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Entry
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- *608944 - FRAS1-RELATED EXTRACELLULAR MATRIX PROTEIN 1; FREM1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608944</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</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="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608944">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 role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000164946;t=ENST00000380880" 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=158326" 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=608944" 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="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=ENSG00000164946;t=ENST00000380880" 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_001177704,NM_001370058,NM_001370060,NM_001370061,NM_001370063,NM_001370065,NM_001379081,NM_144966,NR_163238,NR_163239,NR_163240,NR_163241,NR_163242,XM_006716729,XM_011517758,XM_017014316,XM_017014319,XM_017014320,XM_017014321,XM_017014322,XM_017014324,XM_017014325,XM_017014326,XM_017014327,XM_017014328,XM_017014329,XM_017014330,XM_047422844,XM_047422845,XM_047422846,XM_047422847,XM_047422848,XM_047422849,XM_047422850,XM_047422851,XM_047422852,XM_047422853,XM_047422854,XM_047422855,XM_047422856,XM_047422857,XM_047422858,XM_047422859" 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_001379081" 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=608944" 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=09865&isoform_id=09865_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/FREM1" 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/16554267,34365423,58430435,71051484,119579092,119579093,119579094,122056683,215274141,295293182,578816397,767954574,1034663933,1034663939,1034663941,1034663943,1034663945,1034663950,1034663952,1034663954,1034663956,1034663958,1034663960,1034663966,1624763215,1624763219,1624763221,1624763229,1624763237,1822188089,2217375697,2217375699,2217375705,2217375707,2217375709,2217375717,2217375719,2217375721,2217375723,2217375725,2217375727,2217375729,2217375732,2217375734,2217375736,2217375740,2462622910,2462622912,2462622914,2462622916,2462622918,2462622920,2462622922,2462622924,2462622926,2462622928,2462622931,2462622933,2462622935,2462622937,2462622939,2462622941,2462622943,2462622945,2462622947,2462622949,2462622951,2462622953,2462622955,2462622957,2462622959,2462622961,2462622963,2462622965,2462622967,2462622969,2462622971" 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/Q5H8C1" 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=158326" 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=ENSG00000164946;t=ENST00000380880" 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=FREM1" 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=FREM1" 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+158326" 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/FREM1" 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:158326" 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/158326" 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=chr9&hgg_gene=ENST00000380880.4&hgg_start=14737152&hgg_end=14910995&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:23399" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608944[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=608944[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/FREM1/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/ENSG00000164946" 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=FREM1" 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=FREM1" 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=FREM1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=FREM1&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/PA134892147" 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:23399" 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://www.mousephenotype.org/data/genes/MGI:2670972" 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/FREM1#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:2670972" 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/158326/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=158326" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-050208-783" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<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:158326" 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=FREM1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 703539006, 717940006<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
608944
|
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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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FRAS1-RELATED EXTRACELLULAR MATRIX PROTEIN 1; FREM1
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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">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
CHROMOSOME 9 OPEN READING FRAME 154; C9ORF154
|
|
</span>
|
|
</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=FREM1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">FREM1</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/9/56?start=-3&limit=10&highlight=56">9p22.3</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:14737152-14910995&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'})">9:14,737,152-14,910,995</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</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">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=608980,248450,614485" 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/9/56?start=-3&limit=10&highlight=56">
|
|
9p22.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Bifid nose with or without anorectal and renal anomalies
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/608980"> 608980 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</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>
|
|
</td>
|
|
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</tr>
|
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Manitoba oculotrichoanal syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/248450"> 248450 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p><a href="#9" class="mim-tip-reference" title="Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. <strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong> Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[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.0402760101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345741">Smyth et al. (2004)</a> cloned the mouse Frem1 gene, which encodes a deduced 2,191-amino acid protein. By searching sequence databases, they identified human FREM1. The mouse and human FREM1 proteins contain an N-terminal signal peptide, 12 chondroitin sulfate proteoglycan (CSPG; see <a href="/entry/118661">118661</a>) repeats, a calcium-binding loop similar to those of sodium-calcium exchangers (see <a href="/entry/182305">182305</a>), and a C-terminal C-type lectin (see <a href="/entry/605999">605999</a>) domain. FREM1 also has sites for N- and O-glycosylation. FREM1 shares significant similarity with FRAS1 (<a href="/entry/607830">607830</a>), particularly through the CSPG repeats, but FREM1 lacks additional domains found in FRAS1. In situ hybridization and immunohistochemical analysis detected wide Frem1 expression during mouse embryonic development in the dermis and in a number of differentiating epidermal structures, such as mammary and meibomian glands, teeth, and hair follicles. Expression appeared in regions of epithelial-mesenchymal interaction and epidermal remodeling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15345741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. <strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong> Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[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.2009.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19732862">Alazami et al. (2009)</a> assayed Frem1 expression in mouse embryos and found strong and specific staining in the snout as well as in the midline where the 2 medial nasal processes fuse. In situ hybridization revealed that Frem1 expression in the nose was primarily in the epithelial-mesenchymal transitional region at the midline. Based on these studies and the identification of mutations in the FREM1 gene in patients with bifid nose (see MOLECULAR GENETICS), <a href="#2" class="mim-tip-reference" title="Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. <strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong> Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[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.2009.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19732862">Alazami et al. (2009)</a> concluded that FREM1 plays an important role in fusion of the nasal processes during gestation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19732862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. <strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong> PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21931569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21931569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21931569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21931569">Vissers et al. (2011)</a> performed in situ hybridization of mouse embryos from mid to late gestation (E14.5-E16.5) and observed expression of Frem1 between the developing frontal bones in the region fated to form the posterior frontal suture. Antibody staining at P0 highlighted fibrillar pericranial expression of Frem1 overlying the developing frontal bones as well as staining in the dura mater underlying those bones. Low levels of diffuse Frem1 staining were also noted in the osteogenic precursors between the frontal bones, further suggesting a role for the protein in the development of the posterior frontal suture. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21931569" 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="#9" class="mim-tip-reference" title="Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. <strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong> Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[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.0402760101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345741">Smyth et al. (2004)</a> determined that the mouse Frem1 gene contains 36 coding exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15345741" 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="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> noted that the FREM1 gene maps to chromosome 9p22.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21507892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. <strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong> Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[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.0402760101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345741">Smyth et al. (2004)</a> mapped the mouse Frem1 gene to chromosome 4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15345741" 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>Bifid Nose with or without Anorectal and Renal Anomalies</em></strong></p><p>
