/entry/614863">614863</a>), <a href="#7" class="mim-tip-reference" title="Matsumoto, N., Tamura, S., Moser, A., Moser, H. W., Braverman, N., Suzuki, Y., Shimozawa, N., Kondo, N., Fujiki, Y. <strong>The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6.</strong> J. Hum. Genet. 46: 273-277, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11355018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11355018</a>] [<a href="https://doi.org/10.1007/s100380170078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11355018">Matsumoto et al. (2001)</a> found compound heterozygosity for mutations in the PEX6 gene. One allele had a deletion of nucleotides 619-882 of PEX6; the other allele had a deletion of nucleotides 2095-2362 and an insertion of 21 nucleotides (<a href="#0008">601498.0008</a>). This patient had been described by <a href="#6" class="mim-tip-reference" title="Kelley, R. I., Datta, N. S., Dobyns, W. B., Hajra, A. K., Moser, A. B., Noetzel, M. J., Zackai, E. H., Moser, H. W. <strong>Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes.</strong> Am. J. Med. Genet. 23: 869-901, 1986.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3515938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3515938</a>] [<a href="https://doi.org/10.1002/ajmg.1320230404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3515938">Kelley et al. (1986)</a> as Patient 6. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=3515938+11355018" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 PEROXISOME BIOGENESIS DISORDER 4B</strong>
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PEX6, 269-BP DEL/21-BP INS
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000008599" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008599" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008599</a>
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<p>For discussion of the deletion of nucleotides 2095-2362 along with an insertion of 21 nucleotides in the PEX6 gene that was found in compound heterozygous state in a patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) belonging to complementation group 6 of the peroxisome biogenesis disorders (PBD4B; <a href="/entry/614863">614863</a>) by <a href="#7" class="mim-tip-reference" title="Matsumoto, N., Tamura, S., Moser, A., Moser, H. W., Braverman, N., Suzuki, Y., Shimozawa, N., Kondo, N., Fujiki, Y. <strong>The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6.</strong> J. Hum. Genet. 46: 273-277, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11355018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11355018</a>] [<a href="https://doi.org/10.1007/s100380170078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11355018">Matsumoto et al. (2001)</a>, see <a href="#0007">601498.0007</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11355018" 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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PEX6, LEU534PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906809 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906809;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=rs387906809" 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=rs387906809" 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=RCV000023114" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023114" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023114</a>
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<p>In family M331 (PBD4B; <a href="/entry/614863">614863</a>), <a href="#8" class="mim-tip-reference" title="Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others. <strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong> Nature 478: 57-63, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21937992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21937992</a>] [<a href="https://doi.org/10.1038/nature10423" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21937992">Najmabadi et al. (2011)</a> identified a homozygous A-to-G mutation in the PEX6 gene at genomic coordinate chr6:43,044,093 (NCBI36), resulting in a leu534-to-pro (L534P) substitution, in 5 sibs with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21937992" 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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PEX6, PRO274LEU
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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> rs61753219 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61753219;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/rs61753219?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=rs61753219" 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=rs61753219" 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=RCV000201297 OR RCV000622824 OR RCV000666553 OR RCV000735222 OR RCV001193476 OR RCV001276623 OR RCV001808558 OR RCV002243878 OR RCV004737319 OR RCV005031753" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201297, RCV000622824, RCV000666553, RCV000735222, RCV001193476, RCV001276623, RCV001808558, RCV002243878, RCV004737319, RCV005031753" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201297...</a>
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<p>In 2 sisters with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; <a href="/entry/616617">616617</a>), <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> identified compound heterozygosity for a c.821C-T transition (c.821C-T, NM_000287.3) in the PEX6 gene, resulting in a pro274-to-leu (P274L) substitution, and a c.1930C-T transition, resulting in an arg644-to-trp (R644W; <a href="#0011">601498.0011</a>) substitution. Both mutations segregated with disease in the family; the previously unreported R644W mutation was not found in 770 in-house exomes, but was present in 4 of 121,396 alleles in the ExAC Browser (minor allele frequency less than 0.000033). <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> noted that the P274L mutation had been detected by <a href="#11" class="mim-tip-reference" title="Steinberg, S., Chen, L., Wei, L., Moser, A., Moser, H., Cutting, G., Braverman, N. <strong>The PEX gene screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum.</strong> Molec. Genet. Metab. 83: 252-263, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15542397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15542397</a>] [<a href="https://doi.org/10.1016/j.ymgme.2004.08.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15542397">Steinberg et al. (2004)</a> in 2 patients with peroxisome biogenesis disorder (PBD) Zellweger syndrome spectrum (see <a href="/entry/614862">614862</a> and <a href="/entry/614863">614863</a>), in compound heterozygosity with a splice site mutation and a frameshift mutation, respectively. No clinical information was reported for the Zellweger syndrome spectrum patients, although it was stated that inclusion criteria for the panel under study were elevated very-long-chain fatty acids (VLCFA) with deficient plasmalogen synthesis, and/or mislocalization of catalase (<a href="/entry/115500">115500</a>), and/or elevated VLCFA and pipecolate. Analysis of plasma, erythrocytes, and fibroblasts from the sisters with Heimler syndrome-2 by <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> did not show any peroxisomal biochemical aberrations, consistent with their relatively very mild disease; however, immunofluorescence microscopy of Heimler patient fibroblasts revealed a mosaic peroxisomal pattern similar to that previously associated with hypomorphic variants. In complementation assays, transfection of PEX1-null cells with the c.821C-T and c.1930C-T variants rescued peroxisomal biogenesis in approximately 2% and 20% of cells, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26387595+15542397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs769896492 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs769896492;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/rs769896492?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=rs769896492" 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=rs769896492" 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=RCV000201306 OR RCV001328449 OR RCV001853224 OR RCV004737320 OR RCV005031754" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201306, RCV001328449, RCV001853224, RCV004737320, RCV005031754" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201306...</a>
