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Entry
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- *123101 - MSH HOMEOBOX 2; MSX2
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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">*123101</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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/123101">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000120149;t=ENST00000239243" 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=4488" 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=123101" 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=ENSG00000120149;t=ENST00000239243" 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_001363626,NM_002449" 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_002449" 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=123101" 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=00421&isoform_id=00421_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/MSX2" 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/285931,396174,834012,1321638,1722694,1758335,4261869,15930143,27886557,32879971,114212255,119581785,119581786,311033429,1391723936,2462602649" 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/P35548" 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=4488" 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=ENSG00000120149;t=ENST00000239243" 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=MSX2" 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=MSX2" 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+4488" 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/MSX2" 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:4488" 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/4488" 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=chr5&hgg_gene=ENST00000239243.7&hgg_start=174724582&hgg_end=174730896&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:7392" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7392" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=123101[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=123101[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/MSX2/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/ENSG00000120149" 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=MSX2" 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=MSX2" 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=MSX2" 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=MSX2&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/PA31197" 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:7392" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0000492.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:97169" 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/MSX2#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:97169" 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/4488/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001224/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4488" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00006881;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-980526-322" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4488" 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=MSX2&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> 720817008, 771338002<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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123101
|
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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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MSH HOMEOBOX 2; MSX2
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MUSCLE SEGMENT HOMEOBOX, DROSOPHILA, HOMOLOG OF, 2; MSX2<br />
|
|
MSH, DROSOPHILA, HOMOLOG OF, 2
|
|
</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MSX2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MSX2</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/5/779?start=-3&limit=10&highlight=779">5q35.2</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr5:174724582-174730896&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'})">5:174,724,582-174,730,896</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
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<div>
|
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<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
|
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</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=604757,168500,168550" 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/5/779?start=-3&limit=10&highlight=779">
|
|
5q35.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Craniosynostosis 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/604757"> 604757 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
|
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</td>
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</tr>
|
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Parietal foramina 1
|
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|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/168500"> 168500 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</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>
|
|
|
|
</span>
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<p><a href="#7" class="mim-tip-reference" title="Li, X., Ma, L., Snead, M., Haworth, I., Sparkes, R., Jackson, C., Warman, M., Mulliken, J., Maxson, R., Muller, U., Jabs, E. <strong>A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A213 only, 1993."None>Li et al. (1993)</a> cloned and sequenced the human MSX2 homeobox gene.</p>
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<p>By in situ hybridization, <a href="#7" class="mim-tip-reference" title="Li, X., Ma, L., Snead, M., Haworth, I., Sparkes, R., Jackson, C., Warman, M., Mulliken, J., Maxson, R., Muller, U., Jabs, E. <strong>A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A213 only, 1993."None>Li et al. (1993)</a> mapped the MSX2 gene to the same region of chromosome 5 to which a form of craniosynostosis (CRS2; <a href="/entry/604757">604757</a>) had been mapped.</p><p><a href="#6" class="mim-tip-reference" title="Jabs, E. W., Muller, U., Li, X., Ma, L., Luo, W., Haworth, I. S., Klisak, I., Sparkes, R., Warman, M. L., Mulliken, J. B., Snead, M. L., Maxson, R. <strong>A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis.</strong> Cell 75: 443-450, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8106171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8106171</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90379-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8106171">Jabs et al. (1993)</a> mapped the MSX2 gene to chromosome 5 by study of a human/rodent somatic cell hybrid mapping panel and regionalized it to 5q34-q35 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8106171" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Takahashi, C., Akiyama, N., Matsuzaki, T., Takai, S., Kitayama, H., Noda, M. <strong>Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene.</strong> Oncogene 12: 2137-2146, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8668339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8668339</a>]" pmid="8668339">Takahashi et al. (1996)</a> isolated a cDNA (CT124) encoding the C-terminal 58-amino acid region of human MSX2. CT124 was found to induce a low frequency of reversion when expressed in ras (<a href="/entry/190070">190070</a>)-transformed NIH3T3 cells. Northern hybridization analyses showed that expression of endogenous MSX2 was low in most of the normal adult tissues examined. In contrast, high expression of the MSX2 gene was detected in several cell lines derived from human tumors. In addition, they found that the full-length human MSX2 cDNA induced transformation in chicken myoblast cultures, supporting the view that MSX2 promotes rather than suppresses cell growth under certain conditions (<a href="#2" class="mim-tip-reference" title="Davidson, D. <strong>The function and evolution of Msx genes: pointers and paradoxes.</strong> Trends Genet. 11: 405-411, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7482767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7482767</a>] [<a href="https://doi.org/10.1016/s0168-9525(00)89124-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7482767">Davidson, 1995</a>). <a href="#15" class="mim-tip-reference" title="Takahashi, C., Akiyama, N., Matsuzaki, T., Takai, S., Kitayama, H., Noda, M. <strong>Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene.</strong> Oncogene 12: 2137-2146, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8668339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8668339</a>]" pmid="8668339">Takahashi et al. (1996)</a> also tested the activities of a near full-length human MSX2 cDNA and of CT124 in fibroblast and myoblast cell systems. They found that in NIH3T3 fibroblasts, both antisense MSX2 cDNA and truncated CT124 interfered with the transforming activities of the v-Ki-ras oncogene. In C2C12 myoblasts, MSX2 suppressed MyoD (<a href="/entry/159990">159990</a>) gene expression as did activated RAS oncogenes, and CT124 inhibits the activities of both MSX2 and ras. These findings suggested to <a href="#15" class="mim-tip-reference" title="Takahashi, C., Akiyama, N., Matsuzaki, T., Takai, S., Kitayama, H., Noda, M. <strong>Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene.</strong> Oncogene 12: 2137-2146, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8668339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8668339</a>]" pmid="8668339">Takahashi et al. (1996)</a> that CT124 may act as a dominant suppressor of MSX2 and that the MSX2 gene may be an important target for the RAS signaling pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8668339+7482767" 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="Hassan, M. Q., Javed, A., Morasso, M. I., Karlin, J., Montecino, M., van Wijnen, A. J., Stein, G. S., Stein, J. L., Lian, J. B. <strong>Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene.</strong> Molec. Cell. Biol. 24: 9248-9261, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15456894/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15456894</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15456894[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/10.1128/MCB.24.20.9248-9261.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15456894">Hassan et al. (2004)</a> found that Msx2, Dlx3 (<a href="/entry/600525">600525</a>), Dlx5 (<a href="/entry/600028">600028</a>), and Runx2 (<a href="/entry/600211">600211</a>) regulated the expression of osteocalcin (OC) (BGLAP; <a href="/entry/112260">112260</a>) in mouse embryos and therefore are implicated in the control of bone formation. Msx2 associated with transcriptionally repressed OC chromatin, and Dlx3 and Dlx5 were recruited with Runx2 to initiate OC transcription. In a second regulatory switch, Dlx3 association decreased and Dlx5 recruitment increased coincident with the mineralization stage of osteoblast differentiation. The appearance of Dlx3 followed by Dlx5 in the OC promoter correlated with increased transcription represented by increased occupancy of RNA polymerase II. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15456894" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Shiihara, T., Kato, M., Kimura, T., Hayasaka, K., Yamamori, S., Ogata, T. <strong>Craniosynostosis with extra copy of MSX2 in a patient with partial 5q-trisomy. (Letter)</strong> Am. J. Med. Genet. 128A: 214-216, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15214020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15214020</a>] [<a href="https://doi.org/10.1002/ajmg.a.20552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15214020">Shiihara et al. (2004)</a> described a 2-year-old girl with craniosynostosis with early closure of the sagittal and lambdoid sutures, atrial septal defect, patent ductus arteriosus, and a karyotype showing 46,XX,der(13)t(5;13)(q33.3;q34). FISH analysis demonstrated 3 copies of the MSX2 gene. <a href="#13" class="mim-tip-reference" title="Shiihara, T., Kato, M., Kimura, T., Hayasaka, K., Yamamori, S., Ogata, T. <strong>Craniosynostosis with extra copy of MSX2 in a patient with partial 5q-trisomy. (Letter)</strong> Am. J. Med. Genet. 128A: 214-216, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15214020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15214020</a>] [<a href="https://doi.org/10.1002/ajmg.a.20552" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15214020">Shiihara et al. (2004)</a> suggested that the patient's clinical findings were explained by either partial 13q deletion or partial 5q trisomy, or both, and that the overdose of MSX2 was related to her craniosynostosis through the MSX2-mediated pathway of calvarial osteogenic differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15214020" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Bernardini, L., Castori, M., Capalbo, A., Mokini, V., Mingarelli, R., Simi, P., Bertuccelli, A., Novelli, A., Dallapiccola, B. <strong>Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication.</strong> Am. J. Med. Genet. 143A: 2937-2943, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000908</a>] [<a href="https://doi.org/10.1002/ajmg.a.32092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000908">Bernardini et al. (2007)</a> described a 6-month-old female with premature closure of the metopic, sagittal, lambdoid, and squamous sutures, together with peripheral coronal synostosis and multiple areas of defective parietal ossification, suggestive of craniolacunae. The patient also had prenatal-onset growth deficiency, developmental delay, facial dysmorphism, mitral valve stenosis, bicuspid aortic valve, pulmonary hypertension, and inguinal hernia. An integrated approach of standard cytogenetics, mBAND, locus-specific FISH, and 75-kb resolution array CGH disclosed a complex chromosome 5 rearrangement, resulting in 3 paracentric inversions, 2 between-arm insertions, and partial duplication of 5q35. Molecular cytogenetic studies confirmed an extra copy of the MSX2 gene within the duplicated segment. <a href="#1" class="mim-tip-reference" title="Bernardini, L., Castori, M., Capalbo, A., Mokini, V., Mingarelli, R., Simi, P., Bertuccelli, A., Novelli, A., Dallapiccola, B. <strong>Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication.</strong> Am. J. Med. Genet. 143A: 2937-2943, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000908</a>] [<a href="https://doi.org/10.1002/ajmg.a.32092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18000908">Bernardini et al. (2007)</a> suggested that MSX2 dosage is crucial in the development of craniofacial structures and a distinct form of craniosynostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000908" 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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To determine whether MSX2 expression is consistent with its being a candidate gene for craniosynostosis (CRS2; <a href="/entry/604757">604757</a>), <a href="#7" class="mim-tip-reference" title="Li, X., Ma, L., Snead, M., Haworth, I., Sparkes, R., Jackson, C., Warman, M., Mulliken, J., Maxson, R., Muller, U., Jabs, E. <strong>A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A213 only, 1993."None>Li et al. (1993)</a> demonstrated by in situ hybridization that mouse Msx2 transcripts are present in osteoblasts adjacent to calvarial sutures during mouse embryonic and postnatal development. In addition, <a href="#7" class="mim-tip-reference" title="Li, X., Ma, L., Snead, M., Haworth, I., Sparkes, R., Jackson, C., Warman, M., Mulliken, J., Maxson, R., Muller, U., Jabs, E. <strong>A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A213 only, 1993."None>Li et al. (1993)</a> found that a (CA)n polymorphism within the MSX2 gene segregated with craniosynostosis in the Boston family studied by <a href="#16" class="mim-tip-reference" title="Warman, M. L., Mulliken, J. B., Hayward, P. G., Muller, U. <strong>Newly recognized autosomal dominant disorder with craniosynostosis.</strong> Am. J. Med. Genet. 46: 444-449, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8357019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8357019</a>] [<a href="https://doi.org/10.1002/ajmg.1320460420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8357019">Warman et al. (1993)</a> and <a href="#11" class="mim-tip-reference" title="Muller, U., Warman, M. L., Mulliken, J. B., Weber, J. L. <strong>Assignment of a gene locus involved in craniosynostosis to chromosome 5qter.</strong> Hum. Molec. Genet. 2: 119-122, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8499900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8499900</a>] [<a href="https://doi.org/10.1093/hmg/2.2.119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8499900">Muller et al. (1993)</a>; no recombination was observed, giving a maximum lod score of 4.80. All affected members were found to have substitution of histidine for proline at amino acid position 7 of the homeodomain (P148H; <a href="#0001">123101.0001</a>); the mutation was absent in all unaffected members of the family and 68 controls. This proline residue is conserved in all known MSX genes in organisms as diverse as insects and mammals. <a href="#7" class="mim-tip-reference" title="Li, X., Ma, L., Snead, M., Haworth, I., Sparkes, R., Jackson, C., Warman, M., Mulliken, J., Maxson, R., Muller, U., Jabs, E. <strong>A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A213 only, 1993."None>Li et al. (1993)</a> claimed that this was the first report of a mutation in a homeobox gene associated with a human disorder. See <a href="#6" class="mim-tip-reference" title="Jabs, E. W., Muller, U., Li, X., Ma, L., Luo, W., Haworth, I. S., Klisak, I., Sparkes, R., Warman, M. L., Mulliken, J. B., Snead, M. L., Maxson, R. <strong>A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis.</strong> Cell 75: 443-450, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8106171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8106171</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90379-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8106171">Jabs et al. (1993)</a> for the full report. This is a good example of identification of the defect in a disorder by the candidate gene approach. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8499900+8357019+8106171" 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="Mavrogiannis, L. A., Taylor, I. B., Davies, S. J., Ramos, F. J., Olivares, J. L., Wilkie, A. O. M. <strong>Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype.</strong> Europ. J. Hum. Genet. 14: 151-158, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16319823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16319823</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16319823[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201526" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16319823">Mavrogiannis et al. (2006)</a> did not identify any pathogenic mutations in the MSX2 gene in 181 patients with craniosynostosis, suggesting that it is not a common cause of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16319823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis, <a href="#3" class="mim-tip-reference" title="Florisson, J. M. G., Verkerk, A. J. M. H., Huigh, D., Hoogeboom, A. J. M., Swagemakers, S., Kremer, A., Heijsman, D., Lequin, M. H., Mathijssen, I. M. J., van der Spek, P. J. <strong>Boston type craniosynostosis: report of a second mutation in MSX2.</strong> Am. J. Med. Genet. 161A: 2626-2633, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23949913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23949913</a>] [<a href="https://doi.org/10.1002/ajmg.a.36126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23949913">Florisson et al. (2013)</a> identified heterozygosity for a P148L mutation (<a href="#0009">123101.0009</a>) in the MSX2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23949913" 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>Parietal Foramina</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., Maxson, R. E., Jr. <strong>Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification.</strong> Nature Genet. 24: 387-390, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742103</a>] [<a href="https://doi.org/10.1038/74224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742103">Wilkie et al. (2000)</a> described heterozygous mutations of the MSX2 gene in 3 unrelated families with enlarged parietal foramina (PFM1; <a href="/entry/168500">168500</a>). One was a deletion of approximately 206 kb including the entire gene, and the others were intragenic mutations of the DNA-binding homeodomain that predicted disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal Msx2 DNA-binding site. These findings contrasted with the previously described MSX2 homeodomain mutation pro148 to his, associated with craniosynostosis, which binds with enhanced affinity to the same target. In the family with a 2-amino acid deletion in MSX2 and enlarged parietal foramina (<a href="#0002">123101.0002</a>), the 27-year-old mother had completely false upper teeth, suggesting dental abnormalities consistent with the mouse phenotype. <a href="#17" class="mim-tip-reference" title="Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., Maxson, R. E., Jr. <strong>Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification.</strong> Nature Genet. 24: 387-390, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742103</a>] [<a href="https://doi.org/10.1038/74224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742103">Wilkie et al. (2000)</a> concluded that MSX2 dosage is critical for human skull development and suggested that enlarged parietal foramina and craniosynostosis result, respectively, from loss and gain of activity in an MSX2-mediated pathway of calvarial osteogenic differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In the affected father of a child with parietal foramina, <a href="#14" class="mim-tip-reference" title="Spruijt, L., Verdyck, P., Van Hul, W., Wuyts, W., de Die-Smulders, C. <strong>A novel mutation in the MSX2 gene in a family with foramina parietalia permagna (FPP).</strong> Am. J. Med. Genet. 139A: 45-47, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16222674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16222674</a>] [<a href="https://doi.org/10.1002/ajmg.a.30923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16222674">Spruijt et al. (2005)</a> identified an 8-bp deletion in the MSX2 gene (<a href="#0008">123101.0008</a>). The father and proband both had normal clavicles on examination; DNA analysis was refused for the proband and her grandparents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16222674" 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>Parietal Foramina with Cleidocranial Dysplasia</em></strong></p><p>
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In a 3-generation family segregating parietal foramina with cleidocranial dysplasia (PFMCCD; <a href="/entry/168550">168550</a>), <a href="#4" class="mim-tip-reference" title="Garcia-Minaur, S., Mavrogiannis, L. A., Rannan-Eliya, S. V., Hendry, M. A., Liston, W. A., Porteous, M. E. M., Wilkie, A. O. M. <strong>Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2.</strong> Europ. J. Hum. Genet. 11: 892-895, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14571277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14571277</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14571277">Garcia-Minaur et al. (2003)</a> identified a heterozygous frameshift mutation (<a href="#0007">123101.0007</a>) in the homeodomain of the MSX2 gene in affected family members. The authors noted that the clavicular involvement was mild and difficult to assess on physical examination, and suggested that this finding may be more commonly associated with PFM than previously believed and may be characteristic of individuals with MSX2 rather than ALX4 (<a href="/entry/605420">605420</a>) mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14571277" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To investigate the function of MSX2 in tissue interactions and in vertebrate craniofacial development, and to test further the hypothesis that a mutation of MSX2 is the cause of Boston-type craniosynostosis, <a href="#8" class="mim-tip-reference" title="Liu, Y. H., Kundu, R., Wu, L., Luo, W., Ignelzi, M. A., Jr., Snead, M. L., Maxson, R. E., Jr. <strong>Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull.</strong> Proc. Nat. Acad. Sci. 92: 6137-6141, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597092</a>] [<a href="https://doi.org/10.1073/pnas.92.13.6137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597092">Liu et al. (1995)</a> engineered the pro-to-his mutation in the homeodomain of the mouse Msx2 gene and expressed the mutant gene in the developing skulls of transgenic mice. They showed that these mice exhibited precocious fusion of cranial bones and development of ectopic cranial bone. <a href="#8" class="mim-tip-reference" title="Liu, Y. H., Kundu, R., Wu, L., Luo, W., Ignelzi, M. A., Jr., Snead, M. L., Maxson, R. E., Jr. <strong>Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull.</strong> Proc. Nat. Acad. Sci. 92: 6137-6141, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597092</a>] [<a href="https://doi.org/10.1073/pnas.92.13.6137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597092">Liu et al. (1995)</a> also showed that overexpression of the wildtype Msx2 gene can also produce craniosynostosis in mice, consistent with the possibility that the mutation enhances the normal activity of Msx2. See also <a href="#0001">123101.0001</a> and <a href="#9" class="mim-tip-reference" title="Ma, L., Golden, S., Wu, L., Maxson, R. <strong>The molecular basis of Boston-type craniosynostosis: the pro148-to-his mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences.</strong> Hum. Molec. Genet. 5: 1915-1920, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968743</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968743">Ma et al. (1996)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7597092+8968743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Winograd, J., Reilly, M. P., Roe, R., Lutz, J., Laughner, E., Xu, X., Hu, L., Asakura, T., vander Kolk, C., Strandberg, J. D., Semenza, G. L. <strong>Perinatal lethality and multiple craniofacial malformations in MSX2 transgenic mice.</strong> Hum. Molec. Genet. 6: 369-378, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9147639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9147639</a>] [<a href="https://doi.org/10.1093/hmg/6.3.369" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9147639">Winograd et al. (1997)</a> likewise generated transgenic mice with the P148H MSX2 mutation carried by a 34-kb DNA fragment encompassing the human MSH2 gene (<a href="/entry/609309">609309</a>). Inheritance of either the mutant transgene or a normal transgene resulted in perinatal lethality and multiple craniofacial malformations of varying severity, including mandibular hypoplasia, cleft secondary palate, exencephaly, and median facial cleft, which are among the severe craniofacial malformations observed in humans. Transgenic mice also manifested aplasia of the interparietal bone and decreased ossification of the hyoid. Transgene-induced malformations involved cranial neural-crest derivatives, were characterized by a deficiency of tissue, and were similar to malformations associated with embryonic exposure to ethanol or retinoic acid, teratogens that cause increased cell death. Together with previous observations implicating MSX2 expression in developmentally programmed cell death, these results suggested to the investigators that wildtype levels of MSX2 activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9147639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Satokata, I., Ma, L., Ohshima, H., Bei, M., Woo, I., Nishizawa, K., Maeda, T., Takano, Y., Uchiyama, M., Heaney, S., Peters, H., Tang, Z., Maxson, R., Maas, R. <strong>Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation.</strong> Nature Genet. 24: 391-395, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742104</a>] [<a href="https://doi.org/10.1038/74231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742104">Satokata et al. (2000)</a> generated Msx2-deficient mice by targeted disruption. The mice had defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina. Msx2 -/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, postnatal deficits of parathyroid hormone (<a href="/entry/168450">168450</a>)/parathyroid hormone receptor (see <a href="/entry/168468">168468</a>) signaling and in expression of marker genes for bone differentiation indicate that MSX2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with parietal foramina, Msx2-mutant mice also display defective tooth, hair follicle, and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 (<a href="/entry/142983">142983</a>) loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. <a href="#12" class="mim-tip-reference" title="Satokata, I., Ma, L., Ohshima, H., Bei, M., Woo, I., Nishizawa, K., Maeda, T., Takano, Y., Uchiyama, M., Heaney, S., Peters, H., Tang, Z., Maxson, R., Maas, R. <strong>Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation.</strong> Nature Genet. 24: 391-395, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742104/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742104</a>] [<a href="https://doi.org/10.1038/74231" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742104">Satokata et al. (2000)</a> concluded that their results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis. Msx2 +/- mice were indistinguishable from wildtype mice. Unlike the defect in PFM, the calvarial defect in Msx2 -/- mice was a large, midline foramen spanning the frontal bones, and the interparietal and supraoccipital bones were small and abnormally shaped. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742104" 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>To investigate possible functions of MSX2 in early ocular development, <a href="#19" class="mim-tip-reference" title="Wu, L.-Y., Li, M., Hinton, D. R., Guo, L., Jiang, S., Wang, J. T., Zeng, A., Xie, J. B., Snead, M., Shuler, C., Maxson, R. E., Jr., Liu, Y.-H. <strong>Microphthalmia resulting from Msx2-induced apoptosis in the optic vesicle.</strong> Invest. Ophthal. Vis. Sci. 44: 2404-2412, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12766037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12766037</a>] [<a href="https://doi.org/10.1167/iovs.02-0317" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12766037">Wu et al. (2003)</a> created transgenic mice overexpressing Msx2. Forced expression of the Msx2 gene resulted in optic nerve aplasia and microphthalmia in all transgenic mice. In the developing retinas of the transgenic mice, proliferation was significantly reduced and increased numbers of retinal cells underwent apoptosis. Marker analysis showed suppression of Bmp4 (<a href="/entry/112262">112262</a>) and induction of Bmp7 (<a href="/entry/112267">112267</a>) gene expression in the optic vesicle. Ectopic concurrent expression of the retinal pigment epithelial cell markers Cx43 (<a href="/entry/121014">121014</a>) and Tyrp2 (<a href="/entry/191275">191275</a>) in the neural retinal layer suggested cell fate respecification. These results indicated that forced expression of Msx2 perturbed BMP signaling in the developing eye and was accompanied by an increase in retinal cell death and a reduction in cell proliferation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12766037" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="/allelicVariants/123101" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=123101[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 CRANIOSYNOSTOSIS 2</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">rs104893895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893895;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=rs104893895" 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=rs104893895" 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=RCV000018474 OR RCV001210266" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018474, RCV001210266" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018474...</a>
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<p>In affected members of a 3-generation American family from Boston segregating autosomal dominant variable craniosynostosis (CRS2; <a href="/entry/604757">604757</a>), originally reported by <a href="#16" class="mim-tip-reference" title="Warman, M. L., Mulliken, J. B., Hayward, P. G., Muller, U. <strong>Newly recognized autosomal dominant disorder with craniosynostosis.</strong> Am. J. Med. Genet. 46: 444-449, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8357019/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8357019</a>] [<a href="https://doi.org/10.1002/ajmg.1320460420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8357019">Warman et al. (1993)</a>, <a href="#7" class="mim-tip-reference" title="Li, X., Ma, L., Snead, M., Haworth, I., Sparkes, R., Jackson, C., Warman, M., Mulliken, J., Maxson, R., Muller, U., Jabs, E. <strong>A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. (Abstract)</strong> Am. J. Hum. Genet. 53 (suppl.): A213 only, 1993."None>Li et al. (1993)</a> identified a substitution of histidine for proline at amino acid position 7 of the homeodomain of the MSX2 homeobox gene (residue 148 of the polypeptide). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8357019" 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="Ma, L., Golden, S., Wu, L., Maxson, R. <strong>The molecular basis of Boston-type craniosynostosis: the pro148-to-his mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences.</strong> Hum. Molec. Genet. 5: 1915-1920, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968743</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968743">Ma et al. (1996)</a> reported that the P148H mutation in MSX2 is found exclusively in individuals with craniosynostosis type 2, and that it alters the DNA-binding properties of the MSX2 homeoprotein. They demonstrated that the enhanced DNA-binding affinity of the P148H form of MSX2 is caused by enhanced stability of the MSX2-DNA complex. This mutation had no discernible effect on the sequence specificity of MSX2 binding. They had previously reported (<a href="#8" class="mim-tip-reference" title="Liu, Y. H., Kundu, R., Wu, L., Luo, W., Ignelzi, M. A., Jr., Snead, M. L., Maxson, R. E., Jr. <strong>Premature suture closure and ectopic cranial bone in mice expressing Msx2 transgenes in the developing skull.</strong> Proc. Nat. Acad. Sci. 92: 6137-6141, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7597092/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7597092</a>] [<a href="https://doi.org/10.1073/pnas.92.13.6137" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7597092">Liu et al., 1995</a>) that transgenic mice in which either the mutant or the wildtype Msx2 gene is overexpressed exhibited craniosynostosis. <a href="#9" class="mim-tip-reference" title="Ma, L., Golden, S., Wu, L., Maxson, R. <strong>The molecular basis of Boston-type craniosynostosis: the pro148-to-his mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences.</strong> Hum. Molec. Genet. 5: 1915-1920, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968743</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968743">Ma et al. (1996)</a> noted that their recent results showing increased DNA-binding affinity of P148H and their studies in transgenic mice are consistent with the possibility that the mutation acts via a dominant-positive mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7597092+8968743" 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 PARIETAL FORAMINA 1</strong>
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MSX2, 6-BP DEL, NT475
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2113498725 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2113498725;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=rs2113498725" 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=rs2113498725" 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=RCV000018475" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018475" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018475</a>
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<p>In a family with autosomal dominant enlarged parietal foramina (PFM1; <a href="/entry/168500">168500</a>), <a href="#17" class="mim-tip-reference" title="Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., Maxson, R. E., Jr. <strong>Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification.</strong> Nature Genet. 24: 387-390, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742103</a>] [<a href="https://doi.org/10.1038/74224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742103">Wilkie et al. (2000)</a> identified deletion of 6 nucleotides (475-480) of the MSX2 gene resulting in the deletion of 2 amino acids, arginine and lysine, from codons 159 and 160. This mutation occurs in helix 1. Mouse protein with the same mutation showed DNA-binding affinity reduced to 3% that of wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs104893896 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893896;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/rs104893896?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=rs104893896" 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=rs104893896" 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=RCV000018476" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018476" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018476</a>
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<p>In a family with autosomal dominant enlarged parietal foramina (PFM1; <a href="/entry/168500">168500</a>), <a href="#17" class="mim-tip-reference" title="Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., Maxson, R. E., Jr. <strong>Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification.</strong> Nature Genet. 24: 387-390, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742103</a>] [<a href="https://doi.org/10.1038/74224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742103">Wilkie et al. (2000)</a> identified a G-to-A transition at nucleotide 515 of the MSX2 gene resulting in an arg172-to-his (R172H) substitution. Mouse protein with the same mutation showed DNA-binding affinity reduced to 15% that of wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000018477" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018477" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018477</a>
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<p>In a family with autosomal dominant enlarged parietal foramina (PFM1; <a href="/entry/168500">168500</a>), <a href="#17" class="mim-tip-reference" title="Wilkie, A. O. M., Tang, Z., Elanko, N., Walsh, S., Twigg, S. R. F., Hurst, J. A., Wall, S. A., Chrzanowska, K. H., Maxson, R. E., Jr. <strong>Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification.</strong> Nature Genet. 24: 387-390, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10742103/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10742103</a>] [<a href="https://doi.org/10.1038/74224" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10742103">Wilkie et al. (2000)</a> identified a 206-kb deletion that included the entire MSX2 gene, indicating that haploinsufficiency for MSX2 results in enlarged parietal foramina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10742103" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912971 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912971;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=rs121912971" 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=rs121912971" 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=RCV000018478" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018478" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018478</a>