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In affected members of 3 consanguineous families with bifid nose with or without anorectal and renal anomalies (BNAR; <a href="/entry/608980">608980</a>) mapping to chromosome 9p23-p22.2, including an Egyptian Arab family originally reported by <a href="#1" class="mim-tip-reference" title="Al-Gazali, L. I., Bakir, M., Hamud, O. A., Gerami, S. <strong>An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations.</strong> Clin. Dysmorph. 11: 33-38, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11822703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11822703</a>] [<a href="https://doi.org/10.1097/00019605-200201000-00007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11822703">Al-Gazali et al. (2002)</a>, <a href="#2" class="mim-tip-reference" title="Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. <strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong> Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[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.2009.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19732862">Alazami et al. (2009)</a> sequenced the FREM1 gene and identified homozygosity for a 1-bp deletion and 2 missense mutations, respectively (<a href="#0001">608944.0001</a>-<a href="#0003">608944.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11822703+19732862" 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="Brischoux-Boucher, E., Dahlen, E., Bronier, C., Nobili, F., Marcoux, E., Alkuraya, F. S., Van Maldergem, L. <strong>Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. (Letter)</strong> Clin. Genet. 98: 515-516, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32926405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32926405</a>] [<a href="https://doi.org/10.1111/cge.13821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32926405">Brischoux-Boucher et al. (2020)</a> performed microarray-based comparative genomic hybridization on a Turkish brother and sister with BNAR and detected a homozygous 30- to 52-kb in-frame microdeletion at 9p22.3 encompassing exons 19-30 of the FREM1 gene (<a href="#0010">608944.0010</a>) in both sibs. PCR confirmed biparental inheritance. The brother had unilateral renal agenesis and bifid nose; the sister had only bifid nose. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32926405" 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>Manitoba Oculotrichoanal Syndrome</em></strong></p><p>
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In 8 patients from 5 families with Manitoba oculotrichoanal syndrome (MOTA; <a href="/entry/248450">248450</a>), <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> identified homozygous or compound heterozygous mutations in the FREM1 gene (<a href="#0004">608944.0004</a>-<a href="#0007">608944.0007</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21507892" 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>Trigonocephaly</em></strong></p><p>
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<a href="#10" class="mim-tip-reference" title="Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. <strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong> PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21931569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21931569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21931569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21931569">Vissers et al. (2011)</a> analyzed the FREM1 gene in 104 patients with nonsyndromic trigonocephaly (see TRIGNO2; <a href="/entry/614485">614485</a>) and identified missense mutations in 3 patients (<a href="#0008">608944.0008</a> and <a href="#0009">608944.0009</a>) that were not found in control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21931569" 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="#9" class="mim-tip-reference" title="Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. <strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong> Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[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.0402760101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345741">Smyth et al. (2004)</a> determined that the mouse Frem1 gene is mutated in the spontaneous 'head blebs' (heb) mutation and in the N-ethyl-N-nitrosourea-induced 'bat' mutation. Both mutations cause a truncation of the Frem1 protein and result in blebbing diseases similar to Fraser syndrome (<a href="/entry/219000">219000</a>) and dystrophic epidermolysis bullosa (DEB; <a href="/entry/131750">131750</a>) in human. Heb homozygous fetuses are characterized by cryptophthalmos and blebs restricted to the head, with the epidermis apparently normal after birth. <a href="#9" class="mim-tip-reference" title="Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. <strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong> Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[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.0402760101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345741">Smyth et al. (2004)</a> found that homozygous bat mice displayed embryonic blebbing from about 13.5 days postcoitum that invariably affected the developing eyes. Adult bat homozygotes also displayed cryptophthalmos, and about 20% had unilateral renal agenesis, which is not seen in heb homozygotes. The epidermis of bat embryos separated from the dermis below the level of the lamina densa in a manner analogous to that observed in patients with DEB. <a href="#9" class="mim-tip-reference" title="Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J. <strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong> Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[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.0402760101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15345741">Smyth et al. (2004)</a> concluded that Frem1 is required for epidermal adhesion during embryonic development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15345741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Kiyozumi, D., Sugimoto, N., Sekiguchi, K. <strong>Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects.</strong> Proc. Nat. Acad. Sci. 103: 11981-11986, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880404</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880404[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.0601011103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880404">Kiyozumi et al. (2006)</a> found that Frem1-knockout mice had reduced localization of Fras1 and Frem2 (<a href="/entry/608945">608945</a>) to the epidermal basement membrane. Similarly, Frem2-mutant 'myelencephalic blebs' (my) mice showed depletion of Frem2, as well as Fras1 and Frem1, at the basement membrane. When coexpressed and secreted in transfected cells, Fras1, Frem1, and Frem2 formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane was due to complex formation. <a href="#6" class="mim-tip-reference" title="Kiyozumi, D., Sugimoto, N., Sekiguchi, K. <strong>Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects.</strong> Proc. Nat. Acad. Sci. 103: 11981-11986, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880404</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880404[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.0601011103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16880404">Kiyozumi et al. (2006)</a> suggested that coordinated assembly of the 3 Fraser syndrome-associated proteins at the basement membrane is instrumental in epidermal-dermal interactions during morphogenetic processes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16880404" 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="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> examined Frem1-mutant mice and identified a small but statistically significant proportion of homozygous Frem1 bat/bat mutant animals with anal prolapse, which was not observed in heterozygous or wildtype littermates. Histologic analysis revealed protrusion of the rectal epithelia and an immune infiltrate in exposed tissue, but not in internal mucosa. The musculature of the anal sphincter was present but misplaced; gross malformations in rectal musculature were not apparent. Examination of Frem1-mutant eyes at birth showed that although the majority of animals presented with frank cryptophthalmos, a subset exhibited defects strikingly similar to the eyelid coloboma seen in MOTA, seemingly affecting only 1 part of the eyelid. Histologic analysis demonstrated that these defects were associated with a number of ocular malformations including failure of eyelid formation, defects in the formation of the conjunctiva, and absence of corneal epithelium leading to fibrosis. Morphologic analysis of craniofacial shape in Frem1-deficient mice showed that homozygous mutants had reduced snout length compared to controls, and also had significantly shorter philtrum-columella height, greater intercanthal distance, and greater midface asymmetry compared to heterozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21507892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. <strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong> PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21931569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21931569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21931569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21931569">Vissers et al. (2011)</a> studied C57BL/6J mice carrying the ENU-generated Frem1(bat) mutation, which is thought to represent a hypomorphic allele rather than a null allele. Morphometric analysis of skulls from homozygous and heterozygous mutant mice demonstrated craniofacial malformations consistent with the craniofacial features seen in the 9p22 deletion syndrome (<a href="/entry/158170">158170</a>), in particular metopic craniosynostosis (<a href="/entry/614485">614485</a>) and midface asymmetry and/or hypoplasia. The penetrance of the phenotypes in mice correlated to mutant gene dosage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21931569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Jordan, V. K., Beck, T. F., Hernandez-Garcia, A., Kundert, P. N., Kim, B.