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<p>For discussion of the c.1930C-T transition (c.1930C-T, NM_000287.3) in the PEX6 gene, resulting in an arg644-to-trp (R644W) substitution, that was found in compound heterozygous state in 2 sisters with Heimler syndrome-2 (HMLR2; <a href="/entry/616617">616617</a>) by <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a>, see <a href="#0010">601498.0010</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26387595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000180127 OR RCV000201298 OR RCV000424129 OR RCV000675148 OR RCV000779504 OR RCV000850505 OR RCV001075628 OR RCV001081170 OR RCV001265584 OR RCV003987426" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000180127, RCV000201298, RCV000424129, RCV000675148, RCV000779504, RCV000850505, RCV001075628, RCV001081170, RCV001265584, RCV003987426" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000180127...</a>
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<p>In monozygotic twin sisters with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; <a href="/entry/616617">616617</a>), originally reported by <a href="#9" class="mim-tip-reference" title="Ong, K. R., Visram, S., McKaig, S., Brueton, L. A. <strong>Sensorineural deafness, enamel abnormalities and nail abnormalities: a case report of Heimler syndrome in identical twin girls.</strong> Europ. J. Med. Genet. 49: 187-193, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16530715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16530715</a>] [<a href="https://doi.org/10.1016/j.ejmg.2005.07.003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16530715">Ong et al. (2006)</a>, <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> identified compound heterozygosity for a c.1802G-A transition (c.1802G-A, NM_000287.3) in exon 8 of the PEX6 gene, resulting in an arg601-to-gln (R601Q) substitution, and a 1-bp deletion (c.1841del; <a href="#0013">601498.0013</a>) causing a frameshift resulting in a premature termination codon (Leu614ArgfsTer5). Both mutations segregated with disease in the family, and the previously unreported 1-bp deletion was not found in 770 in-house exomes or in public databases. <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> stated that the R601Q mutation had previously been detected in compound heterozygosity in 7 patients with a Zellweger spectrum disorder (see <a href="/entry/614862">614862</a> and <a href="/entry/614863">614863</a>) by <a href="#14" class="mim-tip-reference" title="Yik, W. Y., Steinberg, S. J., Moser, A. B., Moser, H. W., Hacia, J. G. <strong>Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders.</strong> Hum. Mutat. 30: E467-E480, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19105186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19105186</a>] [<a href="https://doi.org/10.1002/humu.20932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19105186">Yik et al. (2009)</a> and <a href="#2" class="mim-tip-reference" title="Ebberink, M. S., Koster, J., Wanders, R. J. A., Waterham, H. R. <strong>Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.</strong> Hum. Mutat. 31: E1058-E1070, 2010. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19877282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19877282</a>] [<a href="https://doi.org/10.1002/humu.21153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19877282">Ebberink et al. (2010)</a>. No clinical information was reported for the 7 patients diagnosed with Zellweger spectrum disorder. Noting that the PEX6 c.1082G-A allele is present in the ExAC database at a frequency of 0.41% in the European population, <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a> predicted that future whole-exome sequencing would identify additional mildly affected individuals. In complementation assays, transfection of PEX1-null cells with the c.1802G-A and c.1841del variants rescued peroxisomal biogenesis in more than 30% and in no cells, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26387595+16530715+19877282+19105186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs863225083 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs863225083;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/rs863225083?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=rs863225083" 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=rs863225083" 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=RCV000201289 OR RCV000674727 OR RCV001008824 OR RCV001853225 OR RCV002517303 OR RCV005031755" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000201289, RCV000674727, RCV001008824, RCV001853225, RCV002517303, RCV005031755" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000201289...</a>
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<p>For discussion of the 1-bp deletion (c.1841del, NM_000287.3) in the PEX6 gene, causing a frameshift resulting in a premature termination codon (Leu614ArgfsTer5), that was found in compound heterozygous state in twin sisters with Heimler syndrome-2 (HMLR2; <a href="/entry/616617">616617</a>) by <a href="#10" class="mim-tip-reference" title="Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others. <strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong> Am. J. Hum. Genet. 97: 535-545, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26387595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26387595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26387595[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.2015.08.011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26387595">Ratbi et al. (2015)</a>, see <a href="#0012">601498.0012</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26387595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 PEX6 POLYMORPHISM</strong>
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PEX6, 4-BP DEL, +442TAAA, 3-PRIME UTR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144286892;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144286892</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs144286892 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144286892;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/rs144286892?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=rs144286892" 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=rs144286892" 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=RCV000360304 OR RCV000584757 OR RCV000734624 OR RCV000960459 OR RCV001522195 OR RCV003388935" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000360304, RCV000584757, RCV000734624, RCV000960459, RCV001522195, RCV003388935" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000360304...</a>
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<p><a href="#3" class="mim-tip-reference" title="Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R. <strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong> Am. J. Hum. Genet. 101: 965-976, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29220678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29220678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29220678[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.2017.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29220678">Falkenberg et al. (2017)</a> noted that a 4-bp deletion in the 3-prime UTR of the PEX6 gene (c.*442_445delTAAA, NM_000287.3; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144286892;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144286892</a>) is a commonly occurring polymorphism, with a minor allele frequency of 35% in the 1000 Genomes Project database. The variant disrupts the more distal of 2 known polyadenylation signals of PEX6, located at c.*440_445, resulting in a PEX6 mRNA with a shorter 3-prime UTR (c.*1_*326, versus c.*1_*462). <a href="#3" class="mim-tip-reference" title="Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R. <strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong> Am. J. Hum. Genet. 101: 965-976, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29220678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29220678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29220678[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.2017.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29220678">Falkenberg et al. (2017)</a> performed quantitative analysis of PEX6 mRNA expression in fibroblast cell lines with different PEX6 allele combinations and confirmed that the PEX6 c.*442_445delTAAA allele does not produce the longer PEX6 c.*1_462 mRNA. Nevertheless, the total levels of PEX6 mRNA expressed by the PEX6 c.*442_445delTAAA allele were consistently higher than those expressed by the allele without the deletion. Thus allelic expression imbalance (AEI) of PEX6 occurs in all cell lines heterozygous for c.*442_445delTAAA, but not in cell lines homozygous for the polymorphism. Sanger sequencing of PEX6 cDNAs of 22 different fibroblast cell lines from unrelated controls showed AEI of PEX6 in more than 40% of the cell lines, demonstrating that AEI is a common feature of PEX6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29220678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Peroxisome Biogenesis Disorder 4B</em></strong></p><p>