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<p>In a family with autosomal dominant enlarged parietal foramina (PFM1; <a href="/entry/168500">168500</a>), <a href="#20" class="mim-tip-reference" title="Wuyts, W., Reardon, W., Preis, S., Homfray, T., Rasore-Quartino, A., Christians, H., Willems, P. J., Van Hul, W. <strong>Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna.</strong> Hum. Molec. Genet. 9: 1251-1255, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767351</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767351">Wuyts et al. (2000)</a> identified mutations in consecutive nucleotides 265-266 in exon 1 of the MSX2 gene (G265T, C266A), resulting in an ala89-to-ter substitution. The protein product was predicted to lack the entire C terminus, which includes the conserved homeodomain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121912972 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121912972;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=rs121912972" 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=rs121912972" 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=RCV000018479" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018479" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018479</a>
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<p>In a family with autosomal dominant enlarged parietal foramina (PFM1; <a href="/entry/168500">168500</a>), <a href="#20" class="mim-tip-reference" title="Wuyts, W., Reardon, W., Preis, S., Homfray, T., Rasore-Quartino, A., Christians, H., Willems, P. J., Van Hul, W. <strong>Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna.</strong> Hum. Molec. Genet. 9: 1251-1255, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767351</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767351">Wuyts et al. (2000)</a> identified a 1-bp deletion at nucleotide 344 or 345 of the MSX2 gene, resulting in a trp115-to-ter substitution. The protein product was predicted to lack the entire C terminus, which includes the conserved homeodomain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10767351" 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 PARIETAL FORAMINA WITH CLEIDOCRANIAL DYSPLASIA</strong>
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MSX2, 4-BP DUP, NT505
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1561643029 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1561643029;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=rs1561643029" 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=rs1561643029" 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=RCV000018480" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018480" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018480</a>
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<p>In a 3-generation family segregating parietal foramina with cleidocranial dysplasia (PFMCCD; <a href="/entry/168550">168550</a>), <a href="#4" class="mim-tip-reference" title="Garcia-Minaur, S., Mavrogiannis, L. A., Rannan-Eliya, S. V., Hendry, M. A., Liston, W. A., Porteous, M. E. M., Wilkie, A. O. M. <strong>Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2.</strong> Europ. J. Hum. Genet. 11: 892-895, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14571277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14571277</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14571277">Garcia-Minaur et al. (2003)</a> identified a heterozygous duplication of a tetranucleotide (505dupATTG) in exon 2 of the MSX2 gene in affected individuals. The duplication causes a frameshift at residue 29 of the homeodomain, and predicts a termination codon 75 triplets downstream. Affected family members exhibited classic parietal foramina (see <a href="/entry/168500">168500</a>) and short abnormal clavicles with tapering lateral ends. They had mild craniofacial dysmorphism with a broad forehead and central bossing, which was more evident in the children. <a href="#4" class="mim-tip-reference" title="Garcia-Minaur, S., Mavrogiannis, L. A., Rannan-Eliya, S. V., Hendry, M. A., Liston, W. A., Porteous, M. E. M., Wilkie, A. O. M. <strong>Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2.</strong> Europ. J. Hum. Genet. 11: 892-895, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14571277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14571277</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201062" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14571277">Garcia-Minaur et al. (2003)</a> noted that the mild clavicular involvement was difficult to assess on physical examination, and suggested that this finding may be more commonly associated with PFM than previously believed and may be characteristic of individuals with MSX2 rather than ALX4 (<a href="/entry/605420">605420</a>) mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14571277" 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 PARIETAL FORAMINA 1</strong>
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MSX2, 8-BP DEL, NT548
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1561643060 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1561643060;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=rs1561643060" 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=rs1561643060" 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=RCV000018481" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000018481" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000018481</a>
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<p>In the affected father of a child with parietal foramina (PFM1; <a href="/entry/168500">168500</a>), <a href="#14" class="mim-tip-reference" title="Spruijt, L., Verdyck, P., Van Hul, W., Wuyts, W., de Die-Smulders, C. <strong>A novel mutation in the MSX2 gene in a family with foramina parietalia permagna (FPP).</strong> Am. J. Med. Genet. 139A: 45-47, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16222674/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16222674</a>] [<a href="https://doi.org/10.1002/ajmg.a.30923" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16222674">Spruijt et al. (2005)</a> identified an 8-bp deletion in exon 2 of the MSX2 gene, resulting in a frameshift and premature stop codon 59 codons downstream. DNA analysis was refused for the proband and her grandparents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16222674" 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 CRANIOSYNOSTOSIS 2</strong>
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MSX2, PRO148LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs104893895 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs104893895;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=rs104893895" 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=rs104893895" 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=RCV000203576 OR RCV000690192" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000203576, RCV000690192" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000203576...</a>
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<p>In 7 affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis (CRS2; <a href="/entry/604757">604757</a>), <a href="#3" class="mim-tip-reference" title="Florisson, J. M. G., Verkerk, A. J. M. H., Huigh, D., Hoogeboom, A. J. M., Swagemakers, S., Kremer, A., Heijsman, D., Lequin, M. H., Mathijssen, I. M. J., van der Spek, P. J. <strong>Boston type craniosynostosis: report of a second mutation in MSX2.</strong> Am. J. Med. Genet. 161A: 2626-2633, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23949913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23949913</a>] [<a href="https://doi.org/10.1002/ajmg.a.36126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23949913">Florisson et al. (2013)</a> identified heterozygosity for a c.443C-T transition (c.443C-T, NM_002449.4) in exon 2 of the MSX2 gene, resulting in a pro148-to-leu (P148L) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in an in-house database, or in the 1000 Genomes Project or Exome Variant Server databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23949913" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="Bernardini2007" class="mim-anchor"></a>
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Bernardini, L., Castori, M., Capalbo, A., Mokini, V., Mingarelli, R., Simi, P., Bertuccelli, A., Novelli, A., Dallapiccola, B.
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<strong>Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication.</strong>
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Am. J. Med. Genet. 143A: 2937-2943, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18000908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18000908</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18000908" 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.32092" target="_blank">Full Text</a>]
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Davidson, D.
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<strong>The function and evolution of Msx genes: pointers and paradoxes.</strong>
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Trends Genet. 11: 405-411, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7482767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7482767</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7482767" 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/s0168-9525(00)89124-6" target="_blank">Full Text</a>]
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Florisson, J. M. G., Verkerk, A. J. M. H., Huigh, D., Hoogeboom, A. J. M., Swagemakers, S., Kremer, A., Heijsman, D., Lequin, M. H., Mathijssen, I. M. J., van der Spek, P. J.