-J., Jhangiani, S. N., Gambin, T., Starkovich, M., Punetha, J., Paine, I. S., Posey, J. E., Li, A. H., and 11 others. <strong>The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.</strong> Hum. Molec. Genet. 27: 2064-2075, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29618029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29618029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29618029[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/10.1093/hmg/ddy110" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29618029">Jordan et al. (2018)</a> dissected the diaphragms of E16.5 Frem1-deficient (eyes2/eyes2) mice on an inbred B6Brd/129S6 background and observed that development of sac hernias is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29618029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a consanguineous Egyptian Arab family with bifid nose with or without anorectal and renal anomalies (BNAR; <a href="/entry/608980">608980</a>), originally reported by <a href="#1" class="mim-tip-reference" title="Al-Gazali, L. I., Bakir, M., Hamud, O. A., Gerami, S. <strong>An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations.</strong> Clin. Dysmorph. 11: 33-38, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11822703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11822703</a>] [<a href="https://doi.org/10.1097/00019605-200201000-00007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11822703">Al-Gazali et al. (2002)</a>, <a href="#2" class="mim-tip-reference" title="Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. <strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong> Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[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.2009.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19732862">Alazami et al. (2009)</a> identified homozygosity for a 1-bp deletion (2721delG) in exon 16 of the FREM1 gene, predicted to cause a frameshift at amino acid 908 and result in premature termination 17 residues downstream. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11822703+19732862" 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 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</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">rs121912609 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912609;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=rs121912609" 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=rs121912609" 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=RCV000002066 OR RCV000059637 OR RCV003987307 OR RCV005041970" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002066, RCV000059637, RCV003987307, RCV005041970" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002066...</a>
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<p>In affected members of a consanguineous Afghan family with bifid nose with or without anorectal and renal anomalies (BNAR; <a href="/entry/608980">608980</a>), <a href="#2" class="mim-tip-reference" title="Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. <strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong> Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[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.2009.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19732862">Alazami et al. (2009)</a> identified homozygosity for a 1945C-T transition in exon 11 of the FREM1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue. The mutation was not found in 121 Afghan or 97 Indian subcontinental controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19732862" 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 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</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> rs121912610 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912610;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/rs121912610?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=rs121912610" 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=rs121912610" 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=RCV000002067 OR RCV000059639 OR RCV003987308 OR RCV005049312" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002067, RCV000059639, RCV003987308, RCV005049312" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002067...</a>
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<p>In affected members of a consanguineous Pakistani family with bifid nose with or without anorectal and renal anomalies (BNAR; <a href="/entry/608980">608980</a>), <a href="#2" class="mim-tip-reference" title="Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S. <strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong> Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[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.2009.08.010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19732862">Alazami et al. (2009)</a> identified homozygosity for a 4318G-A transition in exon 24 of the FREM1 gene, resulting in a gly1440-to-ser (G1440S) substitution at a highly conserved residue. The mutation was not found in 97 Indian subcontinental or 121 Afghan controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19732862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 MANITOBA OCULOTRICHOANAL SYNDROME</strong>
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FREM1, 60.1-KB DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000023741" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023741" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023741</a>
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<p>In a male patient from an Oji-Cree family with Manitoba oculotrichoanal syndrome (MOTA; <a href="/entry/248450">248450</a>), and 2 patients with MOTA from an unrelated Cree/Ojibway kindred, previously described by <a href="#7" class="mim-tip-reference" title="Li, C., Marles, S. L., Greenberg, C. R., Chodirker, B. N., van de Kamp, J., Slavotinek, A., Chudley, A. E. <strong>Manitoba oculotrichoanal (MOTA) syndrome: report of eight new cases.</strong> Am. J. Med. Genet. 143A: 853-857, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17352387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17352387</a>] [<a href="https://doi.org/10.1002/ajmg.a.31446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17352387">Li et al. (2007)</a>, <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> identified homozygosity for a 60.1-kb deletion (chr9:14,780,425-14,840,536) involving exons 8 through 23 of the FREM1 gene, resulting in removal of amino acids 385 to 1327 but leaving the frame of the protein unchanged. The deletion breakpoints were mapped to 631 bp after the end of exon 7 (IVS7+631) and 1,311 bp before the start of exon 24 (IVS23-1311). In 3 affected sisters, second cousins to the male Oji-Cree patient, <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> identified compound heterozygosity for the 16-exon deletion and a 5556A-G transition in exon 31, located 1 bp before the last coding nucleotide and predicted to abolish the donor splice site. Analysis of cDNA from 1 of the sisters confirmed that exon 31 was spliced out of the FREM1 transcript of the non-deleted allele; however, FREM1 exon 31 was also absent from cDNA from a control fibroblast cell line. <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> concluded that the exon 31 sequence variant was not itself pathogenic, and stated that the second mutation in the 3 sisters remained undetected. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21507892+17352387" 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 MANITOBA OCULOTRICHOANAL SYNDROME</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> rs769407804 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs769407804;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/rs769407804?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=rs769407804" 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=rs769407804" 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=RCV000023742 OR RCV001267163 OR RCV002482903" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023742, RCV001267163, RCV002482903" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023742...</a>
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<p>In a woman with bilateral eyelid coloboma and vaginal atresia (MOTA; <a href="/entry/248450">248450</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Fryns, J. P. <strong>Micro-ablepharon of the upper eyelids and vaginal atresia.</strong> Genet. Counsel. 12: 101-102, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11332973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11332973</a>]" pmid="11332973">Fryns (2001)</a>, <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> identified homozygosity for a 4-bp deletion (2097delATTA) in exon 13 of the FREM1 gene, predicted to cause a frameshift and premature termination of the protein. The unaffected parents were both heterozygous for the deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21507892+11332973" 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 MANITOBA OCULOTRICHOANAL SYNDROME</strong>