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In 7 unrelated patients with a Zellweger spectrum disorder (PBD4B; <a href="/entry/614863">614863</a>) and 1 affected half brother, <a href="#3" class="mim-tip-reference" title="Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R. <strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong> Am. J. Hum. Genet. 101: 965-976, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29220678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29220678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29220678[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.2017.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29220678">Falkenberg et al. (2017)</a> identified heterozygosity for an R860W mutation in the PEX6 gene (<a href="#0015">601498.0015</a>) that was inherited from an unaffected parent in 3 of the families. The authors demonstrated that all affected individuals were also heterozygous for the c.*442_445delTAAA polymorphism in the 3-prime UTR of the mutant allele. Affected individuals exhibited AEI, with levels of the mutant allele that were 3 to 5 times higher than the wildtype allele, whereas the unaffected parents were homozygous for the polymorphic variant and did not show AEI. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29220678" 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>.0015 PEROXISOME BIOGENESIS DISORDER 4B</strong>
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PEX6, ARG860TRP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61753230;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs61753230</a>) AND 4-BP DEL, +442TAAA, 3-PRIME UTR (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144286892;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144286892</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs61753230 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs61753230;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=rs61753230" 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=rs61753230" 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=RCV000360304 OR RCV000584757 OR RCV000734624 OR RCV000802431 OR RCV000960459 OR RCV001522195 OR RCV002248804 OR RCV003388935 OR RCV004696954" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000360304, RCV000584757, RCV000734624, RCV000802431, RCV000960459, RCV001522195, RCV002248804, RCV003388935, RCV004696954" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000360304...</a>
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<p>In 7 unrelated patients with a Zellweger spectrum disorder (PBD4B; <a href="/entry/614863">614863</a>) and 1 affected half brother, <a href="#3" class="mim-tip-reference" title="Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R. <strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong> Am. J. Hum. Genet. 101: 965-976, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29220678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29220678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29220678[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.2017.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29220678">Falkenberg et al. (2017)</a> identified heterozygosity for a c.2578C-T transition (c.2578C-T, NM_000287.3) in the PEX6 gene, resulting in an arg860-to-trp (R860W) substitution at a highly conserved residue that constitutes the arginine finger 2 in the second region of homology (SRH) of the ATP-binding D2 domain. The mutation occurred de novo in 2 patients, but was shown to have been inherited from an unaffected parent in 3 of the families (parental DNA was unavailable from the remaining 2 families). All affected individuals exhibited allelic expression imbalance (AEI), with levels of the mutant allele 3 to 5 times greater than the wildtype allele, whereas the heterozygous parents did not show AEI. Analysis of common variants in PEX6 revealed an AEI-associated polymorphism (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs144286892;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs144286892</a>; <a href="#0014">601498.0014</a>) that was present in heterozygosity on the mutant allele in all 8 affected individuals, but for which the 3 unaffected carrier parents were homozygous. Overexpression of the R860W mutant in control fibroblasts resulted in an accumulation of PEX5 (<a href="/entry/600414">600414</a>) at the peroxisomal membranes and a concomitant defect of catalase import into peroxisomes. Coexpression of mutant and wildtype PEX6 in various ratios in PEX6-deficient fibroblasts demonstrated a significant negative correlation between restoration of peroxisomal matrix protein import and the ratio of mutant to wildtype PEX6. <a href="#3" class="mim-tip-reference" title="Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R. <strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong> Am. J. Hum. Genet. 101: 965-976, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29220678/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29220678</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29220678[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.2017.11.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29220678">Falkenberg et al. (2017)</a> concluded that the PEX6 R860W mutation exerts a dominant-negative effect on PEX1 (<a href="/entry/602136">602136</a>)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29220678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000672797 OR RCV001268931 OR RCV004586868 OR RCV005034267" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000672797, RCV001268931, RCV004586868, RCV005034267" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000672797...</a>
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<p>In 2 sibs, born to consanguineous Egyptian parents, with Heimler syndrome-2 (HMLR2; <a href="/entry/616617">616617</a>), <a href="#15" class="mim-tip-reference" title="Zaki, M. S., Heller, R., Thoenes, M., Nurnberg, G., Stern-Schneider, G., Nurnberg, P., Karnati, S., Swan, D., Fateen, E., Nagel-Wolfrum, K., Mostafa, M. I., Thiele, H., Wolfrum, U., Baumgart-Vogt, E., Bolz, H. J. <strong>PEX6 is expressed in photoreceptor cilia and mutated in deafblindness with enamel dysplasia and microcephaly.</strong> Hum. Mutat. 37: 170-174, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26593283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26593283</a>] [<a href="https://doi.org/10.1002/humu.22934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26593283">Zaki et al. (2016)</a> identified a homozygous c.1238G-T transversion (c.1238G-T, NM_000287.3) in exon 5 of the PEX6 gene, resulting in a gly413-to-val (G413V) substitution at a conserved residue in the HBD domain. The mutation, which was found by genomewide linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The parents were confirmed to be carriers. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26593283" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19105186/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19105186</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19105186" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.20932" 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="15" class="mim-anchor"></a>
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<a id="Zaki2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zaki, M. S., Heller, R., Thoenes, M., Nurnberg, G., Stern-Schneider, G., Nurnberg, P., Karnati, S., Swan, D., Fateen, E., Nagel-Wolfrum, K., Mostafa, M. I., Thiele, H., Wolfrum, U., Baumgart-Vogt, E., Bolz, H. J.
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<strong>PEX6 is expressed in photoreceptor cilia and mutated in deafblindness with enamel dysplasia and microcephaly.</strong>
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Hum. Mutat. 37: 170-174, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26593283/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26593283</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26593283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/humu.22934" 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="16" class="mim-anchor"></a>
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<a id="Zhang1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Z., Suzuki, Y., Shimozawa, N., Fukuda, S., Imamura, A., Tsukamoto, T., Osumi, T., Fujiki, Y., Orii, T., Wanders, R. J. A., Barth, P. G., Moser, H. W., Paton, B. C., Besley, G. T., Kondo, N.