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<strong>Boston type craniosynostosis: report of a second mutation in MSX2.</strong>
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Am. J. Med. Genet. 161A: 2626-2633, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23949913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23949913</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23949913" 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.36126" target="_blank">Full Text</a>]
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<a id="Garcia-Minaur2003" class="mim-anchor"></a>
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[<a href="https://doi.org/10.1038/sj.ejhg.5201062" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1128/MCB.24.20.9248-9261.2004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/0092-8674(93)90379-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.92.13.6137" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/5.12.1915" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201526" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.2.119" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.8.1251" target="_blank">Full Text</a>]
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</li>
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</ol>
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 1/15/2016
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Nara Sobreira - updated : 5/18/2010<br>Patricia A. Hartz - updated : 6/4/2008<br>Cassandra L. Kniffin - updated : 2/17/2006<br>Marla J. F. O'Neill - updated : 11/17/2005<br>Marla J. F. O'Neill - updated : 5/14/2004<br>Jane Kelly - updated : 11/6/2003<br>George E. Tiller - updated : 7/7/2000<br>Ada Hamosh - updated : 3/30/2000<br>Ada Hamosh - updated : 3/29/2000<br>Victor A. McKusick - updated : 4/15/1997<br>Moyra Smith - updated : 1/27/1997<br>Perseveranda M. Cagas - updated : 9/5/1996
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 3/23/1993
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</span>
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</div>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 08/19/2019
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/16/2019<br>joanna : 05/11/2017<br>carol : 05/23/2016<br>carol : 1/15/2016<br>carol : 7/18/2013<br>carol : 7/18/2013<br>terry : 3/16/2012<br>carol : 5/19/2010<br>terry : 5/18/2010<br>terry : 5/18/2010<br>wwang : 8/6/2008<br>carol : 7/23/2008<br>wwang : 6/6/2008<br>terry : 6/4/2008<br>wwang : 2/24/2006<br>ckniffin : 2/17/2006<br>wwang : 11/22/2005<br>wwang : 11/22/2005<br>terry : 11/17/2005<br>mgross : 4/14/2005<br>carol : 5/19/2004<br>carol : 5/18/2004<br>terry : 5/14/2004<br>terry : 3/18/2004<br>tkritzer : 11/14/2003<br>tkritzer : 11/6/2003<br>tkritzer : 10/29/2003<br>alopez : 7/7/2000<br>alopez : 3/30/2000<br>carol : 3/30/2000<br>terry : 3/29/2000<br>carol : 3/29/2000<br>jenny : 4/15/1997<br>terry : 4/9/1997<br>terry : 2/6/1997<br>mark : 1/29/1997<br>terry : 1/27/1997<br>terry : 1/24/1997<br>mark : 1/24/1997<br>mark : 9/5/1996<br>marlene : 9/4/1996<br>mark : 7/24/1995<br>mimadm : 6/25/1994<br>carol : 12/9/1993<br>carol : 10/13/1993<br>carol : 10/1/1993<br>carol : 9/30/1993
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<h3>
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<span class="mim-font">
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<strong>*</strong> 123101
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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MSH HOMEOBOX 2; MSX2
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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MUSCLE SEGMENT HOMEOBOX, DROSOPHILA, HOMOLOG OF, 2; MSX2<br />
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MSH, DROSOPHILA, HOMOLOG OF, 2
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</span>
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</h4>
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</div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MSX2</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 720817008, 771338002;
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 5q35.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 5:174,724,582-174,730,896 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
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5q35.2
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</td>
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<td>
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<span class="mim-font">
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Craniosynostosis 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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604757
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Parietal foramina 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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168500
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Parietal foramina with cleidocranial dysplasia
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</span>
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</td>
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<td>
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<span class="mim-font">
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168550
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Li et al. (1993) cloned and sequenced the human MSX2 homeobox gene.</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By in situ hybridization, Li et al. (1993) mapped the MSX2 gene to the same region of chromosome 5 to which a form of craniosynostosis (CRS2; 604757) had been mapped.</p><p>Jabs et al. (1993) mapped the MSX2 gene to chromosome 5 by study of a human/rodent somatic cell hybrid mapping panel and regionalized it to 5q34-q35 by fluorescence in situ hybridization. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Takahashi et al. (1996) isolated a cDNA (CT124) encoding the C-terminal 58-amino acid region of human MSX2. CT124 was found to induce a low frequency of reversion when expressed in ras (190070)-transformed NIH3T3 cells. Northern hybridization analyses showed that expression of endogenous MSX2 was low in most of the normal adult tissues examined. In contrast, high expression of the MSX2 gene was detected in several cell lines derived from human tumors. In addition, they found that the full-length human MSX2 cDNA induced transformation in chicken myoblast cultures, supporting the view that MSX2 promotes rather than suppresses cell growth under certain conditions (Davidson, 1995). Takahashi et al. (1996) also tested the activities of a near full-length human MSX2 cDNA and of CT124 in fibroblast and myoblast cell systems. They found that in NIH3T3 fibroblasts, both antisense MSX2 cDNA and truncated CT124 interfered with the transforming activities of the v-Ki-ras oncogene. In C2C12 myoblasts, MSX2 suppressed MyoD (159990) gene expression as did activated RAS oncogenes, and CT124 inhibits the activities of both MSX2 and ras. These findings suggested to Takahashi et al. (1996) that CT124 may act as a dominant suppressor of MSX2 and that the MSX2 gene may be an important target for the RAS signaling pathways. </p><p>Hassan et al. (2004) found that Msx2, Dlx3 (600525), Dlx5 (600028), and Runx2 (600211) regulated the expression of osteocalcin (OC) (BGLAP; 112260) in mouse embryos and therefore are implicated in the control of bone formation. Msx2 associated with transcriptionally repressed OC chromatin, and Dlx3 and Dlx5 were recruited with Runx2 to initiate OC transcription. In a second regulatory switch, Dlx3 association decreased and Dlx5 recruitment increased coincident with the mineralization stage of osteoblast differentiation. The appearance of Dlx3 followed by Dlx5 in the OC promoter correlated with increased transcription represented by increased occupancy of RNA polymerase II. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Shiihara et al. (2004) described a 2-year-old girl with craniosynostosis with early closure of the sagittal and lambdoid sutures, atrial septal defect, patent ductus arteriosus, and a karyotype showing 46,XX,der(13)t(5;13)(q33.3;q34). FISH analysis demonstrated 3 copies of the MSX2 gene. Shiihara et al. (2004) suggested that the patient's clinical findings were explained by either partial 13q deletion or partial 5q trisomy, or both, and that the overdose of MSX2 was related to her craniosynostosis through the MSX2-mediated pathway of calvarial osteogenic differentiation. </p><p>Bernardini et al. (2007) described a 6-month-old female with premature closure of the metopic, sagittal, lambdoid, and squamous sutures, together with peripheral coronal synostosis and multiple areas of defective parietal ossification, suggestive of craniolacunae. The patient also had prenatal-onset growth deficiency, developmental delay, facial dysmorphism, mitral valve stenosis, bicuspid aortic valve, pulmonary hypertension, and inguinal hernia. An integrated approach of standard cytogenetics, mBAND, locus-specific FISH, and 75-kb resolution array CGH disclosed a complex chromosome 5 rearrangement, resulting in 3 paracentric inversions, 2 between-arm insertions, and partial duplication of 5q35. Molecular cytogenetic studies confirmed an extra copy of the MSX2 gene within the duplicated segment. Bernardini et al. (2007) suggested that MSX2 dosage is crucial in the development of craniofacial structures and a distinct form of craniosynostosis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Craniosynostosis 2</em></strong></p><p>
|
