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Entry
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- *112261 - BONE MORPHOGENETIC PROTEIN 2; BMP2
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- OMIM
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<p>
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<span class="h4">*112261</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/112261">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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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000125845;t=ENST00000378827" 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=650" 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=112261" 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 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=ENSG00000125845;t=ENST00000378827" 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_001200" 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_001200" 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=112261" 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=00206&isoform_id=00206_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/BMP2" 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/115068,179502,4557369,6649952,119630791,119630792,256862041,256862043,256862045,256862047,256862049,256862051,256862053,256862055,256862057,256862059,256862061,256862063,315458015,459936808,544371686" 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/P12643" 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=650" 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=ENSG00000125845;t=ENST00000378827" 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=BMP2" 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=BMP2" 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+650" 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/BMP2" 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:650" 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/650" 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=chr20&hgg_gene=ENST00000378827.5&hgg_start=6767686&hgg_end=6780246&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=112261[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=112261[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/BMP2/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/ENSG00000125845" 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=BMP2" 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=BMP2" 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=BMP2" 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=BMP2&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/PA25379" 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:1069" 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/FBgn0000490.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:88177" 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/BMP2#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:88177" 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/650/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=650" 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=WBGene00000936;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-980526-388" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
|
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<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:650" 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=BMP2&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> 720569006<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
112261
|
|
</span>
|
|
</span>
|
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</div>
|
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</div>
|
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<div>
|
|
<a id="preferredTitle" class="mim-anchor"></a>
|
|
<h3>
|
|
<span class="mim-font">
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BONE MORPHOGENETIC PROTEIN 2; BMP2
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
BONE MORPHOGENETIC PROTEIN 2A; BMP2A
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
REGULATORY ELEMENT, CIS-ACTING, ENHANCER, 110 KB DOWNSTREAM OF BMP2, INCLUDED; RECE-BMP2, INCLUDED
|
|
</span>
|
|
</div>
|
|
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|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BMP2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BMP2</a></em></strong>
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/20/89?start=-3&limit=10&highlight=89">20p12.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:6767686-6780246&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'})">20:6,767,686-6,780,246</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
|
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|
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|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=235200,112600,617877" 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/20/89?start=-3&limit=10&highlight=89">
|
|
20p12.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{HFE hemochromatosis, modifier of}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/235200"> 235200 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
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|
|
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|
|
|
</tr>
|
|
|
|
|
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|
|
|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Brachydactyly, type A2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/112600"> 112600 </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>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
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<p>The transforming growth factor-beta (TGFB) superfamily encodes at least 12 members, including TGFB1 (<a href="/entry/190180">190180</a>), TGFB2 (<a href="/entry/190220">190220</a>), TGFB3 (<a href="/entry/190230">190230</a>), mullerian inhibitory substance (<a href="/entry/600957">600957</a>), the bone morphogenetic proteins-2A, -2B (BMP4; <a href="/entry/112262">112262</a>), -3 (<a href="/entry/112263">112263</a>), and -6 (<a href="/entry/112266">112266</a>). <a href="#27" class="mim-tip-reference" title="Wozney, J. M., Rosen, V., Celeste, A. J., Mitsock, L. M., Whitters, M. J., Kriz, R. W., Hewick, R. M., Wang, E. A. <strong>Novel regulators of bone formation: molecular clones and activities.</strong> Science 242: 1528-1534, 1988.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3201241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3201241</a>] [<a href="https://doi.org/10.1126/science.3201241" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="3201241">Wozney et al. (1988)</a> purified bone morphogenetic proteins BMP2A and BMP3 from demineralized bone on the basis of their ability to induce the formation of ectopic cartilage when implanted subcutaneously. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3201241" 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="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> analyzed Bmp2 expression in mice at embryonic day 12.5 and observed specific and strong staining in vibrissae follicles, facial and supraorbital dermis, Meckel cartilage, and embryonic dental epithelium. There was strong expression in the cartilaginous primordia of the appendicular and axial skeleton (limbs and ribs), and in the developing heart at the valves and ventricular-atrial junctions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>BMP2 Downstream Enhancer</em></strong></p><p>
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<a href="#3" class="mim-tip-reference" title="Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S. <strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong> Am. J. Hum. Genet. 84: 483-492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19327734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19327734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19327734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19327734">Dathe et al. (2009)</a> identified a 5.5-kb region approximately 110 kb downstream of BMP2 that appeared to contain a cis-acting enhancer element (RECE-BMP2). In a transgenic mouse model this element drove expression of an X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicated that a limb-specific enhancer of Bmp2 is located within the region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19327734" 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="#4" class="mim-tip-reference" title="Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A. <strong>Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.</strong> Genomics 6: 505-520, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1970330/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1970330</a>] [<a href="https://doi.org/10.1016/0888-7543(90)90480-i" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1970330">Dickinson et al. (1990)</a> demonstrated that in the mouse the Bmp2a gene is located on chromosome 2 in a segment that shows homology of synteny with human 20p. They suggested, therefore, that the human BMP2A gene may be located on 20p. They pointed out that in the mouse 5 of the 8 loci (Tgfb1, Bmp2a, Bmp2b1, Bmp2b2, and Vgr1) map near mutant loci associated with connective tissue and skeletal disorders, raising the possibility that at least some of these mutations result from defects in TGFB-related genes. The Bmp2a gene is situated close to the 'tight skin' (Tsk) locus (see <a href="/entry/184900">184900</a>), raising the question that this gene may be the site for the mutation in tight skin. Using cDNA probes for the analysis of somatic cell hybrid lines, <a href="#21" class="mim-tip-reference" title="Tabas, J. A., Zasloff, M., Wasmuth, J. J., Emanuel, B. S., Altherr, M. R., McPherson, J. D., Wozney, J. M., Kaplan, F. S. <strong>Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3.</strong> Genomics 9: 283-289, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004778</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90254-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2004778">Tabas et al. (1991)</a> confirmed the assignment of BMP2A to chromosome 20. By both in situ hybridization and FISH, <a href="#16" class="mim-tip-reference" title="Rao, V. V. N. G., Loffler, C., Wozney, J. M., Hansmann, I. <strong>The gene for bone morphogenetic protein 2A (BMP2A) is localized to human chromosome 20p12 by radioactive and nonradioactive in situ hybridization.</strong> Hum. Genet. 90: 299-302, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1487246/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1487246</a>] [<a href="https://doi.org/10.1007/BF00220084" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1487246">Rao et al. (1992)</a> assigned BMP2A to 20p12. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1970330+2004778+1487246" 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="#25" class="mim-tip-reference" title="Wang, E. A., Rosen, V., D'Alessandro, J. S., Bauduy, M., Cordes, P., Harada, T., Israel, D. I., Hewick, R. M., Kerns, K. M., LaPan, P., Luxenberg, D. P., McQuaid, D., Moutsatsos, I. K., Nove, J., Wozney, J. M. <strong>Recombinant human bone morphogenetic protein induces bone formation.</strong> Proc. Nat. Acad. Sci. 87: 2220-2224, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2315314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2315314</a>] [<a href="https://doi.org/10.1073/pnas.87.6.2220" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2315314">Wang et al. (1990)</a> showed that when BMP2A produced by recombinant DNA techniques was implanted into rats, bone formation occurred by day 14. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2315314" 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="#21" class="mim-tip-reference" title="Tabas, J. A., Zasloff, M., Wasmuth, J. J., Emanuel, B. S., Altherr, M. R., McPherson, J. D., Wozney, J. M., Kaplan, F. S. <strong>Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3.</strong> Genomics 9: 283-289, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004778</a>] [<a href="https://doi.org/10.1016/0888-7543(91)90254-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2004778">Tabas et al. (1991)</a> stated that 'BMP2A has been suggested as a reasonable candidate for the human condition fibrodysplasia (myositis) ossificans progressiva (FOP; <a href="/entry/135100">135100</a>), on the basis of observations in a Drosophila model (<a href="#8" class="mim-tip-reference" title="Kaplan, F. S., Tabas, J. A., Zasloff, M. A. <strong>Fibrodysplasia ossificans progressiva: a clue from the fly?</strong> Calcif. Tissue Int. 47: 117-125, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2117991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2117991</a>] [<a href="https://doi.org/10.1007/BF02555995" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2117991">Kaplan et al., 1990</a>).' <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2004778+2117991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The cytokines LIF (<a href="/entry/159540">159540</a>) and BMP2 signal through different receptors and transcription factors, namely STATs and SMADs, respectively. <a href="#14" class="mim-tip-reference" title="Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., Taga, T. <strong>Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300.</strong> Science 284: 479-482, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10205054/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10205054</a>] [<a href="https://doi.org/10.1126/science.284.5413.479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10205054">Nakashima et al. (1999)</a> found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (<a href="/entry/602700">602700</a>) interacted physically with STAT3 (<a href="/entry/102582">102582</a>) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (<a href="/entry/601595">601595</a>) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10205054" 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>For a review of the role of this gene in limb development, see <a href="#7" class="mim-tip-reference" title="Johnson, R. L., Tabin, C. J. <strong>Molecular models for vertebrate limb development.</strong> Cell 90: 979-990, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9323126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9323126</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)80364-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9323126">Johnson and Tabin (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9323126" 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>Rat neural crest stem cells prospectively isolated from uncultured embryo day 14.5 sciatic nerve and transplanted into chick embryos generate fewer neurons than do neural crest stem cells isolated from embryo day 10.5 neural tube explants. In addition, they differentiate primarily to cholinergic parasympathetic neurons, although in culture they can also generate noradrenergic sympathetic neurons. <a href="#26" class="mim-tip-reference" title="White, P. M., Morrison, S. J., Orimoto, K., Kubu, C. J., Verdi, J. M., Anderson, D. J. <strong>Neural crest stem cells undergo cell-intrinsic developmental changes in sensitivity to instructive differentiation signals.