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<strong>Genomic structure and identification of 11 novel mutations of the PEX6 (peroxisome assembly factor-2) gene in patients with peroxisome biogenesis disorders.</strong>
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Hum. Mutat. 13: 487-496, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10408779/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10408779</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10408779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:6<487::AID-HUMU9>3.0.CO;2-T" target="_blank">Full Text</a>]
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</p>
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 11/25/2020
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 08/10/2020<br>Marla J. F. O'Neill - updated : 02/20/2018<br>Marla J. F. O'Neill - updated : 02/20/2018<br>Marla J. F. O'Neill - updated : 10/27/2015<br>Ada Hamosh - updated : 1/6/2012<br>Victor A. McKusick - updated : 6/15/2004<br>Victor A. McKusick - updated : 6/22/2001<br>Victor A. McKusick - updated : 7/6/1999<br>David Valle - edited : 6/23/1997
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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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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</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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Victor A. McKusick : 11/12/1996
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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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carol : 09/29/2023
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</span>
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</div>
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</div>
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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 : 09/20/2021<br>carol : 11/25/2020<br>carol : 08/10/2020<br>carol : 12/18/2019<br>carol : 07/18/2019<br>alopez : 02/20/2018<br>alopez : 02/20/2018<br>alopez : 01/30/2017<br>carol : 09/19/2016<br>alopez : 11/03/2015<br>alopez : 10/28/2015<br>alopez : 10/27/2015<br>alopez : 9/24/2015<br>alopez : 9/24/2015<br>mcolton : 8/18/2015<br>alopez : 2/19/2015<br>alopez : 10/25/2012<br>alopez : 10/25/2012<br>alopez : 10/24/2012<br>carol : 1/9/2012<br>carol : 1/9/2012<br>terry : 1/6/2012<br>tkritzer : 7/20/2004<br>terry : 6/15/2004<br>alopez : 3/17/2004<br>alopez : 6/17/2002<br>carol : 7/6/2001<br>terry : 6/22/2001<br>jlewis : 7/21/1999<br>terry : 7/6/1999<br>terry : 5/10/1999<br>dkim : 9/10/1998<br>psherman : 6/10/1998<br>carol : 3/21/1998<br>mark : 6/23/1997<br>joanna : 6/23/1997<br>mark : 5/30/1997<br>terry : 1/16/1997<br>jamie : 1/15/1997<br>terry : 1/7/1997<br>jenny : 12/12/1996<br>mark : 12/9/1996<br>mark : 12/9/1996<br>terry : 12/9/1996<br>terry : 11/27/1996<br>terry : 11/26/1996<br>mark : 11/12/1996
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</span>
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601498
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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PEROXISOME BIOGENESIS FACTOR 6; PEX6
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<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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PEROXIN 6<br />
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PEROXISOMAL ASSEMBLY FACTOR 2; PAF2<br />
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PEROXISOMAL-TYPE ATPase 1; PXAAA1
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: PEX6</em></strong>
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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: 6p21.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 6:42,963,865-42,979,181 </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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<div>
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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="3">
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<span class="mim-font">
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6p21.1
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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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Heimler syndrome 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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616617
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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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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Peroxisome biogenesis disorder 4A (Zellweger)
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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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614862
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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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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Peroxisome biogenesis disorder 4B
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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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614863
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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 dominant; 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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</td>
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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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<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>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>Peroxisomal targeting signals (PTSs) are discrete amino acid sequences capable of directing proteins to the peroxisome. Most peroxisomal matrix proteins contain PTS1, a C-terminal tripeptide of the sequence ser-lys-leu (SKL) or a conservative variant. In contrast, the N-terminal PTS2 consists of approximately 10 amino acids (arg/lys-leu-X5-gln/his-leu) and has been observed in only 3 peroxisomal proteins. The only documented human PTS2-containing proteins are peroxisomal thiolase (604054) and phytanic acid oxidase (266500). Yahraus et al. (1996) stated that the only known human PTS2-containing protein is thiolase. The most extensively studied of the factors involved in peroxisomal protein import is the PTS1 receptor, encoded by the peroxin-5 gene (PEX5; 600414) and defective in Zellweger syndrome. Human PEX5 was originally identified by homology probing the human EST database with the S. cerevisiae PAS8 protein sequence. The continued application of this approach by Yahraus et al. (1996) led to the cloning and characterization of a novel human gene (called PXAAA1 by them) based on its similarity to PpPAS5, a gene required for peroxisome assembly in the yeast Pichia pastoris. The 980-amino acid protein product belongs to the AAA family of ATPases and appears to be a predominantly cytoplasmic protein. Yahraus et al. (1996) found that substitution of an arginine for the conserved lysine residue in the ATPase domain of the PXAAA1 protein abolished its biologic activity, suggesting that it is an ATPase. Furthermore, they showed that the protein is required for stability of the predominantly cytoplasmic PTS1 receptor. Yahraus et al. (1996) concluded that the PXAAA1 protein plays a direct role in peroxisomal protein import and is required for PTS1 receptor activity. </p><p>Distel et al. (1996) listed the peroxisomal assembly factor isolated in the rat by Tsukamoto et al. (1995) as identical to PXAAA1 (or PEX6). Tsukamoto et al. (1995) isolated rat peroxisome assembly factor-2 (PAF2) cDNA by functional complementation of the peroxisome deficiency of a mutant Chinese hamster ovary cell line, ZP92, using a transient transfection assay. This cDNA encodes a 978-amino acid protein with 2 putative ATP-binding sites. The investigators stated that PAF2 is a member of a putative ATPase family which includes 2 yeast gene products essential for peroxisome assembly. The stable transformant of ZP92 with the cDNA was morphologically and biochemically restored for peroxisome biogenesis. Fibroblasts derived from patients deficient in peroxisome biogenesis (complementation group C) were also complemented with rat PAF2 cDNA, indicating that PAF2 is a strong candidate for the site of the mutation in one peroxisomal complementation group. The proteins of the ATPase family (AAA proteins) participate in a broad range of cellular processes, as indicated by the designation AAA which comes from 'ATPases associated with diverse cellular activities.' </p><p>Fukuda et al. (1996) found that the 2,940-bp open reading frame of the human PAF2 cDNA encodes a 980-amino acid protein that shows 87.1% identity with rat PAF2. </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>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Zhang et al. (1999) determined that the PEX6 gene consists of 17 exons and 16 introns, spanning about 14 kb. The largest exon, exon 1, has at least 952 nucleotides. </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>To determine the chromosomal localization of PXAAA1, Yahraus et al. (1996) probed a panel of mouse/human hybrid cell lines with the full-length PXAAA1 cDNA. Hybridizing fragments specific for human genomic DNA were detected only in the cell lines containing human chromosome 6. The human cDNA was also used to determine the map position of the mouse ortholog by RFLP analysis of an interspecific backcross DNA panel. The mouse gene mapped to chromosome 17 between markers that show homology of synteny to human 6p22-p11. </p><p>By fluorescence in situ hybridization, Fukuda et al. (1996) mapped the human PEX6 gene to 6p21.1. </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">