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FREM1, LEU1324ARG
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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> rs281875281 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875281;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/rs281875281?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=rs281875281" 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=rs281875281" 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=RCV000023743 OR RCV000059638" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023743, RCV000059638" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023743...</a>
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<p>In a female patient with Manitoba oculotrichoanal syndrome (MOTA; <a href="/entry/248450">248450</a>), originally reported by <a href="#7" class="mim-tip-reference" title="Li, C., Marles, S. L., Greenberg, C. R., Chodirker, B. N., van de Kamp, J., Slavotinek, A., Chudley, A. E. <strong>Manitoba oculotrichoanal (MOTA) syndrome: report of eight new cases.</strong> Am. J. Med. Genet. 143A: 853-857, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17352387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17352387</a>] [<a href="https://doi.org/10.1002/ajmg.a.31446" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17352387">Li et al. (2007)</a>, <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a> identified compound heterozygosity for a 3971T-G transversion in the FREM1 gene, resulting in a leu1324-to-arg (L1324R) substitution at a highly conserved residue, and a 6271G-A transition, resulting in a val209-to-ile substitution (V209I; <a href="#0007">608944.0007</a>) at a highly conserved residue within a motif of the C-type lectin domain. Neither mutation was found in 500 or more Caucasian control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21507892+17352387" 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 MANITOBA OCULOTRICHOANAL SYNDROME</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> rs281875282 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875282;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/rs281875282?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=rs281875282" 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=rs281875282" 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=RCV000059641 OR RCV002291556" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000059641, RCV002291556" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000059641...</a>
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<p>For discussion of the val209-to-ile (V209I) mutation in the FREM1 gene that was found in compound heterozygous state in a patient with Manitoba oculotrichoanal syndrome (MOTA; <a href="/entry/248450">248450</a>) by <a href="#8" class="mim-tip-reference" title="Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others. <strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong> J. Med. Genet. 48: 375-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21507892">Slavotinek et al. (2011)</a>, see <a href="#0006">608944.0006</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21507892" 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 TRIGONOCEPHALY 2</strong>
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FREM1, GLU1500VAL
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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> rs281875280 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281875280;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/rs281875280?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=rs281875280" 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=rs281875280" 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=RCV000023745 OR RCV000059640 OR RCV002247390 OR RCV004752722 OR RCV005042083" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023745, RCV000059640, RCV002247390, RCV004752722, RCV005042083" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023745...</a>
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<p>In 2 patients with trigonocephaly due to metopic craniosynostosis (TRIGNO2; <a href="/entry/614485">614485</a>), <a href="#10" class="mim-tip-reference" title="Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. <strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong> PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21931569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21931569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21931569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21931569">Vissers et al. (2011)</a> identified heterozygosity for a 4499A-T transversion in exon 25 of the FREM1 gene, resulting in a glu1500-to-val (E1500V) substitution at a residue within the chondroitin sulfate proteoglycan repeats. The mutation was de novo in 1 of the patients; in the other patient, who had trigonocephaly and microcephaly, the mutation was also detected in the patient's mother, who had craniofacial abnormalities including hypertelorism and upslanting palpebral fissures, and in his 2 sisters, 1 of whom displayed ptosis and hypertelorism whereas the other had only relative hypertelorism but no significant findings. The mutation was not found in 142 Caucasian control chromosomes or in 110 ethnically matched control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21931569" 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>.0009 TRIGONOCEPHALY 2</strong>
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FREM1, ARG498GLN
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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> rs184394424 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs184394424;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/rs184394424?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=rs184394424" 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=rs184394424" 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=RCV000023746 OR RCV000059636 OR RCV000207399 OR RCV000988143 OR RCV005042084" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023746, RCV000059636, RCV000207399, RCV000988143, RCV005042084" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023746...</a>
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<p>In a 4-year-old boy with nonsyndromic trigonocephaly due to metopic craniosynostosis (TRIGNO2; <a href="/entry/614485">614485</a>), <a href="#10" class="mim-tip-reference" title="Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others. <strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong> PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21931569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21931569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21931569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1002278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21931569">Vissers et al. (2011)</a> identified heterozygosity for a 1493G-A transition in exon 9 of the FREM1 gene, resulting in an arg498-to-gln (R498Q) substitution at a highly conserved residue within the chondroitin sulfate proteoglycan repeats. The mutation was inherited from his unaffected father, but was not found in 138 Caucasian control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21931569" 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>.0010 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</strong>
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FREM1, EX10-30DEL
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001549287" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001549287" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001549287</a>
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<p><a href="#3" class="mim-tip-reference" title="Brischoux-Boucher, E., Dahlen, E., Bronier, C., Nobili, F., Marcoux, E., Alkuraya, F. S., Van Maldergem, L. <strong>Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. (Letter)</strong> Clin. Genet. 98: 515-516, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32926405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32926405</a>] [<a href="https://doi.org/10.1111/cge.13821" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32926405">Brischoux-Boucher et al. (2020)</a> performed microarray-based comparative genomic hybridization on a Turkish brother and sister, born of consanguineous parents, with bifid nose with or without anorectal renal anomalies (BNAR; <a href="/entry/608980">608980</a>) and detected a homozygous 30- to 52-kb in-frame microdeletion encompassing exons 19-30 of the FREM1 gene (<a href="#0010">608944.0010</a>) in both sibs. PCR confirmed biparental inheritance. The brother had unilateral renal agenesis and bifid nose; the sister had only bifid nose. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32926405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Al-Gazali2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Al-Gazali, L. I., Bakir, M., Hamud, O. A., Gerami, S.
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<strong>An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations.</strong>
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Clin. Dysmorph. 11: 33-38, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11822703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11822703</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11822703" 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/10.1097/00019605-200201000-00007" target="_blank">Full Text</a>]
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<a id="Alazami2009" class="mim-anchor"></a>
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Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S.