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To determine whether MSX2 expression is consistent with its being a candidate gene for craniosynostosis (CRS2; 604757), Li et al. (1993) demonstrated by in situ hybridization that mouse Msx2 transcripts are present in osteoblasts adjacent to calvarial sutures during mouse embryonic and postnatal development. In addition, Li et al. (1993) found that a (CA)n polymorphism within the MSX2 gene segregated with craniosynostosis in the Boston family studied by Warman et al. (1993) and Muller et al. (1993); no recombination was observed, giving a maximum lod score of 4.80. All affected members were found to have substitution of histidine for proline at amino acid position 7 of the homeodomain (P148H; 123101.0001); the mutation was absent in all unaffected members of the family and 68 controls. This proline residue is conserved in all known MSX genes in organisms as diverse as insects and mammals. Li et al. (1993) claimed that this was the first report of a mutation in a homeobox gene associated with a human disorder. See Jabs et al. (1993) for the full report. This is a good example of identification of the defect in a disorder by the candidate gene approach. </p><p>Mavrogiannis et al. (2006) did not identify any pathogenic mutations in the MSX2 gene in 181 patients with craniosynostosis, suggesting that it is not a common cause of the disorder. </p><p>In affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis, Florisson et al. (2013) identified heterozygosity for a P148L mutation (123101.0009) in the MSX2 gene. </p><p><strong><em>Parietal Foramina</em></strong></p><p>
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|
Wilkie et al. (2000) described heterozygous mutations of the MSX2 gene in 3 unrelated families with enlarged parietal foramina (PFM1; 168500). One was a deletion of approximately 206 kb including the entire gene, and the others were intragenic mutations of the DNA-binding homeodomain that predicted disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal Msx2 DNA-binding site. These findings contrasted with the previously described MSX2 homeodomain mutation pro148 to his, associated with craniosynostosis, which binds with enhanced affinity to the same target. In the family with a 2-amino acid deletion in MSX2 and enlarged parietal foramina (123101.0002), the 27-year-old mother had completely false upper teeth, suggesting dental abnormalities consistent with the mouse phenotype. Wilkie et al. (2000) concluded that MSX2 dosage is critical for human skull development and suggested that enlarged parietal foramina and craniosynostosis result, respectively, from loss and gain of activity in an MSX2-mediated pathway of calvarial osteogenic differentiation. </p><p>In the affected father of a child with parietal foramina, Spruijt et al. (2005) identified an 8-bp deletion in the MSX2 gene (123101.0008). The father and proband both had normal clavicles on examination; DNA analysis was refused for the proband and her grandparents. </p><p><strong><em>Parietal Foramina with Cleidocranial Dysplasia</em></strong></p><p>
|
|
In a 3-generation family segregating parietal foramina with cleidocranial dysplasia (PFMCCD; 168550), Garcia-Minaur et al. (2003) identified a heterozygous frameshift mutation (123101.0007) in the homeodomain of the MSX2 gene in affected family members. The authors noted that the clavicular involvement was mild and difficult to assess on physical examination, and suggested that this finding may be more commonly associated with PFM than previously believed and may be characteristic of individuals with MSX2 rather than ALX4 (605420) mutations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To investigate the function of MSX2 in tissue interactions and in vertebrate craniofacial development, and to test further the hypothesis that a mutation of MSX2 is the cause of Boston-type craniosynostosis, Liu et al. (1995) engineered the pro-to-his mutation in the homeodomain of the mouse Msx2 gene and expressed the mutant gene in the developing skulls of transgenic mice. They showed that these mice exhibited precocious fusion of cranial bones and development of ectopic cranial bone. Liu et al. (1995) also showed that overexpression of the wildtype Msx2 gene can also produce craniosynostosis in mice, consistent with the possibility that the mutation enhances the normal activity of Msx2. See also 123101.0001 and Ma et al. (1996). </p><p>Winograd et al. (1997) likewise generated transgenic mice with the P148H MSX2 mutation carried by a 34-kb DNA fragment encompassing the human MSH2 gene (609309). Inheritance of either the mutant transgene or a normal transgene resulted in perinatal lethality and multiple craniofacial malformations of varying severity, including mandibular hypoplasia, cleft secondary palate, exencephaly, and median facial cleft, which are among the severe craniofacial malformations observed in humans. Transgenic mice also manifested aplasia of the interparietal bone and decreased ossification of the hyoid. Transgene-induced malformations involved cranial neural-crest derivatives, were characterized by a deficiency of tissue, and were similar to malformations associated with embryonic exposure to ethanol or retinoic acid, teratogens that cause increased cell death. Together with previous observations implicating MSX2 expression in developmentally programmed cell death, these results suggested to the investigators that wildtype levels of MSX2 activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis. </p><p>Satokata et al. (2000) generated Msx2-deficient mice by targeted disruption. The mice had defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina. Msx2 -/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, postnatal deficits of parathyroid hormone (168450)/parathyroid hormone receptor (see 168468) signaling and in expression of marker genes for bone differentiation indicate that MSX2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with parietal foramina, Msx2-mutant mice also display defective tooth, hair follicle, and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 (142983) loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Satokata et al. (2000) concluded that their results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis. Msx2 +/- mice were indistinguishable from wildtype mice. Unlike the defect in PFM, the calvarial defect in Msx2 -/- mice was a large, midline foramen spanning the frontal bones, and the interparietal and supraoccipital bones were small and abnormally shaped. </p><p>To investigate possible functions of MSX2 in early ocular development, Wu et al. (2003) created transgenic mice overexpressing Msx2. Forced expression of the Msx2 gene resulted in optic nerve aplasia and microphthalmia in all transgenic mice. In the developing retinas of the transgenic mice, proliferation was significantly reduced and increased numbers of retinal cells underwent apoptosis. Marker analysis showed suppression of Bmp4 (112262) and induction of Bmp7 (112267) gene expression in the optic vesicle. Ectopic concurrent expression of the retinal pigment epithelial cell markers Cx43 (121014) and Tyrp2 (191275) in the neural retinal layer suggested cell fate respecification. These results indicated that forced expression of Msx2 perturbed BMP signaling in the developing eye and was accompanied by an increase in retinal cell death and a reduction in cell proliferation. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>9 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CRANIOSYNOSTOSIS 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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MSX2, PRO148HIS
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<br />
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SNP: rs104893895,
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ClinVar: RCV000018474, RCV001210266
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a 3-generation American family from Boston segregating autosomal dominant variable craniosynostosis (CRS2; 604757), originally reported by Warman et al. (1993), Li et al. (1993) identified a substitution of histidine for proline at amino acid position 7 of the homeodomain of the MSX2 homeobox gene (residue 148 of the polypeptide). </p><p>Ma et al. (1996) reported that the P148H mutation in MSX2 is found exclusively in individuals with craniosynostosis type 2, and that it alters the DNA-binding properties of the MSX2 homeoprotein. They demonstrated that the enhanced DNA-binding affinity of the P148H form of MSX2 is caused by enhanced stability of the MSX2-DNA complex. This mutation had no discernible effect on the sequence specificity of MSX2 binding. They had previously reported (Liu et al., 1995) that transgenic mice in which either the mutant or the wildtype Msx2 gene is overexpressed exhibited craniosynostosis. Ma et al. (1996) noted that their recent results showing increased DNA-binding affinity of P148H and their studies in transgenic mice are consistent with the possibility that the mutation acts via a dominant-positive mechanism. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 PARIETAL FORAMINA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MSX2, 6-BP DEL, NT475
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<br />
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SNP: rs2113498725,
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ClinVar: RCV000018475
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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 family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wilkie et al. (2000) identified deletion of 6 nucleotides (475-480) of the MSX2 gene resulting in the deletion of 2 amino acids, arginine and lysine, from codons 159 and 160. This mutation occurs in helix 1. Mouse protein with the same mutation showed DNA-binding affinity reduced to 3% that of wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 PARIETAL FORAMINA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MSX2, ARG172HIS