|
|
<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>In an Arabidopsis pex6 mutant with defects in peroxisomal matrix protein import, oil body utilization, peroxisomal metabolism and seedling growth, Gonzalez et al. (2018) found that a pex1 missense mutation (pex1-1), uncovered in a screen for second-site suppressors, can restore the growth defect. Although a major function of PEX6 is involvement in PEX5 retrotranslocation from the peroxisomal membrane (via a PEX1-PEX6 heterohexameric ATPase), Gonzalez et al. (2018) found that the pex1-1 mutant restored seedling growth without restoring PEX5 levels. This supports the hypothesis that PEX6 has additional functions in the peroxisome beyond PEX5 recycling. </p>
|
|
</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Peroxisome Biogenesis Disorder 4A (Zellweger)</em></strong></p><p>
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Yahraus et al. (1996) observed that expression of PXAAA1 restored peroxisomal protein import in fibroblasts from 16 unrelated members of complementation group 4 of the peroxisomal biogenesis disorders (PBD4A,; 614862). Consistent with this observation, a complementation group 4 patient was found to carry mutations in PXAAA1 (601498.0001 and 601498.0002). </p><p>Fukuda et al. (1996) found that human PAF2 restores peroxisome assembly after gene transfer to fibroblasts of group C patients. In 2 patients with what they termed group C Zellweger syndrome (group 4 in the Kennedy-Krieger Institute Classification), the authors demonstrated homozygosity for 2 different mutations in the PAF2 gene. Direct sequencing of the PAF2 gene revealed a homozygous 1-bp insertion at nucleotide 510 in 1 patient (601498.0003) and a splice site mutation in intron 3 resulting in skipping of exon 3 in a second patient (601498.0004). </p><p>Zhang et al. (1999) clarified the genomic DNA structure of PEX6 and identified mutations in patients from various ethnic groups. Eleven novel mutations (18 alleles) were identified by direct sequencing of the PEX6 cDNA from 10 patients. There was no common mutation, but an exon skip was identified in 2 unrelated Japanese patients. Most of the mutations led to premature termination or large deletions of the PEX6 protein and resulted in the most severe peroxisome biogenesis disorder phenotype of Zellweger syndrome. A patient with an atypical Zellweger syndrome had a missense mutation that was shown to disrupt the cell's ability to form peroxisomes. </p><p><strong><em>Peroxisome Biogenesis Disorder 4B</em></strong></p><p>
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Matsumoto et al. (2001) provided several lines of evidence indicating that PEX6, the pathogenic gene for PBD of complementation group 4, is impaired also in complementation group 6 PBD. They found that expression of PEX6 restored peroxisome assembly in fibroblasts from a PBD patient (PBD4B; 614863) who was a compound heterozygote for PEX6 gene alleles. </p><p>Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In family M331, they identified a homozygous missense mutation in the PEX6 gene (601498.0009) in 5 sibs with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children. </p><p>Falkenberg et al. (2017) reported heterozygous mutation in the PEX6 gene resulting in a peroxisome biogenesis disorder ('Zellweger spectrum disorder,' ZSD) due to allelic expression imbalance (AEI) promoting the overrepresentation of a pathogenic allele. In 7 unrelated patients with a ZSD and 1 affected half brother, the authors identified heterozygosity for a missense mutation in the PEX6 gene (R860W; 601498.0015), which was inherited from an unaffected parent in 3 of the families. All affected individuals exhibited AEI, with mutant allele levels 3 to 5 times greater than those of the wildtype allele, whereas the heterozygous parents did not show AEI. Analysis of common variants in PEX6 revealed a polymorphic 4-bp deletion in the 3-prime UTR (rs144286892; 601498.0014) that correlated with AEI of PEX6 when present in heterozygosity but not in homozygosity, being heterozygous and located in cis with the R860W mutation in all 8 affected individuals, but homozygous in the 3 unaffected carrier parents. Functional analysis indicated that the PEX6 R860W mutation has a negative effect on PEX1 (602136)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6. </p><p><strong><em>Heimler Syndrome 2</em></strong></p><p>
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In affected individuals from 2 unrelated families with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; 616617), Ratbi et al. (2015) identified compound heterozygosity for mutations in the PEX6 gene (601498.0010-601498.0013). The authors noted that in contrast to patients with PBDs at the severe end of the clinical spectrum, these patients showed no identifiable dysmorphic or additional neurologic features. Complementation assays in PEX6-null cells with variants from patients with Heimler syndrome-2 demonstrated that all affected individuals had at least 1 PEX variant with residual activity in peroxisomal biogenesis. </p><p>In 2 sibs with HMLR2, born of consanguineous Egyptian parents, Zaki et al. (2016) identified a homozygous missense mutation (G413V; 601498.0016) in the PEX6 gene. The mutation, which was identified by genomewide linkage analysis and whole-exome sequencing, segregated with the disorder in the family. </p>
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</span>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>Nomenclature</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>Distel et al. (1996) provided a unified nomenclature for peroxisome biogenesis. By the use of genetic approaches in a wide variety of experimental organisms, 13 proteins required for peroxisome biogenesis had been identified in the previous 10 years. Three of these had been shown to be defective in lethal peroxisome biogenesis disorders (PBDs). However, the diversity of experimental systems had led to a profusion of names for peroxisome assembly genes and proteins and a great array of numbering systems. Distel et al. (1996) suggested that proteins involved in peroxisome biogenesis should be designated 'peroxins,' with PEX representing the gene acronym. Even though defects in peroxisomal metabolic enzymes or transcription factors may affect peroxisome proliferation and/or morphology, such proteins should not, they recommended, be included in this group. The proteins and genes were to be numbered by date of published characterization, both for known factors and those identified in the future. When necessary, species of origin could be specified by 1-letter abbreviations for genus and species (e.g., hsPEX2). To minimize ambiguities in naming additional proteins identified in the future, Distel et al. (1996) urged authors before publication to contact the ad hoc nomenclature committee. </p>
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</span>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>16 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</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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PEX6, IVSAS, G-A, -1, 8-BP DEL
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<br />
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SNP: rs267608229,
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gnomAD: rs267608229,
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ClinVar: RCV000665084, RCV001280661, RCV002224971, RCV003472068, RCV005034234
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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>After demonstrating that a newly isolated gene they called PXAAA1 corrected the defect in complementation group 4 PBD, Yahraus et al. (1996) used a gene-specific primer to synthesize PXAAA1 cDNA from normal and group 4 (CG4; PBD4A, 614862) fibroblasts. Fragments of the open reading frame were then amplified by PCR and subjected to SSCP analysis. PXAAA1 SSCP migration variants were detected in 9 of 13 CG4 patients examined, even though only 40% of the ORF had been examined. Direct sequencing of RT-PCR-generated cDNA fragments revealed that one patient was a compound heterozygote for 2 different deletions: an 8-bp deletion (nucleotides 1962-1969), and a 20-bp deletion (nucleotides 2398-2417) together with insertion of a single T (601498.0002). Direct sequencing of amplified genomic DNA revealed that 1 allele contained a G-to-A transition at the -1 position of a splice acceptor site. This resulted in the use of a cryptic splice acceptor site 8 bp downstream of the normal site, generating the 8-bp deletion observed in the cDNA. The father was heterozygous for this splice site mutation. The mother was found to be heterozygous for the 20-bp deletion/1-bp insertion found in the other allele of the patient. Both mutations in this patient (whose cell line had the designation PBD106) shifted the reading frame of the PXAAA1 mRNA. The product of the first allele lacked the C-terminal 326 amino acids of the protein product and instead contained the 3 amino acids trp-leu-asp (WLD) in their place. The product of the second allele lacked the C-terminal 181 amino acids and instead contained 15 novel amino acids. Previous studies cited by Yahraus et al. (1996) demonstrated that mutations which affect the reading frame of an mRNA commonly result in mRNA instability and decreased steady-state levels of mRNA. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</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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PEX6, 20-BP DEL/1-BP INS
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<br />
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SNP: rs62653602,
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gnomAD: rs62653602,