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<strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong>
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Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19732862/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19732862</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19732862[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19732862" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2009.08.010" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Brischoux-Boucher2020" class="mim-anchor"></a>
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<div class="">
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Brischoux-Boucher, E., Dahlen, E., Bronier, C., Nobili, F., Marcoux, E., Alkuraya, F. S., Van Maldergem, L.
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<strong>Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. (Letter)</strong>
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Clin. Genet. 98: 515-516, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32926405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32926405</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32926405" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/cge.13821" target="_blank">Full Text</a>]
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<a id="Fryns2001" class="mim-anchor"></a>
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<p class="mim-text-font">
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Fryns, J. P.
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<strong>Micro-ablepharon of the upper eyelids and vaginal atresia.</strong>
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Genet. Counsel. 12: 101-102, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11332973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11332973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11332973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Jordan2018" class="mim-anchor"></a>
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Jordan, V. K., Beck, T. F., Hernandez-Garcia, A., Kundert, P. N., Kim, B.-J., Jhangiani, S. N., Gambin, T., Starkovich, M., Punetha, J., Paine, I. S., Posey, J. E., Li, A. H., and 11 others.
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<strong>The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.</strong>
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Hum. Molec. Genet. 27: 2064-2075, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29618029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29618029</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29618029[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29618029" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddy110" target="_blank">Full Text</a>]
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<a id="Kiyozumi2006" class="mim-anchor"></a>
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Kiyozumi, D., Sugimoto, N., Sekiguchi, K.
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<strong>Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects.</strong>
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Proc. Nat. Acad. Sci. 103: 11981-11986, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16880404/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16880404</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16880404[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16880404" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0601011103" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Li2007" class="mim-anchor"></a>
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<div class="">
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Li, C., Marles, S. L., Greenberg, C. R., Chodirker, B. N., van de Kamp, J., Slavotinek, A., Chudley, A. E.
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<strong>Manitoba oculotrichoanal (MOTA) syndrome: report of eight new cases.</strong>
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Am. J. Med. Genet. 143A: 853-857, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17352387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17352387</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17352387" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.31446" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Slavotinek2011" class="mim-anchor"></a>
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Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others.
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<strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong>
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J. Med. Genet. 48: 375-382, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21507892/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21507892</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21507892[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21507892" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2011.089631" target="_blank">Full Text</a>]
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<a id="Smyth2004" class="mim-anchor"></a>
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Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J.
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<strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong>
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Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15345741/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15345741</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15345741[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15345741" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0402760101" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Vissers2011" class="mim-anchor"></a>
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Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others.
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<strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong>
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PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21931569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21931569</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21931569[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21931569" 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/10.1371/journal.pgen.1002278" target="_blank">Full Text</a>]
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Kelly A. Przylepa - updated : 08/03/2021
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Marla J. F. O'Neill - updated : 04/10/2019<br>Marla J. F. O'Neill - updated : 2/16/2012<br>Marla J. F. O'Neill - updated : 7/12/2011<br>Marla J. F. O'Neill - updated : 10/7/2009<br>Patricia A. Hartz - updated : 9/15/2006
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Patricia A. Hartz : 9/27/2004
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alopez : 10/01/2024
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carol : 08/04/2021<br>carol : 08/03/2021<br>alopez : 04/10/2019<br>carol : 11/21/2017<br>alopez : 06/15/2015<br>mcolton : 6/11/2015<br>alopez : 4/8/2015<br>alopez : 3/12/2015<br>carol : 9/25/2013<br>terry : 11/15/2012<br>carol : 2/17/2012<br>carol : 2/17/2012<br>terry : 2/16/2012<br>wwang : 7/15/2011<br>terry : 7/12/2011<br>carol : 11/25/2009<br>wwang : 10/8/2009<br>terry : 10/7/2009<br>wwang : 9/21/2006<br>terry : 9/15/2006<br>alopez : 3/17/2006<br>mgross : 9/27/2004
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<strong>*</strong> 608944
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FRAS1-RELATED EXTRACELLULAR MATRIX PROTEIN 1; FREM1
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CHROMOSOME 9 OPEN READING FRAME 154; C9ORF154
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<strong><em>HGNC Approved Gene Symbol: FREM1</em></strong>
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<strong>SNOMEDCT:</strong> 703539006, 717940006;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
|
Cytogenetic location: 9p22.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 9:14,737,152-14,910,995 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
9p22.3
|
|
</span>
|
|
</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
Bifid nose with or without anorectal and renal anomalies
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
608980
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Manitoba oculotrichoanal syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
248450
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Trigonocephaly 2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
614485