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<br />
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SNP: rs104893896,
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gnomAD: rs104893896,
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ClinVar: RCV000018476
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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 family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wilkie et al. (2000) identified a G-to-A transition at nucleotide 515 of the MSX2 gene resulting in an arg172-to-his (R172H) substitution. Mouse protein with the same mutation showed DNA-binding affinity reduced to 15% that of wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 PARIETAL FORAMINA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MSX2, 206-KB DEL
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<br />
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ClinVar: RCV000018477
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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 family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wilkie et al. (2000) identified a 206-kb deletion that included the entire MSX2 gene, indicating that haploinsufficiency for MSX2 results in enlarged parietal foramina. </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>.0005 PARIETAL FORAMINA 1</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MSX2, ALA89TER
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<br />
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SNP: rs121912971,
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ClinVar: RCV000018478
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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 family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wuyts et al. (2000) identified mutations in consecutive nucleotides 265-266 in exon 1 of the MSX2 gene (G265T, C266A), resulting in an ala89-to-ter substitution. The protein product was predicted to lack the entire C terminus, which includes the conserved homeodomain. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 PARIETAL FORAMINA 1</strong>
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MSX2, TRP115TER
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<br />
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SNP: rs121912972,
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ClinVar: RCV000018479
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wuyts et al. (2000) identified a 1-bp deletion at nucleotide 344 or 345 of the MSX2 gene, resulting in a trp115-to-ter substitution. The protein product was predicted to lack the entire C terminus, which includes the conserved homeodomain. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 PARIETAL FORAMINA WITH CLEIDOCRANIAL DYSPLASIA</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
MSX2, 4-BP DUP, NT505
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|
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|
|
<br />
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|
|
SNP: rs1561643029,
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|
|
ClinVar: RCV000018480
|
|
|
|
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-generation family segregating parietal foramina with cleidocranial dysplasia (PFMCCD; 168550), Garcia-Minaur et al. (2003) identified a heterozygous duplication of a tetranucleotide (505dupATTG) in exon 2 of the MSX2 gene in affected individuals. The duplication causes a frameshift at residue 29 of the homeodomain, and predicts a termination codon 75 triplets downstream. Affected family members exhibited classic parietal foramina (see 168500) and short abnormal clavicles with tapering lateral ends. They had mild craniofacial dysmorphism with a broad forehead and central bossing, which was more evident in the children. Garcia-Minaur et al. (2003) noted that the mild clavicular involvement was difficult to assess on physical examination, and suggested that this finding may be more commonly associated with PFM than previously believed and may be characteristic of individuals with MSX2 rather than ALX4 (605420) mutations. </p>
|
|
</span>
|
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</div>
|
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 PARIETAL FORAMINA 1</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
MSX2, 8-BP DEL, NT548
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|
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<br />
|
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|
|
SNP: rs1561643060,
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|
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ClinVar: RCV000018481
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In the affected father of a child with parietal foramina (PFM1; 168500), Spruijt et al. (2005) identified an 8-bp deletion in exon 2 of the MSX2 gene, resulting in a frameshift and premature stop codon 59 codons downstream. DNA analysis was refused for the proband and her grandparents. </p>
|
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</span>
|
|
</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 CRANIOSYNOSTOSIS 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
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|
|
MSX2, PRO148LEU
|
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|
|
|
|
<br />
|
|
|
|
SNP: rs104893895,
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|
|
|
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|
|
ClinVar: RCV000203576, RCV000690192
|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In 7 affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis (CRS2; 604757), Florisson et al. (2013) identified heterozygosity for a c.443C-T transition (c.443C-T, NM_002449.4) in exon 2 of the MSX2 gene, resulting in a pro148-to-leu (P148L) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in an in-house database, or in the 1000 Genomes Project or Exome Variant Server databases. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
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</span>
|
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</h4>
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<div>
|
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<p />
|
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
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Bernardini, L., Castori, M., Capalbo, A., Mokini, V., Mingarelli, R., Simi, P., Bertuccelli, A., Novelli, A., Dallapiccola, B.
|
|
<strong>Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication.</strong>
|
|
Am. J. Med. Genet. 143A: 2937-2943, 2007.
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[PubMed: 18000908]
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[Full Text: https://doi.org/10.1002/ajmg.a.32092]
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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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Davidson, D.
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<strong>The function and evolution of Msx genes: pointers and paradoxes.</strong>
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Trends Genet. 11: 405-411, 1995.
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[PubMed: 7482767]
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[Full Text: https://doi.org/10.1016/s0168-9525(00)89124-6]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Florisson, J. M. G., Verkerk, A. J. M. H., Huigh, D., Hoogeboom, A. J. M., Swagemakers, S., Kremer, A., Heijsman, D., Lequin, M. H., Mathijssen, I. M. J., van der Spek, P. J.
|
|
<strong>Boston type craniosynostosis: report of a second mutation in MSX2.</strong>
|
|
Am. J. Med. Genet. 161A: 2626-2633, 2013.
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[PubMed: 23949913]
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[Full Text: https://doi.org/10.1002/ajmg.a.36126]
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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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Garcia-Minaur, S., Mavrogiannis, L. A., Rannan-Eliya, S. V., Hendry, M. A., Liston, W. A., Porteous, M. E. M., Wilkie, A. O. M.
|
|
<strong>Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2.</strong>
|
|
Europ. J. Hum. Genet. 11: 892-895, 2003.
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[PubMed: 14571277]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201062]
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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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Hassan, M. Q., Javed, A., Morasso, M. I., Karlin, J., Montecino, M., van Wijnen, A. J., Stein, G. S., Stein, J. L., Lian, J. B.
|
|
<strong>Dlx3 transcriptional regulation of osteoblast differentiation: temporal recruitment of Msx2, Dlx3, and Dlx5 homeodomain proteins to chromatin of the osteocalcin gene.</strong>
|
|
Molec. Cell. Biol. 24: 9248-9261, 2004.
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[PubMed: 15456894]
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[Full Text: https://doi.org/10.1128/MCB.24.20.9248-9261.2004]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Jabs, E. W., Muller, U., Li, X., Ma, L., Luo, W., Haworth, I. S., Klisak, I., Sparkes, R., Warman, M. L., Mulliken, J. B., Snead, M. L., Maxson, R.
|
|
<strong>A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis.</strong>
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