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ClinVar: RCV000734495, RCV001243165, RCV002279940, RCV003472271, RCV005036073
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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>For discussion of the 20-bp deletion (nucleotides 2398-2417) and insertion of a single T in the PEX6 gene that was found in compound heterozygous state in PBD4A (614862) fibroblasts by Yahraus et al. (1996), see 601498.0001. </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 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</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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PEX6, 1-BP INS, NT511
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<br />
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SNP: rs1491384052,
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ClinVar: RCV000665973, RCV000780593, RCV002279939
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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 cell line from a patient with typical clinical features of Zellweger syndrome (PBD4A; 614862) and ghost peroxisomes (GM04340 in the Coriell Cell Repositories), Fukuda et al. (1996) identified homozygosity for a 1-bp insertion at nucleotide 511 which introduced a premature termination codon in the PXAAA1 gene. The patient was the product of a father-daughter mating. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</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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PEX6, IVS3DS, G-A, +1
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<br />
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SNP: rs267608213,
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ClinVar: RCV000008592, RCV001239904
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In a Japanese girl with Zellweger syndrome, complementation group C (PBD4A; 614862), born of nonconsanguineous parents Fukuda et al. (1996) identified a heterozygous mutation in the consensus 5-prime splice site of intron 3 (IVS3+1G-to-A), which led to skipping of exon 3. The patient at birth was small and had severe asphyxia, profound hypotonia, and clonic convulsions. The patient died of respiratory failure at age 7 months. An insertion introducing frameshift in the transcript from the other allele was also detected. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</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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PEX6, IVS7, G-A, +1
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<br />
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SNP: rs112298166,
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ClinVar: RCV000008594, RCV002512914, RCV003473057
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 unrelated Japanese patients with severe Zellweger syndrome of complementation group C (PBD4A; 614862), Zhang et al. (1999) found homozygosity for a G-to-A transition in the first position of intron 7 of the PEX6 gene. Two abnormal splicing patterns were caused by this mutation: one a skipping of exon 7, and the other a skipping of exons 6 and 7. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 PEROXISOME BIOGENESIS DISORDER 4A (ZELLWEGER)</strong>
|
|
</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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PEX6, 1-BP DEL, 1301C
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<br />
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SNP: rs62641231,
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gnomAD: rs62641231,
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ClinVar: RCV000008596
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a case of severe Zellweger syndrome (PBD4A; 614862) surviving to the age of 8.5 months, Zhang et al. (1999) found homozygosity for a 1-bp deletion, 1301delC. This deletion resulted in a frameshift at serine codon 434 and the creation of a premature termination at codon 449. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PEROXISOME BIOGENESIS DISORDER 4B</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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PEX6, 264-BP DEL, NT619
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<br />
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SNP: rs1554128347,
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ClinVar: RCV000008598
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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 patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) belonging to complementation group 6 of the peroxisome biogenesis disorders (PBD4B; 614863), Matsumoto et al. (2001) found compound heterozygosity for mutations in the PEX6 gene. One allele had a deletion of nucleotides 619-882 of PEX6; the other allele had a deletion of nucleotides 2095-2362 and an insertion of 21 nucleotides (601498.0008). This patient had been described by Kelley et al. (1986) as Patient 6. </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>.0008 PEROXISOME BIOGENESIS DISORDER 4B</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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PEX6, 269-BP DEL/21-BP INS
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<br />
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ClinVar: RCV000008599
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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>For discussion of the deletion of nucleotides 2095-2362 along with an insertion of 21 nucleotides in the PEX6 gene that was found in compound heterozygous state in a patient with a diagnosis of neonatal adrenoleukodystrophy (NALD) belonging to complementation group 6 of the peroxisome biogenesis disorders (PBD4B; 614863) by Matsumoto et al. (2001), see 601498.0007. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>.0009 PEROXISOME BIOGENESIS DISORDER 4B</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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PEX6, LEU534PRO
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<br />
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SNP: rs387906809,
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ClinVar: RCV000023114
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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 family M331 (PBD4B; 614863), Najmabadi et al. (2011) identified a homozygous A-to-G mutation in the PEX6 gene at genomic coordinate chr6:43,044,093 (NCBI36), resulting in a leu534-to-pro (L534P) substitution, in 5 sibs with moderate intellectual disability, retinitis pigmentosa, hearing loss, and ataxia. Their parents, who were second cousins, had 6 healthy children. </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>.0010 HEIMLER SYNDROME 2</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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PEX6, PRO274LEU
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<br />
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SNP: rs61753219,
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gnomAD: rs61753219,
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ClinVar: RCV000201297, RCV000622824, RCV000666553, RCV000735222, RCV001193476, RCV001276623, RCV001808558, RCV002243878, RCV004737319, RCV005031753
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 sisters with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; 616617), Ratbi et al. (2015) identified compound heterozygosity for a c.821C-T transition (c.821C-T, NM_000287.3) in the PEX6 gene, resulting in a pro274-to-leu (P274L) substitution, and a c.1930C-T transition, resulting in an arg644-to-trp (R644W; 601498.0011) substitution. Both mutations segregated with disease in the family; the previously unreported R644W mutation was not found in 770 in-house exomes, but was present in 4 of 121,396 alleles in the ExAC Browser (minor allele frequency less than 0.000033). Ratbi et al. (2015) noted that the P274L mutation had been detected by Steinberg et al. (2004) in 2 patients with peroxisome biogenesis disorder (PBD) Zellweger syndrome spectrum (see 614862 and 614863), in compound heterozygosity with a splice site mutation and a frameshift mutation, respectively. No clinical information was reported for the Zellweger syndrome spectrum patients, although it was stated that inclusion criteria for the panel under study were elevated very-long-chain fatty acids (VLCFA) with deficient plasmalogen synthesis, and/or mislocalization of catalase (115500), and/or elevated VLCFA and pipecolate. Analysis of plasma, erythrocytes, and fibroblasts from the sisters with Heimler syndrome-2 by Ratbi et al. (2015) did not show any peroxisomal biochemical aberrations, consistent with their relatively very mild disease; however, immunofluorescence microscopy of Heimler patient fibroblasts revealed a mosaic peroxisomal pattern similar to that previously associated with hypomorphic variants. In complementation assays, transfection of PEX1-null cells with the c.821C-T and c.1930C-T variants rescued peroxisomal biogenesis in approximately 2% and 20% of cells, respectively. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0011 HEIMLER SYNDROME 2</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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PEX6, ARG644TRP
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<br />
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SNP: rs769896492,
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gnomAD: rs769896492,
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ClinVar: RCV000201306, RCV001328449, RCV001853224, RCV004737320, RCV005031754