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Smyth et al. (2004) cloned the mouse Frem1 gene, which encodes a deduced 2,191-amino acid protein. By searching sequence databases, they identified human FREM1. The mouse and human FREM1 proteins contain an N-terminal signal peptide, 12 chondroitin sulfate proteoglycan (CSPG; see 118661) repeats, a calcium-binding loop similar to those of sodium-calcium exchangers (see 182305), and a C-terminal C-type lectin (see 605999) domain. FREM1 also has sites for N- and O-glycosylation. FREM1 shares significant similarity with FRAS1 (607830), particularly through the CSPG repeats, but FREM1 lacks additional domains found in FRAS1. In situ hybridization and immunohistochemical analysis detected wide Frem1 expression during mouse embryonic development in the dermis and in a number of differentiating epidermal structures, such as mammary and meibomian glands, teeth, and hair follicles. Expression appeared in regions of epithelial-mesenchymal interaction and epidermal remodeling. </p><p>Alazami et al. (2009) assayed Frem1 expression in mouse embryos and found strong and specific staining in the snout as well as in the midline where the 2 medial nasal processes fuse. In situ hybridization revealed that Frem1 expression in the nose was primarily in the epithelial-mesenchymal transitional region at the midline. Based on these studies and the identification of mutations in the FREM1 gene in patients with bifid nose (see MOLECULAR GENETICS), Alazami et al. (2009) concluded that FREM1 plays an important role in fusion of the nasal processes during gestation. </p><p>Vissers et al. (2011) performed in situ hybridization of mouse embryos from mid to late gestation (E14.5-E16.5) and observed expression of Frem1 between the developing frontal bones in the region fated to form the posterior frontal suture. Antibody staining at P0 highlighted fibrillar pericranial expression of Frem1 overlying the developing frontal bones as well as staining in the dura mater underlying those bones. Low levels of diffuse Frem1 staining were also noted in the osteogenic precursors between the frontal bones, further suggesting a role for the protein in the development of the posterior frontal suture. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Smyth et al. (2004) determined that the mouse Frem1 gene contains 36 coding exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Slavotinek et al. (2011) noted that the FREM1 gene maps to chromosome 9p22.3. </p><p>Smyth et al. (2004) mapped the mouse Frem1 gene to chromosome 4. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Bifid Nose with or without Anorectal and Renal Anomalies</em></strong></p><p>
|
|
In affected members of 3 consanguineous families with bifid nose with or without anorectal and renal anomalies (BNAR; 608980) mapping to chromosome 9p23-p22.2, including an Egyptian Arab family originally reported by Al-Gazali et al. (2002), Alazami et al. (2009) sequenced the FREM1 gene and identified homozygosity for a 1-bp deletion and 2 missense mutations, respectively (608944.0001-608944.0003). </p><p>Brischoux-Boucher et al. (2020) performed microarray-based comparative genomic hybridization on a Turkish brother and sister with BNAR and detected a homozygous 30- to 52-kb in-frame microdeletion at 9p22.3 encompassing exons 19-30 of the FREM1 gene (608944.0010) in both sibs. PCR confirmed biparental inheritance. The brother had unilateral renal agenesis and bifid nose; the sister had only bifid nose. </p><p><strong><em>Manitoba Oculotrichoanal Syndrome</em></strong></p><p>
|
|
In 8 patients from 5 families with Manitoba oculotrichoanal syndrome (MOTA; 248450), Slavotinek et al. (2011) identified homozygous or compound heterozygous mutations in the FREM1 gene (608944.0004-608944.0007, respectively). </p><p><strong><em>Trigonocephaly</em></strong></p><p>
|
|
Vissers et al. (2011) analyzed the FREM1 gene in 104 patients with nonsyndromic trigonocephaly (see TRIGNO2; 614485) and identified missense mutations in 3 patients (608944.0008 and 608944.0009) that were not found in control chromosomes. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Smyth et al. (2004) determined that the mouse Frem1 gene is mutated in the spontaneous 'head blebs' (heb) mutation and in the N-ethyl-N-nitrosourea-induced 'bat' mutation. Both mutations cause a truncation of the Frem1 protein and result in blebbing diseases similar to Fraser syndrome (219000) and dystrophic epidermolysis bullosa (DEB; 131750) in human. Heb homozygous fetuses are characterized by cryptophthalmos and blebs restricted to the head, with the epidermis apparently normal after birth. Smyth et al. (2004) found that homozygous bat mice displayed embryonic blebbing from about 13.5 days postcoitum that invariably affected the developing eyes. Adult bat homozygotes also displayed cryptophthalmos, and about 20% had unilateral renal agenesis, which is not seen in heb homozygotes. The epidermis of bat embryos separated from the dermis below the level of the lamina densa in a manner analogous to that observed in patients with DEB. Smyth et al. (2004) concluded that Frem1 is required for epidermal adhesion during embryonic development. </p><p>Kiyozumi et al. (2006) found that Frem1-knockout mice had reduced localization of Fras1 and Frem2 (608945) to the epidermal basement membrane. Similarly, Frem2-mutant 'myelencephalic blebs' (my) mice showed depletion of Frem2, as well as Fras1 and Frem1, at the basement membrane. When coexpressed and secreted in transfected cells, Fras1, Frem1, and Frem2 formed a ternary complex, raising the possibility that their reciprocal stabilization at the basement membrane was due to complex formation. Kiyozumi et al. (2006) suggested that coordinated assembly of the 3 Fraser syndrome-associated proteins at the basement membrane is instrumental in epidermal-dermal interactions during morphogenetic processes. </p><p>Slavotinek et al. (2011) examined Frem1-mutant mice and identified a small but statistically significant proportion of homozygous Frem1 bat/bat mutant animals with anal prolapse, which was not observed in heterozygous or wildtype littermates. Histologic analysis revealed protrusion of the rectal epithelia and an immune infiltrate in exposed tissue, but not in internal mucosa. The musculature of the anal sphincter was present but misplaced; gross malformations in rectal musculature were not apparent. Examination of Frem1-mutant eyes at birth showed that although the majority of animals presented with frank cryptophthalmos, a subset exhibited defects strikingly similar to the eyelid coloboma seen in MOTA, seemingly affecting only 1 part of the eyelid. Histologic analysis demonstrated that these defects were associated with a number of ocular malformations including failure of eyelid formation, defects in the formation of the conjunctiva, and absence of corneal epithelium leading to fibrosis. Morphologic analysis of craniofacial shape in Frem1-deficient mice showed that homozygous mutants had reduced snout length compared to controls, and also had significantly shorter philtrum-columella height, greater intercanthal distance, and greater midface asymmetry compared to heterozygotes. </p><p>Vissers et al. (2011) studied C57BL/6J mice carrying the ENU-generated Frem1(bat) mutation, which is thought to represent a hypomorphic allele rather than a null allele. Morphometric analysis of skulls from homozygous and heterozygous mutant mice demonstrated craniofacial malformations consistent with the craniofacial features seen in the 9p22 deletion syndrome (158170), in particular metopic craniosynostosis (614485) and midface asymmetry and/or hypoplasia. The penetrance of the phenotypes in mice correlated to mutant gene dosage. </p><p>Jordan et al. (2018) dissected the diaphragms of E16.5 Frem1-deficient (eyes2/eyes2) mice on an inbred B6Brd/129S6 background and observed that development of sac hernias is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>10 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FREM1, 1-BP DEL, 2721G
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1588131370,
|
|
|
|
|
|
|
|
ClinVar: RCV000002065, RCV004760316
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a consanguineous Egyptian Arab family with bifid nose with or without anorectal and renal anomalies (BNAR; 608980), originally reported by Al-Gazali et al. (2002), Alazami et al. (2009) identified homozygosity for a 1-bp deletion (2721delG) in exon 16 of the FREM1 gene, predicted to cause a frameshift at amino acid 908 and result in premature termination 17 residues downstream. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FREM1, ARG649TRP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912609,
|
|
|
|
|
|
|
|
ClinVar: RCV000002066, RCV000059637, RCV003987307, RCV005041970