</strong> Neuron 29: 57-71, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182081</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00180-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11182081">White et al. (2001)</a> concluded that this in vivo behavior can be explained, at least in part, by reduced sensitivity of sciatic nerve-derived neural crest stem cells to the neurogenic signal BMP2 and by the observation that cholinergic neurons differentiate at a lower BMP2 concentration than do noradrenergic neurons in vitro. <a href="#26" class="mim-tip-reference" title="White, P. M., Morrison, S. J., Orimoto, K., Kubu, C. J., Verdi, J. M., Anderson, D. J. <strong>Neural crest stem cells undergo cell-intrinsic developmental changes in sensitivity to instructive differentiation signals.</strong> Neuron 29: 57-71, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182081</a>] [<a href="https://doi.org/10.1016/s0896-6273(01)00180-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11182081">White et al. (2001)</a> concluded that neural stem cells can undergo cell-intrinsic changes in their sensitivity to instructive signals, while maintaining multipotency and self-renewal capacity. They also suggested that the choice between sympathetic and parasympathetic fates may be determined by the local concentration of BMP2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182081" 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 mutation in BMPR1A (<a href="/entry/601299">601299</a>) has been linked to rare cases of Cowden syndrome (<a href="/entry/158350">158350</a>), or a Cowden-like syndrome (<a href="/entry/601299#0005">601299.0005</a>), suggesting that there may be a link between BMP signaling and PTEN (<a href="/entry/601728">601728</a>). <a href="#24" class="mim-tip-reference" title="Waite, K. A., Eng, C. <strong>BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels.</strong> Hum. Molec. Genet. 12: 679-684, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12620973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12620973</a>]" pmid="12620973">Waite and Eng (2003)</a> found that exposure to BMP2 increased PTEN protein levels in the breast cancer cell line MCF-7. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, suggesting that BMP2 stimulation inhibited PTEN protein degradation. BMP2 treatment of MCF-7 cells decreased the association of PTEN with 2 proteins in the degradative pathway, UBE2L3 (<a href="/entry/603721">603721</a>) and UBE2E3 (<a href="/entry/604151">604151</a>). <a href="#24" class="mim-tip-reference" title="Waite, K. A., Eng, C. <strong>BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels.</strong> Hum. Molec. Genet. 12: 679-684, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12620973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12620973</a>]" pmid="12620973">Waite and Eng (2003)</a> suggested that BMP2 exposure may regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway, which may explain how BMPR1A may act as a minor susceptibility gene for PTEN-mutation-negative Cowden syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12620973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Hallahan, A. R., Pritchard, J. I., Chandraratna, R. A. S., Ellenbogen, R. G., Geyer, J. R., Overland, R. P., Strand, A. D., Tapscott, S. J., Olson, J. M. <strong>BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.</strong> Nature Med. 9: 1033-1038, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872164</a>] [<a href="https://doi.org/10.1038/nm904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12872164">Hallahan et al. (2003)</a> established that retinoids cause extensive apoptosis of medulloblastoma (see <a href="/entry/155255">155255</a>) cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, <a href="#6" class="mim-tip-reference" title="Hallahan, A. R., Pritchard, J. I., Chandraratna, R. A. S., Ellenbogen, R. G., Geyer, J. R., Overland, R. P., Strand, A. D., Tapscott, S. J., Olson, J. M. <strong>BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.</strong> Nature Med. 9: 1033-1038, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12872164/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12872164</a>] [<a href="https://doi.org/10.1038/nm904" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12872164">Hallahan et al. (2003)</a> defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. They also identified BMP2 as a candidate mediator of retinoid activity. BMP2 protein induced medulloblastoma cell apoptosis, whereas the BMP2 antagonist Noggin (<a href="/entry/602991">602991</a>) blocked both retinoid and BMP2-induced apoptosis. BMP2 also induced p38 MAPK (<a href="/entry/600289">600289</a>), which is necessary for BMP2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12872164" 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="Meyer, R. A., Jr., Meyer, M. H., Tenholder, M., Wondracek, S., Wasserman, R., Garges, P. <strong>Gene expression in older rats with delayed union of femoral fractures.</strong> J. Bone Joint Surg. Am. 85: 1243-1254, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12851349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12851349</a>] [<a href="https://doi.org/10.2106/00004623-200307000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12851349">Meyer et al. (2003)</a> created closed midshaft femoral fractures in 6-week-old and 1-year-old rats and periodically measured mRNA levels in the fracture callus for 27 matrix, cytokine, and cytokine receptor genes for 6 weeks. The younger rats healed radiographically by 4 weeks after the fracture, whereas none of the older rats had healed at 6 weeks. All genes studied were upregulated by the fracture in both age groups, with peak mRNA levels at 1 to 2 weeks after the fracture and a return to low or undetectable levels at 4 to 6 weeks. Significantly lower levels of mRNA for BMP2 and Indian hedgehog (IHH; <a href="/entry/600726">600726</a>) were detected in the fracture calluses of the older rats, which may have contributed to slower fracture repair. The return of mRNA gene expression to baseline in the older rats prior to healing may also have contributed to the delayed union. The slower healing response of the older rats did not stimulate a negative feedback increase in the mRNA expression of stimulatory cytokines. <a href="#12" class="mim-tip-reference" title="Meyer, R. A., Jr., Meyer, M. H., Tenholder, M., Wondracek, S., Wasserman, R., Garges, P. <strong>Gene expression in older rats with delayed union of femoral fractures.</strong> J. Bone Joint Surg. Am. 85: 1243-1254, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12851349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12851349</a>] [<a href="https://doi.org/10.2106/00004623-200307000-00010" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12851349">Meyer et al. (2003)</a> suggested that if cytokines are administered to enhance bone repair, the age and metabolic status of the patient may influence the optimal timing of their administration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12851349" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Cheng, H., Jiang, W., Phillips, F. M., Haydon, R. C., Peng, Y., Zhou, L., Luu, H. H., An, N., Breyer, B., Vanichakarn, P., Szatkowski, J. P., Park, J. Y., He, T.-C. <strong>Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs).</strong> J. Bone Joint Surg. Am. 85: 1544-1552, 2003. Note: Erratum: J. Bone Joint Surg. Am. 86: 141 only, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925636</a>] [<a href="https://doi.org/10.2106/00004623-200308000-00017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12925636">Cheng et al. (2003)</a> measured the ability of 14 human BMPs to induce osteogenic transformation in a mouse pluripotential stem cell line, a mouse mesenchymal stem cell line, and a mature human osteoblastic cell line. Osteogenic activity was determined by measuring the induction of alkaline phosphatase (see <a href="/entry/171760">171760</a>), osteocalcin (<a href="/entry/112260">112260</a>), and matrix mineralization upon BMP stimulation. All BMPs except BMP3 (<a href="/entry/112263">112263</a>) and BMP12 (<a href="/entry/604651">604651</a>) were able to stimulate alkaline phosphatase activity in the mature osteoblasts; however, BMP2 was among the few able to induce all markers of osteoblast differentiation in pluripotential and mesenchymal stem cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12925636" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR, <a href="#11" class="mim-tip-reference" title="Lories, R. J. U., Derese, I., Ceuppens, J. L., Luyten, F. P. <strong>Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis.</strong> Arthritis Rheum. 48: 2807-2818, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14558086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14558086</a>] [<a href="https://doi.org/10.1002/art.11389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14558086">Lories et al. (2003)</a> detected BMP transcripts, predominantly BMP2 and BMP6, in synovial tissues. Western blot analysis detected BMP2 and BMP6 precursor proteins in rheumatoid arthritis (RA) and spondylarthropathy (SpA) synovial tissue extracts, but not in extracts of noninflamed synovial tissue. Immunohistochemical analysis found BMP2 and BMP6 in the hyperplastic lining and sublining layer of synovium from RA and SpA patients, both in CD90 (THY1; <a href="/entry/188230">188230</a>)-positive fibroblast-like synoviocytes and in some CD68 (<a href="/entry/153634">153634</a>)-positive macrophages. Proinflammatory cytokines, such as interleukin-1B (<a href="/entry/147720">147720</a>) and TNF-alpha (<a href="/entry/191160">191160</a>), but not interferon-gamma (<a href="/entry/147570">147570</a>), enhanced the expression of BMP2 and BMP6 transcripts in synoviocytes in vitro. Neither BMP2 nor BMP6 affected synoviocyte proliferation. BMP2 promoted synoviocyte apoptosis, whereas BMP6 protected against nitric oxide-induced apoptosis. BMP2-positive apoptotic cells were found in arthritic synovium. <a href="#11" class="mim-tip-reference" title="Lories, R. J. U., Derese, I., Ceuppens, J. L., Luyten, F. P. <strong>Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis.</strong> Arthritis Rheum. 48: 2807-2818, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14558086/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14558086</a>] [<a href="https://doi.org/10.1002/art.11389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14558086">Lories et al. (2003)</a> concluded that BMP2 and BMP6 modulate fibroblast-like synoviocyte cell populations in inflamed synovium. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14558086" 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>Canonical Wnt (see <a href="/entry/164820">164820</a>) signaling promotes sensory neurogenesis in early neural crest stem cells in a beta-catenin (CTNNB1; <a href="/entry/116806">116806</a>)-dependent manner. <a href="#9" class="mim-tip-reference" title="Kleber, M., Lee, H.-Y., Wurdak, H., Buchstaller, J., Riccomagno, M. M., Ittner, L. M., Suter, U., Epstein, D. J., Sommer, L. <strong>Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling.</strong> J. Cell Biol. 169: 309-320, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15837799/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15837799</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15837799[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/10.1083/jcb.200411095" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15837799">Kleber et al. (2005)</a> found that Bmp2 signaling antagonized the sensory fate-inducing activity of Wnt/beta-catenin. Wnt and Bmp2 acted synergistically to suppress differentiation and to maintain mouse neural crest stem cell marker expression and multipotency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15837799" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using RT-PCR, immunofluorescence, and flow cytometric analyses, <a href="#1" class="mim-tip-reference" title="Cejalvo, T., Sacedon, R., Hernandez-Lopez, C., Diez, B., Gutierrez-Frias, C., Valencia, J., Zapata, A. G., Varas, A., Vicente, A. <strong>Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development.</strong> Immunology 121: 94-104, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17425602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17425602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17425602[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/10.1111/j.1365-2567.2007.02541.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17425602">Cejalvo et al. (2007)</a> demonstrated that human thymus and cortical epithelial cells produced BMP2 and BMP4 (<a href="/entry/112262">112262</a>) and that both thymocytes and thymic epithelium expressed the molecular machinery to respond to these proteins. The receptors BMPR1A and BMPR2 (<a href="/entry/600799">600799</a>) were mainly expressed by cortical thymocytes, whereas BMPR1B (<a href="/entry/603248">603248</a>) was expressed in the majority of thymocytes. BMP4 treatment of chimeric human-mouse fetal thymic organ cultures seeded with CD34 (<a href="/entry/142230">142230</a>)-positive human thymic progenitors resulted in reduced cell recovery and inhibition of differentiation of CD4 (<a href="/entry/186940">186940</a>)/CD8 (see <a href="/entry/186910">186910</a>) double-negative to double-positive stages. <a href="#1" class="mim-tip-reference" title="Cejalvo, T., Sacedon, R., Hernandez-Lopez, C., Diez, B., Gutierrez-Frias, C., Valencia, J., Zapata, A. G., Varas, A., Vicente, A. <strong>Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development.</strong> Immunology 121: 94-104, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17425602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17425602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17425602[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/10.1111/j.1365-2567.2007.02541.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17425602">Cejalvo et al. (2007)</a> concluded that BMP2 and BMP4 have a role in human T-cell differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17425602" 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 hair follicle cycles through anagen (growth), catagen (involution), and telogen (resting) phases and then reenters the anagen phase. <a href="#15" class="mim-tip-reference" title="Plikus, M. V., Mayer, J. A., de la Cruz, D., Baker, R. E., Maini, P. K., Maxson, R., Chuong, C.