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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>For discussion of the c.1930C-T transition (c.1930C-T, NM_000287.3) in the PEX6 gene, resulting in an arg644-to-trp (R644W) substitution, that was found in compound heterozygous state in 2 sisters with Heimler syndrome-2 (HMLR2; 616617) by Ratbi et al. (2015), see 601498.0010. </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>.0012 HEIMLER SYNDROME 2</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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PEX6, ARG601GLN
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<br />
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SNP: rs34324426,
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gnomAD: rs34324426,
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ClinVar: RCV000180127, RCV000201298, RCV000424129, RCV000675148, RCV000779504, RCV000850505, RCV001075628, RCV001081170, RCV001265584, RCV003987426
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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 monozygotic twin sisters with sensorineural hearing loss, enamel hypoplasia, and nail defects (HMLR2; 616617), originally reported by Ong et al. (2006), Ratbi et al. (2015) identified compound heterozygosity for a c.1802G-A transition (c.1802G-A, NM_000287.3) in exon 8 of the PEX6 gene, resulting in an arg601-to-gln (R601Q) substitution, and a 1-bp deletion (c.1841del; 601498.0013) causing a frameshift resulting in a premature termination codon (Leu614ArgfsTer5). Both mutations segregated with disease in the family, and the previously unreported 1-bp deletion was not found in 770 in-house exomes or in public databases. Ratbi et al. (2015) stated that the R601Q mutation had previously been detected in compound heterozygosity in 7 patients with a Zellweger spectrum disorder (see 614862 and 614863) by Yik et al. (2009) and Ebberink et al. (2010). No clinical information was reported for the 7 patients diagnosed with Zellweger spectrum disorder. Noting that the PEX6 c.1082G-A allele is present in the ExAC database at a frequency of 0.41% in the European population, Ratbi et al. (2015) predicted that future whole-exome sequencing would identify additional mildly affected individuals. In complementation assays, transfection of PEX1-null cells with the c.1802G-A and c.1841del variants rescued peroxisomal biogenesis in more than 30% and in no cells, respectively. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0013 HEIMLER SYNDROME 2</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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PEX6, 1-BP DEL, NT1841
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<br />
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SNP: rs863225083,
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gnomAD: rs863225083,
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ClinVar: RCV000201289, RCV000674727, RCV001008824, RCV001853225, RCV002517303, RCV005031755
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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>For discussion of the 1-bp deletion (c.1841del, NM_000287.3) in the PEX6 gene, causing a frameshift resulting in a premature termination codon (Leu614ArgfsTer5), that was found in compound heterozygous state in twin sisters with Heimler syndrome-2 (HMLR2; 616617) by Ratbi et al. (2015), see 601498.0012. </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>.0014 PEX6 POLYMORPHISM</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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PEX6, 4-BP DEL, +442TAAA, 3-PRIME UTR ({dbSNP rs144286892})
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<br />
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SNP: rs144286892,
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gnomAD: rs144286892,
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ClinVar: RCV000360304, RCV000584757, RCV000734624, RCV000960459, RCV001522195, RCV003388935
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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>Falkenberg et al. (2017) noted that a 4-bp deletion in the 3-prime UTR of the PEX6 gene (c.*442_445delTAAA, NM_000287.3; rs144286892) is a commonly occurring polymorphism, with a minor allele frequency of 35% in the 1000 Genomes Project database. The variant disrupts the more distal of 2 known polyadenylation signals of PEX6, located at c.*440_445, resulting in a PEX6 mRNA with a shorter 3-prime UTR (c.*1_*326, versus c.*1_*462). Falkenberg et al. (2017) performed quantitative analysis of PEX6 mRNA expression in fibroblast cell lines with different PEX6 allele combinations and confirmed that the PEX6 c.*442_445delTAAA allele does not produce the longer PEX6 c.*1_462 mRNA. Nevertheless, the total levels of PEX6 mRNA expressed by the PEX6 c.*442_445delTAAA allele were consistently higher than those expressed by the allele without the deletion. Thus allelic expression imbalance (AEI) of PEX6 occurs in all cell lines heterozygous for c.*442_445delTAAA, but not in cell lines homozygous for the polymorphism. Sanger sequencing of PEX6 cDNAs of 22 different fibroblast cell lines from unrelated controls showed AEI of PEX6 in more than 40% of the cell lines, demonstrating that AEI is a common feature of PEX6. </p><p><strong><em>Peroxisome Biogenesis Disorder 4B</em></strong></p><p>
|
|
In 7 unrelated patients with a Zellweger spectrum disorder (PBD4B; 614863) and 1 affected half brother, Falkenberg et al. (2017) identified heterozygosity for an R860W mutation in the PEX6 gene (601498.0015) that was inherited from an unaffected parent in 3 of the families. The authors demonstrated that all affected individuals were also heterozygous for the c.*442_445delTAAA polymorphism in the 3-prime UTR of the mutant allele. Affected individuals exhibited AEI, with levels of the mutant allele that were 3 to 5 times higher than the wildtype allele, whereas the unaffected parents were homozygous for the polymorphic variant and did not show AEI. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 PEROXISOME BIOGENESIS DISORDER 4B</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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PEX6, ARG860TRP ({dbSNP rs61753230}) AND 4-BP DEL, +442TAAA, 3-PRIME UTR ({dbSNP rs144286892})
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<br />
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|
|
SNP: rs61753230,
|
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|
|
ClinVar: RCV000360304, RCV000584757, RCV000734624, RCV000802431, RCV000960459, RCV001522195, RCV002248804, RCV003388935, RCV004696954
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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 7 unrelated patients with a Zellweger spectrum disorder (PBD4B; 614863) and 1 affected half brother, Falkenberg et al. (2017) identified heterozygosity for a c.2578C-T transition (c.2578C-T, NM_000287.3) in the PEX6 gene, resulting in an arg860-to-trp (R860W) substitution at a highly conserved residue that constitutes the arginine finger 2 in the second region of homology (SRH) of the ATP-binding D2 domain. The mutation occurred de novo in 2 patients, but was shown to have been inherited from an unaffected parent in 3 of the families (parental DNA was unavailable from the remaining 2 families). All affected individuals exhibited allelic expression imbalance (AEI), with levels of the mutant allele 3 to 5 times greater than the wildtype allele, whereas the heterozygous parents did not show AEI. Analysis of common variants in PEX6 revealed an AEI-associated polymorphism (rs144286892; 601498.0014) that was present in heterozygosity on the mutant allele in all 8 affected individuals, but for which the 3 unaffected carrier parents were homozygous. Overexpression of the R860W mutant in control fibroblasts resulted in an accumulation of PEX5 (600414) at the peroxisomal membranes and a concomitant defect of catalase import into peroxisomes. Coexpression of mutant and wildtype PEX6 in various ratios in PEX6-deficient fibroblasts demonstrated a significant negative correlation between restoration of peroxisomal matrix protein import and the ratio of mutant to wildtype PEX6. Falkenberg et al. (2017) concluded that the PEX6 R860W mutation exerts a dominant-negative effect on PEX1 (602136)-PEX6 complex function, but results in a disease phenotype only when PEX6 R860W is at least 2 to 3 times more abundant than wildtype PEX6. </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>.0016 HEIMLER SYNDROME 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
PEX6, GLY413VAL
|
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<br />
|
|
|
|
SNP: rs1554127531,
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|
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|
|
|
|
|
ClinVar: RCV000672797, RCV001268931, RCV004586868, RCV005034267
|
|
|
|
|
|
</span>
|
|
</div>
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sibs, born to consanguineous Egyptian parents, with Heimler syndrome-2 (HMLR2; 616617), Zaki et al. (2016) identified a homozygous c.1238G-T transversion (c.1238G-T, NM_000287.3) in exon 5 of the PEX6 gene, resulting in a gly413-to-val (G413V) substitution at a conserved residue in the HBD domain. The mutation, which was found by genomewide linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing. The parents were confirmed to be carriers. Functional studies were not performed. </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>
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|
</span>
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</h4>
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<div>
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Distel, B., Erdmann, R., Gould, S. J., Blobel, G., Crane, D. I., Cregg, J. M., Dodt, G., Fujiki, Y., Goodman, J. M., Just, W. W., Kiel, J. A. K. W., Kunau, W.-H., Lazarow, P. B., Mannaerts, G. P., Moser, H. W., Osumi, T., Rachubinski, R. A., Roscher, A., Subramani, S., Tabak, H. F., Tsukamoto, T., Valle, D., van der Klei, I., van Veldhoven, P. P., Veenhuis, M.