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a consanguineous Afghan family with bifid nose with or without anorectal and renal anomalies (BNAR; 608980), Alazami et al. (2009) identified homozygosity for a 1945C-T transition in exon 11 of the FREM1 gene, resulting in an arg649-to-trp (R649W) substitution at a highly conserved residue. The mutation was not found in 121 Afghan or 97 Indian subcontinental controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FREM1, GLY1440SER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121912610,
|
|
|
|
|
|
gnomAD: rs121912610,
|
|
|
|
|
|
ClinVar: RCV000002067, RCV000059639, RCV003987308, RCV005049312
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a consanguineous Pakistani family with bifid nose with or without anorectal and renal anomalies (BNAR; 608980), Alazami et al. (2009) identified homozygosity for a 4318G-A transition in exon 24 of the FREM1 gene, resulting in a gly1440-to-ser (G1440S) substitution at a highly conserved residue. The mutation was not found in 97 Indian subcontinental or 121 Afghan controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 MANITOBA OCULOTRICHOANAL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FREM1, 60.1-KB DEL
|
|
|
|
|
|
<br />
|
|
|
|
|
|
|
|
ClinVar: RCV000023741
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a male patient from an Oji-Cree family with Manitoba oculotrichoanal syndrome (MOTA; 248450), and 2 patients with MOTA from an unrelated Cree/Ojibway kindred, previously described by Li et al. (2007), Slavotinek et al. (2011) identified homozygosity for a 60.1-kb deletion (chr9:14,780,425-14,840,536) involving exons 8 through 23 of the FREM1 gene, resulting in removal of amino acids 385 to 1327 but leaving the frame of the protein unchanged. The deletion breakpoints were mapped to 631 bp after the end of exon 7 (IVS7+631) and 1,311 bp before the start of exon 24 (IVS23-1311). In 3 affected sisters, second cousins to the male Oji-Cree patient, Slavotinek et al. (2011) identified compound heterozygosity for the 16-exon deletion and a 5556A-G transition in exon 31, located 1 bp before the last coding nucleotide and predicted to abolish the donor splice site. Analysis of cDNA from 1 of the sisters confirmed that exon 31 was spliced out of the FREM1 transcript of the non-deleted allele; however, FREM1 exon 31 was also absent from cDNA from a control fibroblast cell line. Slavotinek et al. (2011) concluded that the exon 31 sequence variant was not itself pathogenic, and stated that the second mutation in the 3 sisters remained undetected. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MANITOBA OCULOTRICHOANAL SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
FREM1, 4-BP DEL, 2097ATTA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs769407804,
|
|
|
|
|
|
gnomAD: rs769407804,
|
|
|
|
|
|
ClinVar: RCV000023742, RCV001267163, RCV002482903
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a woman with bilateral eyelid coloboma and vaginal atresia (MOTA; 248450), originally reported by Fryns (2001), Slavotinek et al. (2011) identified homozygosity for a 4-bp deletion (2097delATTA) in exon 13 of the FREM1 gene, predicted to cause a frameshift and premature termination of the protein. The unaffected parents were both heterozygous for the deletion. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 MANITOBA OCULOTRICHOANAL SYNDROME</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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FREM1, LEU1324ARG
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<br />
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SNP: rs281875281,
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gnomAD: rs281875281,
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ClinVar: RCV000023743, RCV000059638
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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 female patient with Manitoba oculotrichoanal syndrome (MOTA; 248450), originally reported by Li et al. (2007), Slavotinek et al. (2011) identified compound heterozygosity for a 3971T-G transversion in the FREM1 gene, resulting in a leu1324-to-arg (L1324R) substitution at a highly conserved residue, and a 6271G-A transition, resulting in a val209-to-ile substitution (V209I; 608944.0007) at a highly conserved residue within a motif of the C-type lectin domain. Neither mutation was found in 500 or more Caucasian control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0007 MANITOBA OCULOTRICHOANAL SYNDROME</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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FREM1, VAL209ILE
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<br />
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SNP: rs281875282,
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gnomAD: rs281875282,
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ClinVar: RCV000059641, RCV002291556
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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 val209-to-ile (V209I) mutation in the FREM1 gene that was found in compound heterozygous state in a patient with Manitoba oculotrichoanal syndrome (MOTA; 248450) by Slavotinek et al. (2011), see 608944.0006. </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 TRIGONOCEPHALY 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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FREM1, GLU1500VAL
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<br />
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SNP: rs281875280,
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gnomAD: rs281875280,
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ClinVar: RCV000023745, RCV000059640, RCV002247390, RCV004752722, RCV005042083
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 patients with trigonocephaly due to metopic craniosynostosis (TRIGNO2; 614485), Vissers et al. (2011) identified heterozygosity for a 4499A-T transversion in exon 25 of the FREM1 gene, resulting in a glu1500-to-val (E1500V) substitution at a residue within the chondroitin sulfate proteoglycan repeats. The mutation was de novo in 1 of the patients; in the other patient, who had trigonocephaly and microcephaly, the mutation was also detected in the patient's mother, who had craniofacial abnormalities including hypertelorism and upslanting palpebral fissures, and in his 2 sisters, 1 of whom displayed ptosis and hypertelorism whereas the other had only relative hypertelorism but no significant findings. The mutation was not found in 142 Caucasian control chromosomes or in 110 ethnically matched control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 TRIGONOCEPHALY 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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FREM1, ARG498GLN
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<br />
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SNP: rs184394424,
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gnomAD: rs184394424,
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ClinVar: RCV000023746, RCV000059636, RCV000207399, RCV000988143, RCV005042084
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 4-year-old boy with nonsyndromic trigonocephaly due to metopic craniosynostosis (TRIGNO2; 614485), Vissers et al. (2011) identified heterozygosity for a 1493G-A transition in exon 9 of the FREM1 gene, resulting in an arg498-to-gln (R498Q) substitution at a highly conserved residue within the chondroitin sulfate proteoglycan repeats. The mutation was inherited from his unaffected father, but was not found in 138 Caucasian control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0010 BIFID NOSE WITH OR WITHOUT ANORECTAL AND RENAL ANOMALIES</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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FREM1, EX10-30DEL
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<br />
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ClinVar: RCV001549287
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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>Brischoux-Boucher et al. (2020) performed microarray-based comparative genomic hybridization on a Turkish brother and sister, born of consanguineous parents, with bifid nose with or without anorectal renal anomalies (BNAR; 608980) and detected a homozygous 30- to 52-kb in-frame microdeletion encompassing exons 19-30 of the FREM1 gene (608944.0010) in both sibs. PCR confirmed biparental inheritance. The brother had unilateral renal agenesis and bifid nose; the sister had only bifid nose. </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>REFERENCES</strong>
|
|
</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">
|
|
Al-Gazali, L. I., Bakir, M., Hamud, O. A., Gerami, S.