-M. <strong>Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.</strong> Nature 451: 340-344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18202659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18202659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18202659[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/nature06457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18202659">Plikus et al. (2008)</a> demonstrated that unexpected periodic expression of BMP2 and BMP4 in the dermis regulates the process of hair follicle regeneration. This BMP cycle is out of phase with the WNT/beta catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signaling, respectively. Overexpression of noggin (<a href="/entry/602991">602991</a>), a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wildtype host showed that follicles in donor and host can affect their cycling behaviors mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. The existence of a substance termed 'chalone' had been proposed to explain the phenomenon of telogen refractivity, which can inhibit anagen development. <a href="#15" class="mim-tip-reference" title="Plikus, M. V., Mayer, J. A., de la Cruz, D., Baker, R. E., Maini, P. K., Maxson, R., Chuong, C.-M. <strong>Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.</strong> Nature 451: 340-344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18202659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18202659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18202659[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/nature06457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18202659">Plikus et al. (2008)</a> suggested that BMPs may be the long-sought 'chalone' postulated by classical experiments. <a href="#15" class="mim-tip-reference" title="Plikus, M. V., Mayer, J. A., de la Cruz, D., Baker, R. E., Maini, P. K., Maxson, R., Chuong, C.-M. <strong>Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.</strong> Nature 451: 340-344, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18202659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18202659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18202659[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/nature06457" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18202659">Plikus et al. (2008)</a> concluded that, taken together, the results presented in this study provided an example of hierarchical regulation of local organ stem cell homeostasis by the interorgan macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiologic integration between the 2 thermoregulatory organs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18202659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By combining experiments and modeling, <a href="#17" class="mim-tip-reference" title="Raspopovic, J., Marcon, L., Russo, L., Sharpe, J. <strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong> Science 345: 566-570, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25082703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25082703</a>] [<a href="https://doi.org/10.1126/science.1252960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25082703">Raspopovic et al. (2014)</a> revealed evidence that a Turing network implemented by BMP2, SOX9 (<a href="/entry/608160">608160</a>), and Wnt drives digit specification during development. <a href="#17" class="mim-tip-reference" title="Raspopovic, J., Marcon, L., Russo, L., Sharpe, J. <strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong> Science 345: 566-570, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25082703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25082703</a>] [<a href="https://doi.org/10.1126/science.1252960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25082703">Raspopovic et al. (2014)</a> developed a realistic 2-dimensional simulation of digit patterning and showed that this network, when modulated by morphogen gradients, recapitulates the expression patterns of SOX9 in the wildtype and in perturbation experiments. <a href="#17" class="mim-tip-reference" title="Raspopovic, J., Marcon, L., Russo, L., Sharpe, J. <strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong> Science 345: 566-570, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25082703/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25082703</a>] [<a href="https://doi.org/10.1126/science.1252960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25082703">Raspopovic et al. (2014)</a> concluded that their systems biology approach revealed how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25082703" 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="#18" class="mim-tip-reference" title="Sahoo, T., Theisen, A., Sanchez-Lara, P. A., Marble, M., Schweitzer, D. N., Torchia, B. S., Lamb, A. N., Bejjani, B. A., Shaffer, L. G., Lacassie, Y. <strong>Microdeletion 20p12.3 involving BMP2 contributes to syndromic forms of cleft palate.</strong> Am. J. Med. Genet. 155A: 1646-1653, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21671386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21671386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21671386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.34063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21671386">Sahoo et al. (2011)</a> reported 2 individuals and 1 multigenerational family with microdeletions at chromosome 20p12.3 that included the BMP2 gene. The deletions in 2 patients were 592.7 kb and 566.4 kb, respectively, and included only the BMP2 gene; the deletion in the third patient was confirmed to have occurred de novo and much larger (5.37 Mb), including at least 20 known genes. All 3 probands had cleft palate and facial dysmorphism, including long philtrum and micrognathia, 2 had Pierre-Robin sequence, 2 had hearing loss, and 2 had microcephaly. The 592.7-kb deletion was present in the patient's mother, maternal grandmother, and maternal great-grandmother, all of whom had high palate, trochlear nerve palsy, and either short fifth finger or abnormal palmar creases. <a href="#18" class="mim-tip-reference" title="Sahoo, T., Theisen, A., Sanchez-Lara, P. A., Marble, M., Schweitzer, D. N., Torchia, B. S., Lamb, A. N., Bejjani, B. A., Shaffer, L. G., Lacassie, Y. <strong>Microdeletion 20p12.3 involving BMP2 contributes to syndromic forms of cleft palate.</strong> Am. J. Med. Genet. 155A: 1646-1653, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21671386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21671386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21671386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1002/ajmg.a.34063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21671386">Sahoo et al. (2011)</a> concluded that haploinsufficiency for BMP2 may play a role in syndromic cleft palate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21671386" 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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In 2 families with brachydactyly type A2 (<a href="/entry/112600">112600</a>), one of which was the large Brazilian family of German descent reported by <a href="#5" class="mim-tip-reference" title="Freire-Maia, N., Maia, N. A., Pacheco, C. N. A. <strong>Mohr-Wriedt (A2) brachydactyly: analysis of a large Brazilian kindred.</strong> Hum. Hered. 30: 225-231, 1980.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7390514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7390514</a>] [<a href="https://doi.org/10.1159/000153133" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7390514">Freire-Maia et al. (1980)</a>, <a href="#3" class="mim-tip-reference" title="Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S. <strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong> Am. J. Hum. Genet. 84: 483-492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19327734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19327734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19327734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19327734">Dathe et al. (2009)</a> found duplication of a 3-prime regulatory element approximately 110 kb downstream of BMP2 (<a href="#0001">112261.0001</a>). The duplicated region contained highly conserved sequences suggestive of a long-range regulator. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19327734+7390514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Su, P., Ding, H., Huang, D., Zhou, Y., Huang, W., Zhong, L., Vyse, T. J., Wang, Y. <strong>A 4.6 kb genomic duplication on 20p12.2-12.3 is associated with brachydactyly type A2 in a Chinese family.</strong> J. Med. Genet. 48: 312-316, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21357617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21357617</a>] [<a href="https://doi.org/10.1136/jmg.2010.084814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21357617">Su et al. (2011)</a> identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20: 6,809,382-6,814,044, NCBI36) in affected members of a 6-generation Chinese family with brachydactyly type A2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21357617" 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>Craniosynostosis 7, Modifier of</em></strong></p><p>
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In 13 families with craniosynostosis (CRS7; <a href="/entry/617439">617439</a>) in which heterozygosity for variants in the SMAD6 gene (see, e.g., <a href="/entry/602931#0003">602931.0003</a>-<a href="/entry/602931#0005">602931.0005</a>) had been detected, <a href="#23" class="mim-tip-reference" title="Timberlake, A. T., Choi, J., Zaidi, S., Lu, Q., Nelson-Williams, C., Brooks, E. D., Bilguvar, K., Tikhonova, I., Mane, S., Yang, J. F., Sawh-Martinez, R., Persing, S., and 12 others. <strong>Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles.</strong> eLife 5: e20125, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27606499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27606499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27606499[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/10.7554/eLife.20125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27606499">Timberlake et al. (2016)</a> observed striking incomplete penetrance (57%), nearly all of which could be explained by the presence or absence of the 'C' risk allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1884302</a> (<a href="#0002">112261.0002</a>), a common variant located approximately 345-kb downstream of the BMP2 gene. None of the 18 family members who carried only the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1884302</a> modifier allele, including 2 homozygotes, had craniosynostosis. <a href="#23" class="mim-tip-reference" title="Timberlake, A. T., Choi, J., Zaidi, S., Lu, Q., Nelson-Williams, C., Brooks, E. D., Bilguvar, K., Tikhonova, I., Mane, S., Yang, J. F., Sawh-Martinez, R., Persing, S., and 12 others. <strong>Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles.</strong> eLife 5: e20125, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27606499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27606499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27606499[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/10.7554/eLife.20125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27606499">Timberlake et al. (2016)</a> suggested a threshold-effect model in which quantitative increases in SMAD signaling, resulting from reduced inhibition due to SMAD6 haploinsufficiency as well as from increased BMP2 expression via the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1884302</a> risk allele, cause accelerated closure of midline sutures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27606499" 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>Short Stature, Facial Dysmorphism, and Skeletal Anomalies with or without Cardiac Anomalies 1</em></strong></p><p>
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In 8 patients from 6 unrelated families with short stature and facial dysmorphism as well as skeletal and cardiac anomalies (SSFSC1; <a href="/entry/617877">617877</a>), <a href="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> identified heterozygosity for 6 different variants in the BMP2 gene (see, e.g., <a href="#0003">112261.0003</a>-<a href="#0006">112261.0006</a>) that were all predicted to be truncating and to result in haploinsufficiency. In addition, overlapping 2.5- to 2.6-Mb microdeletions, involving BMP2 as well as surrounding genes, were detected in 4 similarly affected patients from 2 families. None of the BMP2 mutations were found in public variant databases. Functional studies were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" 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>Associations Pending Confirmation</em></strong></p><p>