|
|
<strong>A unified nomenclature for peroxisome biogenesis factors.</strong>
|
|
J. Cell Biol. 135: 1-3, 1996.
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[PubMed: 8858157]
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[Full Text: https://doi.org/10.1083/jcb.135.1.1]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ebberink, M. S., Koster, J., Wanders, R. J. A., Waterham, H. R.
|
|
<strong>Spectrum of PEX6 mutations in Zellweger syndrome spectrum patients.</strong>
|
|
Hum. Mutat. 31: E1058-E1070, 2010. Note: Electronic Article.
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|
[PubMed: 19877282]
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[Full Text: https://doi.org/10.1002/humu.21153]
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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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Falkenberg, K. D., Braverman, N. E., Moser, A. B., Steinberg, S. J., Klouwer, F. C. C., Schluter, A., Ruiz, M., Pujol, A., Engvall, M., Naess, K., van Spronsen, F., Korver-Keularts, I., Rubio-Gozalbo, M. E., Ferdinandusse, S., Wanders, R. J. A., Waterham, H. R.
|
|
<strong>Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder.</strong>
|
|
Am. J. Hum. Genet. 101: 965-976, 2017.
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[PubMed: 29220678]
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[Full Text: https://doi.org/10.1016/j.ajhg.2017.11.007]
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</p>
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<li>
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<p class="mim-text-font">
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Fukuda, S., Shimozawa, N., Suzuki, Y., Zhang, Z., Tomatsu, S., Tsukamoto, T., Hashiguchi, N., Osumi, T., Masuno, M., Imaizumi, K., Kuroki, Y., Fujiki, Y., Orii, T., Kondo, N.
|
|
<strong>Human peroxisome assembly factor-2 (PAF-2): a gene responsible for group C peroxisome biogenesis disorder in humans.</strong>
|
|
Am. J. Hum. Genet. 59: 1210-1220, 1996.
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[PubMed: 8940266]
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<p class="mim-text-font">
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Gonzalez, K. L., Ratzel, S. E., Burks, K. H., Danan, C. H., Wages, J. M., Zolman, B. k., Bartel, B.
|
|
<strong>A pex1 missense mutation improves peroxisome function in a subset of Arabidopsis pex6 mutants without restoring PEX5 recycling.</strong>
|
|
Proc. Nat. Acad. Sci. 115: E3163-E3172, 2018.
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[PubMed: 29555730]
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[Full Text: https://doi.org/10.1073/pnas.1721279115]
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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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Kelley, R. I., Datta, N. S., Dobyns, W. B., Hajra, A. K., Moser, A. B., Noetzel, M. J., Zackai, E. H., Moser, H. W.
|
|
<strong>Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes.</strong>
|
|
Am. J. Med. Genet. 23: 869-901, 1986.
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[PubMed: 3515938]
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[Full Text: https://doi.org/10.1002/ajmg.1320230404]
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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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Matsumoto, N., Tamura, S., Moser, A., Moser, H. W., Braverman, N., Suzuki, Y., Shimozawa, N., Kondo, N., Fujiki, Y.
|
|
<strong>The peroxin Pex6p gene is impaired in peroxisomal biogenesis disorders of complementation group 6.</strong>
|
|
J. Hum. Genet. 46: 273-277, 2001.
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|
[PubMed: 11355018]
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[Full Text: https://doi.org/10.1007/s100380170078]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., Zecha, A., Mohseni, M., and 33 others.
|
|
<strong>Deep sequencing reveals 50 novel genes for recessive cognitive disorders.</strong>
|
|
Nature 478: 57-63, 2011.
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|
[PubMed: 21937992]
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[Full Text: https://doi.org/10.1038/nature10423]
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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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Ong, K. R., Visram, S., McKaig, S., Brueton, L. A.
|
|
<strong>Sensorineural deafness, enamel abnormalities and nail abnormalities: a case report of Heimler syndrome in identical twin girls.</strong>
|
|
Europ. J. Med. Genet. 49: 187-193, 2006.
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|
[PubMed: 16530715]
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[Full Text: https://doi.org/10.1016/j.ejmg.2005.07.003]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Ratbi, I., Falkenberg, K. D., Sommen, M., Al-Sheqaih, N., Guaoua, S., Vandeweyer, G., Urquhart, J. E., Chandler, K. E., Williams, S. G., Roberts, N. A., El Alloussi, M., Black, G. C., and 19 others.
|
|
<strong>Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6.</strong>
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Zhang, Z., Suzuki, Y., Shimozawa, N., Fukuda, S., Imamura, A., Tsukamoto, T., Osumi, T., Fujiki, Y., Orii, T., Wanders, R. J. A., Barth, P. G., Moser, H. W., Paton, B. C., Besley, G. T., Kondo, N.
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