|
|
<strong>An autosomal recessive syndrome of nasal anomalies associated with renal and anorectal malformations.</strong>
|
|
Clin. Dysmorph. 11: 33-38, 2002.
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[PubMed: 11822703]
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[Full Text: https://doi.org/10.1097/00019605-200201000-00007]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Alazami, A. M., Shaheen, R., Alzahrani, F., Snape, K., Saggar, A., Brinkmann, B., Bavi, P., Al-Gazali, L. I., Alkuraya, F. S.
|
|
<strong>FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.</strong>
|
|
Am. J. Hum. Genet. 85: 414-418, 2009. Note: Erratum: Am. J. Hum. Genet. 85: 756 only, 2009.
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|
[PubMed: 19732862]
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[Full Text: https://doi.org/10.1016/j.ajhg.2009.08.010]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Brischoux-Boucher, E., Dahlen, E., Bronier, C., Nobili, F., Marcoux, E., Alkuraya, F. S., Van Maldergem, L.
|
|
<strong>Bifid nose as the sole manifestation of BNAR syndrome, a FREM1-related condition. (Letter)</strong>
|
|
Clin. Genet. 98: 515-516, 2020.
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|
[PubMed: 32926405]
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[Full Text: https://doi.org/10.1111/cge.13821]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fryns, J. P.
|
|
<strong>Micro-ablepharon of the upper eyelids and vaginal atresia.</strong>
|
|
Genet. Counsel. 12: 101-102, 2001.
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|
|
[PubMed: 11332973]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jordan, V. K., Beck, T. F., Hernandez-Garcia, A., Kundert, P. N., Kim, B.-J., Jhangiani, S. N., Gambin, T., Starkovich, M., Punetha, J., Paine, I. S., Posey, J. E., Li, A. H., and 11 others.
|
|
<strong>The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.</strong>
|
|
Hum. Molec. Genet. 27: 2064-2075, 2018.
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[PubMed: 29618029]
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[Full Text: https://doi.org/10.1093/hmg/ddy110]
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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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Kiyozumi, D., Sugimoto, N., Sekiguchi, K.
|
|
<strong>Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 11981-11986, 2006.
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[PubMed: 16880404]
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[Full Text: https://doi.org/10.1073/pnas.0601011103]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Li, C., Marles, S. L., Greenberg, C. R., Chodirker, B. N., van de Kamp, J., Slavotinek, A., Chudley, A. E.
|
|
<strong>Manitoba oculotrichoanal (MOTA) syndrome: report of eight new cases.</strong>
|
|
Am. J. Med. Genet. 143A: 853-857, 2007.
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|
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[PubMed: 17352387]
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[Full Text: https://doi.org/10.1002/ajmg.a.31446]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Slavotinek, A. M., Baranzini, S. E., Schanze, D., Labelle-Dumais, C., Short, K. M., Chao, R., Yahyavi, M., Bijlsma, E. K., Chu, C., Musone, S., Wheatley, A., Kwok, P.-Y., and 11 others.
|
|
<strong>Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.</strong>
|
|
J. Med. Genet. 48: 375-382, 2011.
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[PubMed: 21507892]
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[Full Text: https://doi.org/10.1136/jmg.2011.089631]
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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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Smyth, I., Du, X., Taylor, M. S., Justice, M. J., Beutler, B., Jackson, I. J.
|
|
<strong>The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis.</strong>
|
|
Proc. Nat. Acad. Sci. 101: 13560-13565, 2004.
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[PubMed: 15345741]
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[Full Text: https://doi.org/10.1073/pnas.0402760101]
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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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Vissers, L. E. L. M., Cox, T. C., Maga, A. M., Short, K. M., Wiradjaja, F., Janssen, I. M., Jehee, F., Bertola, D., Liu, J., Yagnik, G., Sekiguchi, K., Kiyozumi, D., and 10 others.
|
|
<strong>Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice.</strong>
|
|
PLoS Genet. 7: e1002278, 2011. Note: Electronic Article.
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[PubMed: 21931569]
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[Full Text: https://doi.org/10.1371/journal.pgen.1002278]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Kelly A. Przylepa - updated : 08/03/2021<br>Marla J. F. O'Neill - updated : 04/10/2019<br>Marla J. F. O'Neill - updated : 2/16/2012<br>Marla J. F. O'Neill - updated : 7/12/2011<br>Marla J. F. O'Neill - updated : 10/7/2009<br>Patricia A. Hartz - updated : 9/15/2006
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</span>
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</div>
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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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<span class="text-nowrap mim-text-font">
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Creation Date:
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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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Patricia A. Hartz : 9/27/2004
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</span>
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</div>
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Edit History:
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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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alopez : 10/01/2024<br>carol : 08/04/2021<br>carol : 08/03/2021<br>alopez : 04/10/2019<br>carol : 11/21/2017<br>alopez : 06/15/2015<br>mcolton : 6/11/2015<br>alopez : 4/8/2015<br>alopez : 3/12/2015<br>carol : 9/25/2013<br>terry : 11/15/2012<br>carol : 2/17/2012<br>carol : 2/17/2012<br>terry : 2/16/2012<br>wwang : 7/15/2011<br>terry : 7/12/2011<br>carol : 11/25/2009<br>wwang : 10/8/2009<br>terry : 10/7/2009<br>wwang : 9/21/2006<br>terry : 9/15/2006<br>alopez : 3/17/2006<br>mgross : 9/27/2004
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