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---Hemochromatosis</p><p>In white populations, most cases of genetic hemochromatosis are associated with homozygosity for the C282Y missense change in the HFE gene (<a href="/entry/235200#0001">235200.0001</a>). The symptoms expressed by C282Y homozygotes are highly variable; only a few suffer from overt disease. In addition to environmental factors, a genetic component appears to explain a substantial part of this phenotypic variation. <a href="#13" class="mim-tip-reference" title="Milet, J., Dehais, V., Bourgain, C., Jouanolle, A. M., Mosser, A., Perrin, M., Morcet, J., Brissot, P., David, V., Deugnier, Y., Mosser, J. <strong>Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance.</strong> Am. J. Hum. Genet. 81: 799-807, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17847004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17847004</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17847004[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/520001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17847004">Milet et al. (2007)</a> tested the association between common variants in candidate genes and hemochromatosis penetrance in a large sample of C282Y homozygotes using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. They focused on 2 biologically relevant gene categories: one, the genes involved in non-HFE genetic hemochromatosis, and the other comprising genes involved in the regulation of hepcidin (<a href="/entry/606464">606464</a>) expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway and the IL6 gene from the inflammation-mediated regulation pathway. A significant association was detected between serum ferritin level and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs235756;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs235756</a>, a common SNP in the BMP2 gene region (corrected for multiple testing P = 0.002). Mean ferritin level, adjusted for age and sex, was 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. The subjects studied were all homozygous for the common C282Y mutation. The results further suggested an interactive effect on serum ferritin level of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs235756;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs235756</a> in BMP2 and a SNP in HJV (<a href="/entry/608374">608374</a>), with a small additive effect of a SNP in BMP4 (<a href="/entry/112262">112262</a>). The association between common variants in the BMP pathway and iron burden suggested that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. The results suggested that the BMP regulation pathway is a good candidate for identification of further modifier genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17847004" 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>---Bone Mineral Density Quantitative Trait Locus 7</p><p><a href="#19" class="mim-tip-reference" title="Styrkarsdottir, U., Cazier, J.-B., Kong, A., Rolfsson, O., Larsen, H., Bjarnadottir, E., Johannsdottir, V. D., Sigurdardottir, M. S., Bagger, Y., Christiansen, C., Reynisdottir, I., Grant, S. F. A., Jonasson, K., Frigge, M. L., Gulcher, J. R., Sigurdsson, G., Stefansson, K. <strong>Linkage of osteoporosis to chromosome 20p12 and association to BMP2.</strong> PLoS Biol. 1: e69, 2003. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14691541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14691541</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14691541[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pbio.0000069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14691541">Styrkarsdottir et al. (2003)</a> sequenced the BMP2 gene in 188 Icelandic patients with low BMD and osteoporotic fracture mapping to chromosome 20p12.3 (BMND7; <a href="/entry/611738">611738</a>) and 94 controls and found that a missense polymorphism (S37A) and 2 SNP haplotypes were associated with osteoporosis. A replication study in postmenopausal Danish women, in one group with persistently low BMD and in another with osteoporotic fracture, showed a significant association for haplotype 'C' (p = 0.0038) for low BMD, whereas S37A and haplotype 'B' were nominally significant for osteoporotic fractures and low BMD, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14691541" 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="#10" class="mim-tip-reference" title="Kugimiya, F., Kawaguchi, H., Kamekura, S., Chikuda, H., Ohba, S., Yano, F., Ogata, N., Katagiri, T., Harada, Y., Azuma, Y., Nakamura, K., Chung, U. <strong>Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation.</strong> J. Biol. Chem. 280: 35704-35712, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109715</a>] [<a href="https://doi.org/10.1074/jbc.M505166200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16109715">Kugimiya et al. (2005)</a> noted that Bmp2 -/- mice die during an early embryonic stage, and that Bmp6 (<a href="/entry/112266">112266</a>) -/- mice show no skeletal abnormality except for a slight delay in ossification of the sternum. They found that these BMPs were the main BMP subtypes expressed in hypertrophic chondrocytes that induced endochondrial bone formation in mice. Compound deficiency for these BMPs (Bmp2 +/- Bmp6 -/-) resulted in moderate growth retardation compared with wildtype littermates. Both fetal and adult Bmp2 +/- Bmp6 -/- mice showed reduced trabecular bone volume with suppressed bone formation, but normal bone resorption. Single-deficient Bmp2 +/- or Bmp6 -/- mice did not show these phenotypes. <a href="#10" class="mim-tip-reference" title="Kugimiya, F., Kawaguchi, H., Kamekura, S., Chikuda, H., Ohba, S., Yano, F., Ogata, N., Katagiri, T., Harada, Y., Azuma, Y., Nakamura, K., Chung, U. <strong>Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation.</strong> J. Biol. Chem. 280: 35704-35712, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16109715/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16109715</a>] [<a href="https://doi.org/10.1074/jbc.M505166200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16109715">Kugimiya et al. (2005)</a> concluded that BMP2 and BMP6 cooperate in long bone formation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16109715" 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="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> performed CT scans of Bmp2 +/- mice at 10 weeks and observed that all were missing the thirteenth ribs, mostly bilaterally but sometimes unilaterally. The body of the heterozygous mice was significantly shorter than that of wildtype mice, although there were no differences in femur or tibia length. The heterozygous mice also exhibited significantly less bone mineral content and volume than wildtype mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 2 families with brachydactyly type A2 (<a href="/entry/112600">112600</a>), <a href="#3" class="mim-tip-reference" title="Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S. <strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong> Am. J. Hum. Genet. 84: 483-492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19327734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19327734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19327734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19327734">Dathe et al. (2009)</a> found duplication of a 3-prime regulatory element (RECE-BMP2) approximately 110 kb downstream of BMP2. The duplicated region contained evolutionarily highly conserved sequences suggestive of a long-range regulator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19327734" 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 6-generation Chinese family with brachydactyly type A2, <a href="#20" class="mim-tip-reference" title="Su, P., Ding, H., Huang, D., Zhou, Y., Huang, W., Zhong, L., Vyse, T. J., Wang, Y. <strong>A 4.6 kb genomic duplication on 20p12.2-12.3 is associated with brachydactyly type A2 in a Chinese family.</strong> J. Med. Genet. 48: 312-316, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21357617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21357617</a>] [<a href="https://doi.org/10.1136/jmg.2010.084814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21357617">Su et al. (2011)</a> identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20:6,809,382-6,814,044, NCBI36). There was a 2.1-kb fragment that overlapped with the duplications reported by <a href="#3" class="mim-tip-reference" title="Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S. <strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong> Am. J. Hum. Genet. 84: 483-492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19327734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19327734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19327734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19327734">Dathe et al. (2009)</a>. Luciferase activity assays showed that the 2.1-kb fragment was associated with a 2.21-fold (p = 0.00011) reduction of transcription activity in osteosarcoma U2OS cells and a 3.25-fold (p = 0.0018) reduction in transcription activity in HeLa cells, suggesting a repressive effect on BMP2 gene expression. These findings were opposite to the functional effects observed by <a href="#3" class="mim-tip-reference" title="Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S. <strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong> Am. J. Hum. Genet. 84: 483-492, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19327734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19327734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19327734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.03.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19327734">Dathe et al. (2009)</a>, but <a href="#20" class="mim-tip-reference" title="Su, P., Ding, H., Huang, D., Zhou, Y., Huang, W., Zhong, L., Vyse, T. J., Wang, Y. <strong>A 4.6 kb genomic duplication on 20p12.2-12.3 is associated with brachydactyly type A2 in a Chinese family.</strong> J. Med. Genet. 48: 312-316, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21357617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21357617</a>] [<a href="https://doi.org/10.1136/jmg.2010.084814" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21357617">Su et al. (2011)</a> concluded that the findings overall identified cis-regulatory sequences in the duplication 3-prime to the BMP2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21357617+19327734" 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> rs1884302 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;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/rs1884302?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=rs1884302" 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=rs1884302" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 13 families with craniosynostosis (CRS7; <a href="/entry/617439">617439</a>) in which heterozygosity for variants in the SMAD6 gene (see, e.g., <a href="/entry/602931#0003">602931.0003</a>-<a href="/entry/602931#0005">602931.0005</a>) had been detected, <a href="#23" class="mim-tip-reference" title="Timberlake, A. T., Choi, J., Zaidi, S., Lu, Q., Nelson-Williams, C., Brooks, E. D., Bilguvar, K., Tikhonova, I., Mane, S., Yang, J. F., Sawh-Martinez, R., Persing, S., and 12 others. <strong>Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles.</strong> eLife 5: e20125, 2016. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27606499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27606499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27606499[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/10.7554/eLife.20125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27606499">Timberlake et al. (2016)</a> observed striking incomplete penetrance (57%), nearly all of which could be explained by the presence or absence of the 'C' risk allele of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1884302</a>, a common variant located approximately 345-kb downstream of the BMP2 gene. All 14 individuals with a SMAD6 mutation who also carried the 'C' modifier allele had craniosynostosis, whereas only 3 (19%) of 16 individuals with a SMAD6 mutation and no <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1884302</a> risk allele were affected. None of the 18 family members who carried only the <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1884302;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1884302</a> modifier allele, including 2 homozygotes, had craniosynostosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27606499" 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">rs1555785715 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555785715;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=rs1555785715" 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=rs1555785715" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a Greek mother and son (family 2) with short stature, facial dysmorphism, and skeletal anomalies, who did not exhibit cardiac anomalies (SSFSC1; <a href="/entry/617877">617877</a>), <a href="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> identified heterozygosity for a c.79G-T transversion (c.79G-T, NM_001200.3) in the BMP2 gene, resulting in a glu27-to-ter (E27X) substitution. The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITH OR WITHOUT CARDIAC ANOMALIES 1</strong>
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<p>In 2 sisters (family 1) with short stature, facial dysmorphism, and skeletal anomalies, 1 of whom also had transposition of the great arteries (SSFSC1; <a href="/entry/617877">617877</a>), <a href="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> identified heterozygosity for a deletion/insertion involving the acceptor splice site of intron 1 in the 5-prime UTR of the BMP2 gene (c.-7-2_-7-1delAGinsCC, NM_001200.3), predicted to result in a truncated mRNA lacking part of exon 2. Sanger sequencing did not detect the mutation in either parent, but mutant-allele-specific PCR revealed mosaicism in their unaffected father. The mutation was not found in more than 4,000 in-house samples or in the 1000 Genomes Project, COSMIC v.80, ESP6500SI, or gnomAD databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITH CARDIAC ANOMALIES 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555786145 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555786145;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=rs1555786145" 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=rs1555786145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 4.75-year-old boy (patient S2) with short stature, facial dysmorphism, and skeletal anomalies, who also exhibited Ebstein anomaly (SSFSC1; <a href="/entry/617877">617877</a>), <a href="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> identified heterozygosity for a de novo 1-bp duplication (c.949dupC, NM_001200.3) in the BMP2 gene, predicted to result in a premature termination codon (Tyr320ValfsTer16). The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITH CARDIAC ANOMALIES 1</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555786156 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555786156;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=rs1555786156" 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=rs1555786156" 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=RCV000584742 OR RCV001800813" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000584742, RCV001800813" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000584742...</a>
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<p>In a 6-month-old girl (patient S3) with short stature, facial dysmorphism, and skeletal anomalies, who also had a perimembranous ventricular septal defect and Wolff-Parkinson-White syndrome (SSFSC1; <a href="/entry/617877">617877</a>), <a href="#22" class="mim-tip-reference" title="Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others. <strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong> Am. J. Hum. Genet. 101: 985-994, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29198724">Tan et al. (2017)</a> identified heterozygosity for a de novo c.987C-A transversion (c.987C-A, NM_001200.3) in the BMP2 gene, resulting in a cys329-to-ter (C329X) substitution. The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" 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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Cejalvo, T., Sacedon, R., Hernandez-Lopez, C., Diez, B., Gutierrez-Frias, C., Valencia, J., Zapata, A. G., Varas, A., Vicente, A.
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<strong>Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development.</strong>
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Immunology 121: 94-104, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17425602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17425602</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17425602[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17425602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1365-2567.2007.02541.x" target="_blank">Full Text</a>]
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Cheng, H., Jiang, W., Phillips, F. M., Haydon, R. C., Peng, Y., Zhou, L., Luu, H. H., An, N., Breyer, B., Vanichakarn, P., Szatkowski, J. P., Park, J. Y., He, T.-C.
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<strong>Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs).</strong>
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J. Bone Joint Surg. Am. 85: 1544-1552, 2003. Note: Erratum: J. Bone Joint Surg. Am. 86: 141 only, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12925636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12925636</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12925636" 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/10.2106/00004623-200308000-00017" target="_blank">Full Text</a>]
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Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S.
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<strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong>
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Am. J. Hum. Genet. 84: 483-492, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19327734/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19327734</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19327734[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19327734" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A.
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<strong>Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.</strong>
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Genomics 6: 505-520, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21357617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21357617</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21357617" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2010.084814" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="21" class="mim-anchor"></a>
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<a id="Tabas1991" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tabas, J. A., Zasloff, M., Wasmuth, J. J., Emanuel, B. S., Altherr, M. R., McPherson, J. D., Wozney, J. M., Kaplan, F. S.
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|
<strong>Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3.</strong>
|
|
Genomics 9: 283-289, 1991.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2004778/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2004778</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2004778" 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/10.1016/0888-7543(91)90254-c" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="22" class="mim-anchor"></a>
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<a id="Tan2017" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tan, T. Y., Gonzaga-Jauregui, C., Bhoj, E. J., Strauss, K. S., Brigatti, K., Puffenberger, E., Li, D., Xie, L., Das, N., Skubas, I., Deckelbaum, R. A., Hughes, V., and 23 others.
|
|
<strong>Monoallelic BMP2 variants predicted to result in haploinsufficiency cause craniofacial, skeletal, and cardiac features overlapping those of 20p12 deletions.</strong>
|
|
Am. J. Hum. Genet. 101: 985-994, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29198724/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29198724</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29198724[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29198724" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2017.10.006" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Timberlake2016" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Timberlake, A. T., Choi, J., Zaidi, S., Lu, Q., Nelson-Williams, C., Brooks, E. D., Bilguvar, K., Tikhonova, I., Mane, S., Yang, J. F., Sawh-Martinez, R., Persing, S., and 12 others.
|
|
<strong>Two locus inheritance of non-syndromic midline craniosynostosis via rare SMAD6 and common BMP2 alleles.</strong>
|
|
eLife 5: e20125, 2016. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27606499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27606499</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27606499[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27606499" 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/10.7554/eLife.20125" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Waite2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Waite, K. A., Eng, C.
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<strong>BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels.</strong>
|
|
Hum. Molec. Genet. 12: 679-684, 2003.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12620973/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12620973</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12620973" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="25" class="mim-anchor"></a>
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<a id="Wang1990" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wang, E. A., Rosen, V., D'Alessandro, J. S., Bauduy, M., Cordes, P., Harada, T., Israel, D. I., Hewick, R. M., Kerns, K. M., LaPan, P., Luxenberg, D. P., McQuaid, D., Moutsatsos, I. K., Nove, J., Wozney, J. M.
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|
<strong>Recombinant human bone morphogenetic protein induces bone formation.</strong>
|
|
Proc. Nat. Acad. Sci. 87: 2220-2224, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2315314/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2315314</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2315314" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.87.6.2220" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="White2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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White, P. M., Morrison, S. J., Orimoto, K., Kubu, C. J., Verdi, J. M., Anderson, D. J.
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<strong>Neural crest stem cells undergo cell-intrinsic developmental changes in sensitivity to instructive differentiation signals.</strong>
|
|
Neuron 29: 57-71, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11182081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11182081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11182081" 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/s0896-6273(01)00180-5" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Wozney1988" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wozney, J. M., Rosen, V., Celeste, A. J., Mitsock, L. M., Whitters, M. J., Kriz, R. W., Hewick, R. M., Wang, E. A.
|
|
<strong>Novel regulators of bone formation: molecular clones and activities.</strong>
|
|
Science 242: 1528-1534, 1988.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/3201241/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">3201241</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=3201241" 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/10.1126/science.3201241" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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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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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </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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Marla J. F. O'Neill - updated : 02/16/2018
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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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Marla J. F. O'Neill - updated : 06/01/2017<br>Ada Hamosh - updated : 09/30/2014<br>Cassandra L. Kniffin - updated : 10/13/2011<br>Cassandra L. Kniffin - updated : 6/13/2011<br>Paul J. Converse - updated : 10/12/2010<br>Patricia A. Hartz - updated : 9/21/2009<br>Ada Hamosh - updated : 8/25/2009<br>Ada Hamosh - updated : 2/21/2008<br>Marla J. F. O'Neill - updated : 1/7/2008<br>Victor A. McKusick - updated : 10/3/2007<br>Patricia A. Hartz - updated : 9/8/2005<br>Patricia A. Hartz - updated : 5/26/2005<br>George E. Tiller - updated : 2/15/2005<br>Patricia A. Hartz - updated : 3/23/2004<br>Ada Hamosh - updated : 8/5/2003<br>Ada Hamosh - updated : 4/26/2001<br>Ada Hamosh - updated : 4/15/1999<br>Ada Hamosh - updated : 4/9/1998
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</span>
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</div>
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</div>
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</div>
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<div>
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<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 : 5/15/1990
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/08/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 10/04/2024<br>carol : 10/03/2024<br>alopez : 02/15/2021<br>carol : 02/19/2018<br>carol : 02/16/2018<br>carol : 06/01/2017<br>alopez : 09/30/2014<br>carol : 9/24/2014<br>carol : 8/29/2014<br>alopez : 3/13/2013<br>carol : 10/14/2011<br>ckniffin : 10/13/2011<br>alopez : 10/7/2011<br>wwang : 6/21/2011<br>ckniffin : 6/13/2011<br>terry : 1/13/2011<br>mgross : 10/18/2010<br>terry : 10/12/2010<br>joanna : 7/27/2010<br>mgross : 10/6/2009<br>terry : 9/21/2009<br>alopez : 9/4/2009<br>alopez : 9/2/2009<br>terry : 8/25/2009<br>terry : 9/26/2008<br>wwang : 3/24/2008<br>alopez : 3/19/2008<br>alopez : 3/19/2008<br>terry : 2/21/2008<br>carol : 1/18/2008<br>terry : 1/7/2008<br>alopez : 10/10/2007<br>terry : 10/3/2007<br>terry : 10/3/2007<br>mgross : 9/8/2005<br>wwang : 6/15/2005<br>wwang : 6/7/2005<br>terry : 5/26/2005<br>wwang : 2/22/2005<br>wwang : 2/21/2005<br>wwang : 2/17/2005<br>terry : 2/15/2005<br>mgross : 4/12/2004<br>terry : 3/23/2004<br>tkritzer : 3/17/2004<br>tkritzer : 3/16/2004<br>alopez : 8/6/2003<br>terry : 8/5/2003<br>carol : 11/24/2001<br>mcapotos : 5/7/2001<br>mcapotos : 5/3/2001<br>terry : 4/26/2001<br>terry : 4/30/1999<br>carol : 4/23/1999<br>alopez : 4/15/1999<br>alopez : 4/15/1999<br>terry : 6/18/1998<br>alopez : 4/9/1998<br>mark : 7/3/1996<br>mark : 12/12/1995<br>mimadm : 2/11/1994<br>carol : 9/21/1993<br>carol : 1/22/1993<br>carol : 11/5/1992<br>supermim : 3/16/1992<br>carol : 9/10/1991
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 112261
|
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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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BONE MORPHOGENETIC PROTEIN 2; BMP2
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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BONE MORPHOGENETIC PROTEIN 2A; BMP2A
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<span class="h3 mim-font">
|
|
REGULATORY ELEMENT, CIS-ACTING, ENHANCER, 110 KB DOWNSTREAM OF BMP2, INCLUDED; RECE-BMP2, INCLUDED
|
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</span>
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: BMP2</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> 720569006;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
|
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Cytogenetic location: 20p12.3
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|
Genomic coordinates <span class="small">(GRCh38)</span> : 20:6,767,686-6,780,246 </span>
|
|
</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
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">
|
|
20p12.3
|
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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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{HFE hemochromatosis, modifier of}
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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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235200
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Brachydactyly, type A2
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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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112600
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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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Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 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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617877
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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>The transforming growth factor-beta (TGFB) superfamily encodes at least 12 members, including TGFB1 (190180), TGFB2 (190220), TGFB3 (190230), mullerian inhibitory substance (600957), the bone morphogenetic proteins-2A, -2B (BMP4; 112262), -3 (112263), and -6 (112266). Wozney et al. (1988) purified bone morphogenetic proteins BMP2A and BMP3 from demineralized bone on the basis of their ability to induce the formation of ectopic cartilage when implanted subcutaneously. </p><p>Tan et al. (2017) analyzed Bmp2 expression in mice at embryonic day 12.5 and observed specific and strong staining in vibrissae follicles, facial and supraorbital dermis, Meckel cartilage, and embryonic dental epithelium. There was strong expression in the cartilaginous primordia of the appendicular and axial skeleton (limbs and ribs), and in the developing heart at the valves and ventricular-atrial junctions. </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 Structure</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>BMP2 Downstream Enhancer</em></strong></p><p>
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Dathe et al. (2009) identified a 5.5-kb region approximately 110 kb downstream of BMP2 that appeared to contain a cis-acting enhancer element (RECE-BMP2). In a transgenic mouse model this element drove expression of an X-Gal reporter construct in the limbs. The almost complete overlap with endogenous Bmp2 expression indicated that a limb-specific enhancer of Bmp2 is located within the region. </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>Dickinson et al. (1990) demonstrated that in the mouse the Bmp2a gene is located on chromosome 2 in a segment that shows homology of synteny with human 20p. They suggested, therefore, that the human BMP2A gene may be located on 20p. They pointed out that in the mouse 5 of the 8 loci (Tgfb1, Bmp2a, Bmp2b1, Bmp2b2, and Vgr1) map near mutant loci associated with connective tissue and skeletal disorders, raising the possibility that at least some of these mutations result from defects in TGFB-related genes. The Bmp2a gene is situated close to the 'tight skin' (Tsk) locus (see 184900), raising the question that this gene may be the site for the mutation in tight skin. Using cDNA probes for the analysis of somatic cell hybrid lines, Tabas et al. (1991) confirmed the assignment of BMP2A to chromosome 20. By both in situ hybridization and FISH, Rao et al. (1992) assigned BMP2A to 20p12. </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>Wang et al. (1990) showed that when BMP2A produced by recombinant DNA techniques was implanted into rats, bone formation occurred by day 14. </p><p>Tabas et al. (1991) stated that 'BMP2A has been suggested as a reasonable candidate for the human condition fibrodysplasia (myositis) ossificans progressiva (FOP; 135100), on the basis of observations in a Drosophila model (Kaplan et al., 1990).' </p><p>The cytokines LIF (159540) and BMP2 signal through different receptors and transcription factors, namely STATs and SMADs, respectively. Nakashima et al. (1999) found that LIF and BMP2 act in synergy on primary fetal neural progenitor cells to induce astrocytes. The transcriptional coactivator p300 (602700) interacted physically with STAT3 (102582) at its amino terminus in a cytokine stimulation-independent manner, and with SMAD1 (601595) at its carboxyl terminus in a cytokine stimulation-dependent manner. The formation of a complex between STAT3 and SMAD1, bridged by p300, is involved in the cooperative signaling of LIF and BMP2 and the subsequent induction of astrocytes from neuronal progenitors. </p><p>For a review of the role of this gene in limb development, see Johnson and Tabin (1997). </p><p>Rat neural crest stem cells prospectively isolated from uncultured embryo day 14.5 sciatic nerve and transplanted into chick embryos generate fewer neurons than do neural crest stem cells isolated from embryo day 10.5 neural tube explants. In addition, they differentiate primarily to cholinergic parasympathetic neurons, although in culture they can also generate noradrenergic sympathetic neurons. White et al. (2001) concluded that this in vivo behavior can be explained, at least in part, by reduced sensitivity of sciatic nerve-derived neural crest stem cells to the neurogenic signal BMP2 and by the observation that cholinergic neurons differentiate at a lower BMP2 concentration than do noradrenergic neurons in vitro. White et al. (2001) concluded that neural stem cells can undergo cell-intrinsic changes in their sensitivity to instructive signals, while maintaining multipotency and self-renewal capacity. They also suggested that the choice between sympathetic and parasympathetic fates may be determined by the local concentration of BMP2. </p><p>A mutation in BMPR1A (601299) has been linked to rare cases of Cowden syndrome (158350), or a Cowden-like syndrome (601299.0005), suggesting that there may be a link between BMP signaling and PTEN (601728). Waite and Eng (2003) found that exposure to BMP2 increased PTEN protein levels in the breast cancer cell line MCF-7. The increase in PTEN protein was rapid and was not due to an increase in new protein synthesis, suggesting that BMP2 stimulation inhibited PTEN protein degradation. BMP2 treatment of MCF-7 cells decreased the association of PTEN with 2 proteins in the degradative pathway, UBE2L3 (603721) and UBE2E3 (604151). Waite and Eng (2003) suggested that BMP2 exposure may regulate PTEN protein levels by decreasing PTEN's association with the degradative pathway, which may explain how BMPR1A may act as a minor susceptibility gene for PTEN-mutation-negative Cowden syndrome. </p><p>Hallahan et al. (2003) established that retinoids cause extensive apoptosis of medulloblastoma (see 155255) cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, Hallahan et al. (2003) defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. They also identified BMP2 as a candidate mediator of retinoid activity. BMP2 protein induced medulloblastoma cell apoptosis, whereas the BMP2 antagonist Noggin (602991) blocked both retinoid and BMP2-induced apoptosis. BMP2 also induced p38 MAPK (600289), which is necessary for BMP2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells. </p><p>Meyer et al. (2003) created closed midshaft femoral fractures in 6-week-old and 1-year-old rats and periodically measured mRNA levels in the fracture callus for 27 matrix, cytokine, and cytokine receptor genes for 6 weeks. The younger rats healed radiographically by 4 weeks after the fracture, whereas none of the older rats had healed at 6 weeks. All genes studied were upregulated by the fracture in both age groups, with peak mRNA levels at 1 to 2 weeks after the fracture and a return to low or undetectable levels at 4 to 6 weeks. Significantly lower levels of mRNA for BMP2 and Indian hedgehog (IHH; 600726) were detected in the fracture calluses of the older rats, which may have contributed to slower fracture repair. The return of mRNA gene expression to baseline in the older rats prior to healing may also have contributed to the delayed union. The slower healing response of the older rats did not stimulate a negative feedback increase in the mRNA expression of stimulatory cytokines. Meyer et al. (2003) suggested that if cytokines are administered to enhance bone repair, the age and metabolic status of the patient may influence the optimal timing of their administration. </p><p>Cheng et al. (2003) measured the ability of 14 human BMPs to induce osteogenic transformation in a mouse pluripotential stem cell line, a mouse mesenchymal stem cell line, and a mature human osteoblastic cell line. Osteogenic activity was determined by measuring the induction of alkaline phosphatase (see 171760), osteocalcin (112260), and matrix mineralization upon BMP stimulation. All BMPs except BMP3 (112263) and BMP12 (604651) were able to stimulate alkaline phosphatase activity in the mature osteoblasts; however, BMP2 was among the few able to induce all markers of osteoblast differentiation in pluripotential and mesenchymal stem cells. </p><p>Using RT-PCR, Lories et al. (2003) detected BMP transcripts, predominantly BMP2 and BMP6, in synovial tissues. Western blot analysis detected BMP2 and BMP6 precursor proteins in rheumatoid arthritis (RA) and spondylarthropathy (SpA) synovial tissue extracts, but not in extracts of noninflamed synovial tissue. Immunohistochemical analysis found BMP2 and BMP6 in the hyperplastic lining and sublining layer of synovium from RA and SpA patients, both in CD90 (THY1; 188230)-positive fibroblast-like synoviocytes and in some CD68 (153634)-positive macrophages. Proinflammatory cytokines, such as interleukin-1B (147720) and TNF-alpha (191160), but not interferon-gamma (147570), enhanced the expression of BMP2 and BMP6 transcripts in synoviocytes in vitro. Neither BMP2 nor BMP6 affected synoviocyte proliferation. BMP2 promoted synoviocyte apoptosis, whereas BMP6 protected against nitric oxide-induced apoptosis. BMP2-positive apoptotic cells were found in arthritic synovium. Lories et al. (2003) concluded that BMP2 and BMP6 modulate fibroblast-like synoviocyte cell populations in inflamed synovium. </p><p>Canonical Wnt (see 164820) signaling promotes sensory neurogenesis in early neural crest stem cells in a beta-catenin (CTNNB1; 116806)-dependent manner. Kleber et al. (2005) found that Bmp2 signaling antagonized the sensory fate-inducing activity of Wnt/beta-catenin. Wnt and Bmp2 acted synergistically to suppress differentiation and to maintain mouse neural crest stem cell marker expression and multipotency. </p><p>Using RT-PCR, immunofluorescence, and flow cytometric analyses, Cejalvo et al. (2007) demonstrated that human thymus and cortical epithelial cells produced BMP2 and BMP4 (112262) and that both thymocytes and thymic epithelium expressed the molecular machinery to respond to these proteins. The receptors BMPR1A and BMPR2 (600799) were mainly expressed by cortical thymocytes, whereas BMPR1B (603248) was expressed in the majority of thymocytes. BMP4 treatment of chimeric human-mouse fetal thymic organ cultures seeded with CD34 (142230)-positive human thymic progenitors resulted in reduced cell recovery and inhibition of differentiation of CD4 (186940)/CD8 (see 186910) double-negative to double-positive stages. Cejalvo et al. (2007) concluded that BMP2 and BMP4 have a role in human T-cell differentiation. </p><p>A hair follicle cycles through anagen (growth), catagen (involution), and telogen (resting) phases and then reenters the anagen phase. Plikus et al. (2008) demonstrated that unexpected periodic expression of BMP2 and BMP4 in the dermis regulates the process of hair follicle regeneration. This BMP cycle is out of phase with the WNT/beta catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signaling, respectively. Overexpression of noggin (602991), a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wildtype host showed that follicles in donor and host can affect their cycling behaviors mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. The existence of a substance termed 'chalone' had been proposed to explain the phenomenon of telogen refractivity, which can inhibit anagen development. Plikus et al. (2008) suggested that BMPs may be the long-sought 'chalone' postulated by classical experiments. Plikus et al. (2008) concluded that, taken together, the results presented in this study provided an example of hierarchical regulation of local organ stem cell homeostasis by the interorgan macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiologic integration between the 2 thermoregulatory organs. </p><p>By combining experiments and modeling, Raspopovic et al. (2014) revealed evidence that a Turing network implemented by BMP2, SOX9 (608160), and Wnt drives digit specification during development. Raspopovic et al. (2014) developed a realistic 2-dimensional simulation of digit patterning and showed that this network, when modulated by morphogen gradients, recapitulates the expression patterns of SOX9 in the wildtype and in perturbation experiments. Raspopovic et al. (2014) concluded that their systems biology approach revealed how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation. </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>Sahoo et al. (2011) reported 2 individuals and 1 multigenerational family with microdeletions at chromosome 20p12.3 that included the BMP2 gene. The deletions in 2 patients were 592.7 kb and 566.4 kb, respectively, and included only the BMP2 gene; the deletion in the third patient was confirmed to have occurred de novo and much larger (5.37 Mb), including at least 20 known genes. All 3 probands had cleft palate and facial dysmorphism, including long philtrum and micrognathia, 2 had Pierre-Robin sequence, 2 had hearing loss, and 2 had microcephaly. The 592.7-kb deletion was present in the patient's mother, maternal grandmother, and maternal great-grandmother, all of whom had high palate, trochlear nerve palsy, and either short fifth finger or abnormal palmar creases. Sahoo et al. (2011) concluded that haploinsufficiency for BMP2 may play a role in syndromic cleft palate. </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>Brachydactyly Type A2</em></strong></p><p>
|
|
In 2 families with brachydactyly type A2 (112600), one of which was the large Brazilian family of German descent reported by Freire-Maia et al. (1980), Dathe et al. (2009) found duplication of a 3-prime regulatory element approximately 110 kb downstream of BMP2 (112261.0001). The duplicated region contained highly conserved sequences suggestive of a long-range regulator. </p><p>Su et al. (2011) identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20: 6,809,382-6,814,044, NCBI36) in affected members of a 6-generation Chinese family with brachydactyly type A2. </p><p><strong><em>Craniosynostosis 7, Modifier of</em></strong></p><p>
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In 13 families with craniosynostosis (CRS7; 617439) in which heterozygosity for variants in the SMAD6 gene (see, e.g., 602931.0003-602931.0005) had been detected, Timberlake et al. (2016) observed striking incomplete penetrance (57%), nearly all of which could be explained by the presence or absence of the 'C' risk allele of rs1884302 (112261.0002), a common variant located approximately 345-kb downstream of the BMP2 gene. None of the 18 family members who carried only the rs1884302 modifier allele, including 2 homozygotes, had craniosynostosis. Timberlake et al. (2016) suggested a threshold-effect model in which quantitative increases in SMAD signaling, resulting from reduced inhibition due to SMAD6 haploinsufficiency as well as from increased BMP2 expression via the rs1884302 risk allele, cause accelerated closure of midline sutures. </p><p><strong><em>Short Stature, Facial Dysmorphism, and Skeletal Anomalies with or without Cardiac Anomalies 1</em></strong></p><p>
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|
In 8 patients from 6 unrelated families with short stature and facial dysmorphism as well as skeletal and cardiac anomalies (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for 6 different variants in the BMP2 gene (see, e.g., 112261.0003-112261.0006) that were all predicted to be truncating and to result in haploinsufficiency. In addition, overlapping 2.5- to 2.6-Mb microdeletions, involving BMP2 as well as surrounding genes, were detected in 4 similarly affected patients from 2 families. None of the BMP2 mutations were found in public variant databases. Functional studies were not performed. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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---Hemochromatosis</p><p>In white populations, most cases of genetic hemochromatosis are associated with homozygosity for the C282Y missense change in the HFE gene (235200.0001). The symptoms expressed by C282Y homozygotes are highly variable; only a few suffer from overt disease. In addition to environmental factors, a genetic component appears to explain a substantial part of this phenotypic variation. Milet et al. (2007) tested the association between common variants in candidate genes and hemochromatosis penetrance in a large sample of C282Y homozygotes using pretherapeutic serum ferritin level as marker of hemochromatosis penetrance. They focused on 2 biologically relevant gene categories: one, the genes involved in non-HFE genetic hemochromatosis, and the other comprising genes involved in the regulation of hepcidin (606464) expression, including genes from the bone morphogenetic protein (BMP) regulatory pathway and the IL6 gene from the inflammation-mediated regulation pathway. A significant association was detected between serum ferritin level and rs235756, a common SNP in the BMP2 gene region (corrected for multiple testing P = 0.002). Mean ferritin level, adjusted for age and sex, was 655 ng/ml among TT genotypes, 516 ng/ml in TC genotypes, and 349 ng/ml in CC genotypes. The subjects studied were all homozygous for the common C282Y mutation. The results further suggested an interactive effect on serum ferritin level of rs235756 in BMP2 and a SNP in HJV (608374), with a small additive effect of a SNP in BMP4 (112262). The association between common variants in the BMP pathway and iron burden suggested that full expression of HFE hemochromatosis is linked to abnormal liver expression of hepcidin, not only through impairment in the HFE function but also through functional modulation in the BMP pathway. The results suggested that the BMP regulation pathway is a good candidate for identification of further modifier genes. </p><p>---Bone Mineral Density Quantitative Trait Locus 7</p><p>Styrkarsdottir et al. (2003) sequenced the BMP2 gene in 188 Icelandic patients with low BMD and osteoporotic fracture mapping to chromosome 20p12.3 (BMND7; 611738) and 94 controls and found that a missense polymorphism (S37A) and 2 SNP haplotypes were associated with osteoporosis. A replication study in postmenopausal Danish women, in one group with persistently low BMD and in another with osteoporotic fracture, showed a significant association for haplotype 'C' (p = 0.0038) for low BMD, whereas S37A and haplotype 'B' were nominally significant for osteoporotic fractures and low BMD, respectively. </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>Kugimiya et al. (2005) noted that Bmp2 -/- mice die during an early embryonic stage, and that Bmp6 (112266) -/- mice show no skeletal abnormality except for a slight delay in ossification of the sternum. They found that these BMPs were the main BMP subtypes expressed in hypertrophic chondrocytes that induced endochondrial bone formation in mice. Compound deficiency for these BMPs (Bmp2 +/- Bmp6 -/-) resulted in moderate growth retardation compared with wildtype littermates. Both fetal and adult Bmp2 +/- Bmp6 -/- mice showed reduced trabecular bone volume with suppressed bone formation, but normal bone resorption. Single-deficient Bmp2 +/- or Bmp6 -/- mice did not show these phenotypes. Kugimiya et al. (2005) concluded that BMP2 and BMP6 cooperate in long bone formation. </p><p>Tan et al. (2017) performed CT scans of Bmp2 +/- mice at 10 weeks and observed that all were missing the thirteenth ribs, mostly bilaterally but sometimes unilaterally. The body of the heterozygous mice was significantly shorter than that of wildtype mice, although there were no differences in femur or tibia length. The heterozygous mice also exhibited significantly less bone mineral content and volume than wildtype mice. </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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<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>6 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 BRACHYDACTYLY, TYPE A2</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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BMP2, 2.1-KB DUP, +110 KB
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<br />
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ClinVar: RCV000022453
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 families with brachydactyly type A2 (112600), Dathe et al. (2009) found duplication of a 3-prime regulatory element (RECE-BMP2) approximately 110 kb downstream of BMP2. The duplicated region contained evolutionarily highly conserved sequences suggestive of a long-range regulator. </p><p>In affected members of a 6-generation Chinese family with brachydactyly type A2, Su et al. (2011) identified a heterozygous 4.6-kb duplication about 110 kb downstream of the BMP2 gene (Chr20:6,809,382-6,814,044, NCBI36). There was a 2.1-kb fragment that overlapped with the duplications reported by Dathe et al. (2009). Luciferase activity assays showed that the 2.1-kb fragment was associated with a 2.21-fold (p = 0.00011) reduction of transcription activity in osteosarcoma U2OS cells and a 3.25-fold (p = 0.0018) reduction in transcription activity in HeLa cells, suggesting a repressive effect on BMP2 gene expression. These findings were opposite to the functional effects observed by Dathe et al. (2009), but Su et al. (2011) concluded that the findings overall identified cis-regulatory sequences in the duplication 3-prime to the BMP2 gene. </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 CRANIOSYNOSTOSIS 7, MODIFIER OF</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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BMP2, T-C, +345 KB ({dbSNP rs1884302})
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<br />
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SNP: rs1884302,
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gnomAD: rs1884302,
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ClinVar: RCV000490626
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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 13 families with craniosynostosis (CRS7; 617439) in which heterozygosity for variants in the SMAD6 gene (see, e.g., 602931.0003-602931.0005) had been detected, Timberlake et al. (2016) observed striking incomplete penetrance (57%), nearly all of which could be explained by the presence or absence of the 'C' risk allele of rs1884302, a common variant located approximately 345-kb downstream of the BMP2 gene. All 14 individuals with a SMAD6 mutation who also carried the 'C' modifier allele had craniosynostosis, whereas only 3 (19%) of 16 individuals with a SMAD6 mutation and no rs1884302 risk allele were affected. None of the 18 family members who carried only the rs1884302 modifier allele, including 2 homozygotes, had craniosynostosis. </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 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITHOUT CARDIAC ANOMALIES 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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BMP2, GLU27TER
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<br />
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SNP: rs1555785715,
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ClinVar: RCV000584741, RCV001800810
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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 Greek mother and son (family 2) with short stature, facial dysmorphism, and skeletal anomalies, who did not exhibit cardiac anomalies (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a c.79G-T transversion (c.79G-T, NM_001200.3) in the BMP2 gene, resulting in a glu27-to-ter (E27X) substitution. The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project 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>
|
|
<span class="mim-font">
|
|
<strong>.0004 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITH OR WITHOUT CARDIAC ANOMALIES 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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BMP2, IVS1AS, 2-BP DEL/2-BP INS, -7-2AG/CC, 5-PRIME UTR
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<br />
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SNP: rs1600170070,
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ClinVar: RCV001800812
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 sisters (family 1) with short stature, facial dysmorphism, and skeletal anomalies, 1 of whom also had transposition of the great arteries (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a deletion/insertion involving the acceptor splice site of intron 1 in the 5-prime UTR of the BMP2 gene (c.-7-2_-7-1delAGinsCC, NM_001200.3), predicted to result in a truncated mRNA lacking part of exon 2. Sanger sequencing did not detect the mutation in either parent, but mutant-allele-specific PCR revealed mosaicism in their unaffected father. The mutation was not found in more than 4,000 in-house samples or in the 1000 Genomes Project, COSMIC v.80, ESP6500SI, or gnomAD 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>.0005 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITH CARDIAC ANOMALIES 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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BMP2, 1-BP DUP, 949C
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<br />
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SNP: rs1555786145,
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ClinVar: RCV001800811
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4.75-year-old boy (patient S2) with short stature, facial dysmorphism, and skeletal anomalies, who also exhibited Ebstein anomaly (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a de novo 1-bp duplication (c.949dupC, NM_001200.3) in the BMP2 gene, predicted to result in a premature termination codon (Tyr320ValfsTer16). The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases. </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>.0006 SHORT STATURE, FACIAL DYSMORPHISM, AND SKELETAL ANOMALIES WITH CARDIAC ANOMALIES 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
BMP2, CYS329TER
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<br />
|
|
|
|
SNP: rs1555786156,
|
|
|
|
|
|
|
|
ClinVar: RCV000584742, RCV001800813
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 6-month-old girl (patient S3) with short stature, facial dysmorphism, and skeletal anomalies, who also had a perimembranous ventricular septal defect and Wolff-Parkinson-White syndrome (SSFSC1; 617877), Tan et al. (2017) identified heterozygosity for a de novo c.987C-A transversion (c.987C-A, NM_001200.3) in the BMP2 gene, resulting in a cys329-to-ter (C329X) substitution. The mutation was not found in in-house databases or in the ExAC, gnomAD, NHLBI Exome Variant Server, or 1000 Genomes Project databases. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
|
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</div>
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</div>
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
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<p />
|
|
</div>
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<div>
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<ol>
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|
<li>
|
|
<p class="mim-text-font">
|
|
Cejalvo, T., Sacedon, R., Hernandez-Lopez, C., Diez, B., Gutierrez-Frias, C., Valencia, J., Zapata, A. G., Varas, A., Vicente, A.
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<strong>Bone morphogenetic protein-2/4 signalling pathway components are expressed in the human thymus and inhibit early T-cell development.</strong>
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Immunology 121: 94-104, 2007.
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[PubMed: 17425602]
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[Full Text: https://doi.org/10.1111/j.1365-2567.2007.02541.x]
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</li>
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<li>
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<p class="mim-text-font">
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Cheng, H., Jiang, W., Phillips, F. M., Haydon, R. C., Peng, Y., Zhou, L., Luu, H. H., An, N., Breyer, B., Vanichakarn, P., Szatkowski, J. P., Park, J. Y., He, T.-C.
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<strong>Osteogenic activity of the fourteen types of human bone morphogenetic proteins (BMPs).</strong>
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J. Bone Joint Surg. Am. 85: 1544-1552, 2003. Note: Erratum: J. Bone Joint Surg. Am. 86: 141 only, 2003.
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[Full Text: https://doi.org/10.2106/00004623-200308000-00017]
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<p class="mim-text-font">
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Dathe, K., Kjaer, K. W., Brehm, A., Meinecke, P., Nurnberg, P., Neto, J. C., Brunoni, D., Tommerup, N., Ott, C. E., Klopocki, E., Seemann, P., Mundlos, S.
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<strong>Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.</strong>
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Am. J. Hum. Genet. 84: 483-492, 2009.
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[PubMed: 19327734]
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[Full Text: https://doi.org/10.1016/j.ajhg.2009.03.001]
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<p class="mim-text-font">
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Dickinson, M. E., Kobrin, M. S., Silan, C. M., Kingsley, D. M., Justice, M. J., Miller, D. A., Ceci, J. D., Lock, L. F., Lee, A., Buchberg, A. M., Siracusa, L. D., Lyons, K. M., Derynck, R., Hogan, B. L. M., Copeland, N. G., Jenkins, N. A.
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<strong>Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.</strong>
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Genomics 6: 505-520, 1990.
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[PubMed: 1970330]
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[Full Text: https://doi.org/10.1016/0888-7543(90)90480-i]
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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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Freire-Maia, N., Maia, N. A., Pacheco, C. N. A.
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<strong>Mohr-Wriedt (A2) brachydactyly: analysis of a large Brazilian kindred.</strong>
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Hum. Hered. 30: 225-231, 1980.
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[PubMed: 7390514]
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[Full Text: https://doi.org/10.1159/000153133]
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</p>
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<li>
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<p class="mim-text-font">
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Hallahan, A. R., Pritchard, J. I., Chandraratna, R. A. S., Ellenbogen, R. G., Geyer, J. R., Overland, R. P., Strand, A. D., Tapscott, S. J., Olson, J. M.
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<strong>BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.</strong>
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Nature Med. 9: 1033-1038, 2003.
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[PubMed: 12872164]
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[Full Text: https://doi.org/10.1038/nm904]
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<p class="mim-text-font">
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Johnson, R. L., Tabin, C. J.
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<strong>Molecular models for vertebrate limb development.</strong>
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Cell 90: 979-990, 1997.
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[PubMed: 9323126]
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[Full Text: https://doi.org/10.1016/s0092-8674(00)80364-5]
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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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Kaplan, F. S., Tabas, J. A., Zasloff, M. A.
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<strong>Fibrodysplasia ossificans progressiva: a clue from the fly?</strong>
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Calcif. Tissue Int. 47: 117-125, 1990.
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[PubMed: 2117991]
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[Full Text: https://doi.org/10.1007/BF02555995]
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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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Kleber, M., Lee, H.-Y., Wurdak, H., Buchstaller, J., Riccomagno, M. M., Ittner, L. M., Suter, U., Epstein, D. J., Sommer, L.
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<strong>Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling.</strong>
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J. Cell Biol. 169: 309-320, 2005.
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[PubMed: 15837799]
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</p>
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<li>
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<p class="mim-text-font">
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Kugimiya, F., Kawaguchi, H., Kamekura, S., Chikuda, H., Ohba, S., Yano, F., Ogata, N., Katagiri, T., Harada, Y., Azuma, Y., Nakamura, K., Chung, U.
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<strong>Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation.</strong>
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J. Biol. Chem. 280: 35704-35712, 2005.
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[PubMed: 16109715]
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[Full Text: https://doi.org/10.1074/jbc.M505166200]
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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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Lories, R. J. U., Derese, I., Ceuppens, J. L., Luyten, F. P.
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<strong>Bone morphogenetic proteins 2 and 6, expressed in arthritic synovium, are regulated by proinflammatory cytokines and differentially modulate fibroblast-like synoviocyte apoptosis.</strong>
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Arthritis Rheum. 48: 2807-2818, 2003.
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[PubMed: 14558086]
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[Full Text: https://doi.org/10.1002/art.11389]
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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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Meyer, R. A., Jr., Meyer, M. H., Tenholder, M., Wondracek, S., Wasserman, R., Garges, P.
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<strong>Gene expression in older rats with delayed union of femoral fractures.</strong>
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J. Bone Joint Surg. Am. 85: 1243-1254, 2003.
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[PubMed: 12851349]
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[Full Text: https://doi.org/10.2106/00004623-200307000-00010]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Milet, J., Dehais, V., Bourgain, C., Jouanolle, A. M., Mosser, A., Perrin, M., Morcet, J., Brissot, P., David, V., Deugnier, Y., Mosser, J.
|
|
<strong>Common variants in the BMP2, BMP4, and HJV genes of the hepcidin regulation pathway modulate HFE hemochromatosis penetrance.</strong>
|
|
Am. J. Hum. Genet. 81: 799-807, 2007.
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[PubMed: 17847004]
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[Full Text: https://doi.org/10.1086/520001]
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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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|
Nakashima, K., Yanagisawa, M., Arakawa, H., Kimura, N., Hisatsune, T., Kawabata, M., Miyazono, K., Taga, T.
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<strong>Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300.</strong>
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Science 284: 479-482, 1999.
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[PubMed: 10205054]
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[Full Text: https://doi.org/10.1126/science.284.5413.479]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Plikus, M. V., Mayer, J. A., de la Cruz, D., Baker, R. E., Maini, P. K., Maxson, R., Chuong, C.-M.
|
|
<strong>Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.</strong>
|
|
Nature 451: 340-344, 2008.
|
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|
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|
|
[PubMed: 18202659]
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|
[Full Text: https://doi.org/10.1038/nature06457]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Rao, V. V. N. G., Loffler, C., Wozney, J. M., Hansmann, I.
|
|
<strong>The gene for bone morphogenetic protein 2A (BMP2A) is localized to human chromosome 20p12 by radioactive and nonradioactive in situ hybridization.</strong>
|
|
Hum. Genet. 90: 299-302, 1992.
|
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|
|
|
|
[PubMed: 1487246]
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|
[Full Text: https://doi.org/10.1007/BF00220084]
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</p>
|
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Raspopovic, J., Marcon, L., Russo, L., Sharpe, J.
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|
<strong>Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.</strong>
|
|
Science 345: 566-570, 2014.
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|
[PubMed: 25082703]
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|
[Full Text: https://doi.org/10.1126/science.1252960]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Sahoo, T., Theisen, A., Sanchez-Lara, P. A., Marble, M., Schweitzer, D. N., Torchia, B. S., Lamb, A. N., Bejjani, B. A., Shaffer, L. G., Lacassie, Y.
|
|
<strong>Microdeletion 20p12.3 involving BMP2 contributes to syndromic forms of cleft palate.</strong>
|
|
Am. J. Med. Genet. 155A: 1646-1653, 2011.
|
|
|
|
|
|
[PubMed: 21671386]
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|
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[Full Text: https://doi.org/10.1002/ajmg.a.34063]
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</p>
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</li>
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<li>
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